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Elevated CAC not linked to increased death risk in physically active men
In highly active individuals, high levels of coronary artery calcification do not appear to confer an elevated mortality risk, a large, observational study suggests.
There was an increased risk of elevated levels of coronary artery calcification (CAC) in men with levels of exercise training comparable with that seen in master marathon runners, the study authors reported. However, elevated CAC in highly active men didn’t translate into a significant increase in all-cause or cardiovascular disease mortality risk in the study.
That result is contrary to the hypothesis that high activity levels would increase mortality risk in individuals with CAC, according to senior author Benjamin D. Levine, MD, of Texas Health Presbyterian Hospital in Dallas, and his coauthors.
“Our findings should reassure patients and their health care professionals that it appears these highly active individuals can safely continue their exercise programs,” Dr. Levine and his coauthors wrote in JAMA Cardiology.
The present analysis focused on 21,758 generally healthy men without prevalent cardiovascular disease. They were enrolled in the Cooper Center Longitudinal Study, a prospective, longitudinal study designed to assess linkages between physical activity, cardiorespiratory fitness, and health. The mean age of these men was 52 years at baseline; the mean duration of follow-up was 10.4 years.
Out of 21,758 male participants, 1,561 reported very high levels of physical activity, or at least 3,000 metabolic equivalent of task (MET) minutes per week, while 3,750 reported 1,500-2,999 MET minutes per week, and 16,477 reported low levels of physical activity, or less than 1,500 MET minutes per week.
The adjusted risk of elevated CAC, defined as at least 100 Agatston units, was 11% higher in the individuals reporting very high physical activity levels, the investigators found.
Presence of elevated CAC nearly doubled the risk of death in men with low levels of exercise, with a hazard ratio of 1.93 (95% confidence interval, 1.34-2.78), the investigators found. By contrast, there was no significant increase in all-cause mortality in the most active group (HR, 0.77; 95% CI, 0.52-1.15).
Taken together, these findings seem to provide evidence that high activity levels do not increase mortality risk, the investigators wrote, noting that the study is believed to have the “best available” mortality data in a large CAC population that includes measurement of physical activity.
The research was supported in partly through the National Space Biomedical Research Institute. One study author reported disclosures related to Abbott, AstraZeneca, and the American Heart Association.
SOURCE: Levine BD et al. JAMA Cardiol. 2019 Jan 30. doi: 10.1001/jamacardio.2018.4628.
This major study shows that, for most high-volume exercisers, very high doses of running and exercise can be performed, even among those with “hearts of stone,” wrote authors of an invited commentary.
A more novel finding, however, was that men with CAC in the highest physical activity group had lower mortality risk, compared with men without CAC who reported low levels of activity, the commentary authors wrote.
“One may speculate whether there are similarities with high-intensity statin therapy, because high-intensity physical activity and exercise may promote more calcific atherosclerosis, which may be more stable than soft, noncalcified plaques, potentially leading to coronary stability and lower propensity to more morbid CVD [cardiovascular disease] events,” the authors wrote.
Even so, CAC testing appears to “retain its utility” in high-volume exercisers, they added. “High CAC scores were still associated with higher risk at any given physical activity level in this study, which is why CAC assessment is being promoted to help risk assessment and intensify preventive therapies, such as vigorous lipid treatment.”
Dr. Lavie is with the John Ochsner Heart and Vascular Institute in New Orleans; Dr. Wisløff is with the Norwegian University of Science and Technology, Trondheim; Dr. Blumenthal is director of the Ciccarone Center for the Prevention of Cardiovascular Disease at John Hopkins Hospital, Baltimore. Their invited commentary appears in JAMA Cardiology. Authors reported conflict of interest with Mio Global Canada (Dr. Lavie) and PAI Health (Dr. Wisloff).
This major study shows that, for most high-volume exercisers, very high doses of running and exercise can be performed, even among those with “hearts of stone,” wrote authors of an invited commentary.
A more novel finding, however, was that men with CAC in the highest physical activity group had lower mortality risk, compared with men without CAC who reported low levels of activity, the commentary authors wrote.
“One may speculate whether there are similarities with high-intensity statin therapy, because high-intensity physical activity and exercise may promote more calcific atherosclerosis, which may be more stable than soft, noncalcified plaques, potentially leading to coronary stability and lower propensity to more morbid CVD [cardiovascular disease] events,” the authors wrote.
Even so, CAC testing appears to “retain its utility” in high-volume exercisers, they added. “High CAC scores were still associated with higher risk at any given physical activity level in this study, which is why CAC assessment is being promoted to help risk assessment and intensify preventive therapies, such as vigorous lipid treatment.”
Dr. Lavie is with the John Ochsner Heart and Vascular Institute in New Orleans; Dr. Wisløff is with the Norwegian University of Science and Technology, Trondheim; Dr. Blumenthal is director of the Ciccarone Center for the Prevention of Cardiovascular Disease at John Hopkins Hospital, Baltimore. Their invited commentary appears in JAMA Cardiology. Authors reported conflict of interest with Mio Global Canada (Dr. Lavie) and PAI Health (Dr. Wisloff).
This major study shows that, for most high-volume exercisers, very high doses of running and exercise can be performed, even among those with “hearts of stone,” wrote authors of an invited commentary.
A more novel finding, however, was that men with CAC in the highest physical activity group had lower mortality risk, compared with men without CAC who reported low levels of activity, the commentary authors wrote.
“One may speculate whether there are similarities with high-intensity statin therapy, because high-intensity physical activity and exercise may promote more calcific atherosclerosis, which may be more stable than soft, noncalcified plaques, potentially leading to coronary stability and lower propensity to more morbid CVD [cardiovascular disease] events,” the authors wrote.
Even so, CAC testing appears to “retain its utility” in high-volume exercisers, they added. “High CAC scores were still associated with higher risk at any given physical activity level in this study, which is why CAC assessment is being promoted to help risk assessment and intensify preventive therapies, such as vigorous lipid treatment.”
Dr. Lavie is with the John Ochsner Heart and Vascular Institute in New Orleans; Dr. Wisløff is with the Norwegian University of Science and Technology, Trondheim; Dr. Blumenthal is director of the Ciccarone Center for the Prevention of Cardiovascular Disease at John Hopkins Hospital, Baltimore. Their invited commentary appears in JAMA Cardiology. Authors reported conflict of interest with Mio Global Canada (Dr. Lavie) and PAI Health (Dr. Wisloff).
In highly active individuals, high levels of coronary artery calcification do not appear to confer an elevated mortality risk, a large, observational study suggests.
There was an increased risk of elevated levels of coronary artery calcification (CAC) in men with levels of exercise training comparable with that seen in master marathon runners, the study authors reported. However, elevated CAC in highly active men didn’t translate into a significant increase in all-cause or cardiovascular disease mortality risk in the study.
That result is contrary to the hypothesis that high activity levels would increase mortality risk in individuals with CAC, according to senior author Benjamin D. Levine, MD, of Texas Health Presbyterian Hospital in Dallas, and his coauthors.
“Our findings should reassure patients and their health care professionals that it appears these highly active individuals can safely continue their exercise programs,” Dr. Levine and his coauthors wrote in JAMA Cardiology.
The present analysis focused on 21,758 generally healthy men without prevalent cardiovascular disease. They were enrolled in the Cooper Center Longitudinal Study, a prospective, longitudinal study designed to assess linkages between physical activity, cardiorespiratory fitness, and health. The mean age of these men was 52 years at baseline; the mean duration of follow-up was 10.4 years.
Out of 21,758 male participants, 1,561 reported very high levels of physical activity, or at least 3,000 metabolic equivalent of task (MET) minutes per week, while 3,750 reported 1,500-2,999 MET minutes per week, and 16,477 reported low levels of physical activity, or less than 1,500 MET minutes per week.
The adjusted risk of elevated CAC, defined as at least 100 Agatston units, was 11% higher in the individuals reporting very high physical activity levels, the investigators found.
Presence of elevated CAC nearly doubled the risk of death in men with low levels of exercise, with a hazard ratio of 1.93 (95% confidence interval, 1.34-2.78), the investigators found. By contrast, there was no significant increase in all-cause mortality in the most active group (HR, 0.77; 95% CI, 0.52-1.15).
Taken together, these findings seem to provide evidence that high activity levels do not increase mortality risk, the investigators wrote, noting that the study is believed to have the “best available” mortality data in a large CAC population that includes measurement of physical activity.
The research was supported in partly through the National Space Biomedical Research Institute. One study author reported disclosures related to Abbott, AstraZeneca, and the American Heart Association.
SOURCE: Levine BD et al. JAMA Cardiol. 2019 Jan 30. doi: 10.1001/jamacardio.2018.4628.
In highly active individuals, high levels of coronary artery calcification do not appear to confer an elevated mortality risk, a large, observational study suggests.
There was an increased risk of elevated levels of coronary artery calcification (CAC) in men with levels of exercise training comparable with that seen in master marathon runners, the study authors reported. However, elevated CAC in highly active men didn’t translate into a significant increase in all-cause or cardiovascular disease mortality risk in the study.
That result is contrary to the hypothesis that high activity levels would increase mortality risk in individuals with CAC, according to senior author Benjamin D. Levine, MD, of Texas Health Presbyterian Hospital in Dallas, and his coauthors.
“Our findings should reassure patients and their health care professionals that it appears these highly active individuals can safely continue their exercise programs,” Dr. Levine and his coauthors wrote in JAMA Cardiology.
The present analysis focused on 21,758 generally healthy men without prevalent cardiovascular disease. They were enrolled in the Cooper Center Longitudinal Study, a prospective, longitudinal study designed to assess linkages between physical activity, cardiorespiratory fitness, and health. The mean age of these men was 52 years at baseline; the mean duration of follow-up was 10.4 years.
Out of 21,758 male participants, 1,561 reported very high levels of physical activity, or at least 3,000 metabolic equivalent of task (MET) minutes per week, while 3,750 reported 1,500-2,999 MET minutes per week, and 16,477 reported low levels of physical activity, or less than 1,500 MET minutes per week.
The adjusted risk of elevated CAC, defined as at least 100 Agatston units, was 11% higher in the individuals reporting very high physical activity levels, the investigators found.
Presence of elevated CAC nearly doubled the risk of death in men with low levels of exercise, with a hazard ratio of 1.93 (95% confidence interval, 1.34-2.78), the investigators found. By contrast, there was no significant increase in all-cause mortality in the most active group (HR, 0.77; 95% CI, 0.52-1.15).
Taken together, these findings seem to provide evidence that high activity levels do not increase mortality risk, the investigators wrote, noting that the study is believed to have the “best available” mortality data in a large CAC population that includes measurement of physical activity.
The research was supported in partly through the National Space Biomedical Research Institute. One study author reported disclosures related to Abbott, AstraZeneca, and the American Heart Association.
SOURCE: Levine BD et al. JAMA Cardiol. 2019 Jan 30. doi: 10.1001/jamacardio.2018.4628.
FROM JAMA CARDIOLOGY
Key clinical point: In highly active men, high levels of coronary artery calcification do not appear to confer an elevated mortality risk.
Major finding: Elevated coronary artery calcification nearly doubled risk of death in men with low levels of exercise (HR, 1.93), while no significant increase in all-cause mortality was seen in highly active men with coronary artery calcification.
Study details: An observational study including 21,758 generally healthy men without prevalent cardiovascular disease enrolled in the Cooper Center Longitudinal Study.
Disclosures: The research was supported in partly through the National Space Biomedical Research Institute. One study coauthor reported disclosures related to Abbott, AstraZeneca, and the American Heart Association.
Source: Levine BD et al. JAMA Cardiol. 2019 Jan 30. doi: 10.1001/jamacardio.2018.4628.
Tool might help assessment of prodromal symptoms in children
Brooklyn, N.Y. – A risk calculator for bipolar disorder that has reached late stages of development might merit a trial to test whether treating prodromal symptoms delays or prevents the disease from developing in young patients, an expert said at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
Clinicians often are confronted with children who have prodromal symptoms of bipolar disorder, but only about half of those children eventually convert to full disease expression. As a result, treatment is not routine practice, said Boris Birmaher, MD, Endowed Chair, Early Onset Bipolar Disease, at the University of Pittsburgh.
A risk calculator that more effectively identifies those at highest risk of converting might be a tool that could allow early intervention to be tested. Such a calculator has been in development for some years, and the most recent research suggests that it is nearing a degree of accuracy that is clinically meaningful (J Am Acad Child Adolesc Psychiatry. 2018;57:755-63).
Accuracy might improve further with the identification and incorporation of more predictive variables. High-risk features for conversion include a parent with bipolar disorder, particularly one with childhood onset, and specific clinical features, such as prominent episodes of mania.
“Once replicated, the risk calculator will be instrumental to predict personalized risk to develop bipolar disease,” Dr. Birmaher said. He compared it to risk calculators now in use in other fields of medicine, such as cancer and cardiovascular disease, which generate information used by patients and their physicians for treatment decisions.
In the most recent study with the risk calculator, which has been the topic of several previous publications, 140 children with a diagnosis of bipolar disorder not otherwise specified (BP-NOS) were assessed every 7 months for a median of 11.5 years. BP-NOS is the diagnosis of a prodromal syndrome that includes mood lability and other features of bipolar disorder but not at levels reaching DSM-5 diagnostic criteria. The primary outcome of the study was conversion from BP-NOS to bipolar I or II, which are DSM-5 categories.
At the end of follow-up, 53.6% of the population had converted to bipolar I or II, which is consistent with previous risk estimates in this population. In specific patients, the correlation between predicted and observed conversions was “excellent.” Furthermore, the risk calculator was reported to have provided “good” discrimination between converters and nonconverters.
The risk calculator already is accessible online (http://www.cabsresearch.pitt.edu/bpriskcalculator/). Dr. Birmaher invited clinicians to visit and “play around” with its features, but he also issued a warning. “Be careful because we need to further validate this, which we are doing now, to see if it’s truly accurate or not. If it is, it would be a very good tool for us,” he said.
There are many potential clinical applications of the risk calculator, but Dr. Birmaher emphasized its possible value in selecting at-risk patients for therapy studies. Although several therapy trials already have been conducted in high-risk children on the basis of clinical presentation alone, such as a double-blind trial in BP-NOS patients that associated aripiprazole with a reduction in mania (J Child Adolesc Psychopharmacol. 2017;27:864-74), Dr. Birmaher sees the risk calculator as potentially more precise in identifying candidates.
Brooklyn, N.Y. – A risk calculator for bipolar disorder that has reached late stages of development might merit a trial to test whether treating prodromal symptoms delays or prevents the disease from developing in young patients, an expert said at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
Clinicians often are confronted with children who have prodromal symptoms of bipolar disorder, but only about half of those children eventually convert to full disease expression. As a result, treatment is not routine practice, said Boris Birmaher, MD, Endowed Chair, Early Onset Bipolar Disease, at the University of Pittsburgh.
A risk calculator that more effectively identifies those at highest risk of converting might be a tool that could allow early intervention to be tested. Such a calculator has been in development for some years, and the most recent research suggests that it is nearing a degree of accuracy that is clinically meaningful (J Am Acad Child Adolesc Psychiatry. 2018;57:755-63).
Accuracy might improve further with the identification and incorporation of more predictive variables. High-risk features for conversion include a parent with bipolar disorder, particularly one with childhood onset, and specific clinical features, such as prominent episodes of mania.
“Once replicated, the risk calculator will be instrumental to predict personalized risk to develop bipolar disease,” Dr. Birmaher said. He compared it to risk calculators now in use in other fields of medicine, such as cancer and cardiovascular disease, which generate information used by patients and their physicians for treatment decisions.
In the most recent study with the risk calculator, which has been the topic of several previous publications, 140 children with a diagnosis of bipolar disorder not otherwise specified (BP-NOS) were assessed every 7 months for a median of 11.5 years. BP-NOS is the diagnosis of a prodromal syndrome that includes mood lability and other features of bipolar disorder but not at levels reaching DSM-5 diagnostic criteria. The primary outcome of the study was conversion from BP-NOS to bipolar I or II, which are DSM-5 categories.
At the end of follow-up, 53.6% of the population had converted to bipolar I or II, which is consistent with previous risk estimates in this population. In specific patients, the correlation between predicted and observed conversions was “excellent.” Furthermore, the risk calculator was reported to have provided “good” discrimination between converters and nonconverters.
The risk calculator already is accessible online (http://www.cabsresearch.pitt.edu/bpriskcalculator/). Dr. Birmaher invited clinicians to visit and “play around” with its features, but he also issued a warning. “Be careful because we need to further validate this, which we are doing now, to see if it’s truly accurate or not. If it is, it would be a very good tool for us,” he said.
There are many potential clinical applications of the risk calculator, but Dr. Birmaher emphasized its possible value in selecting at-risk patients for therapy studies. Although several therapy trials already have been conducted in high-risk children on the basis of clinical presentation alone, such as a double-blind trial in BP-NOS patients that associated aripiprazole with a reduction in mania (J Child Adolesc Psychopharmacol. 2017;27:864-74), Dr. Birmaher sees the risk calculator as potentially more precise in identifying candidates.
Brooklyn, N.Y. – A risk calculator for bipolar disorder that has reached late stages of development might merit a trial to test whether treating prodromal symptoms delays or prevents the disease from developing in young patients, an expert said at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
Clinicians often are confronted with children who have prodromal symptoms of bipolar disorder, but only about half of those children eventually convert to full disease expression. As a result, treatment is not routine practice, said Boris Birmaher, MD, Endowed Chair, Early Onset Bipolar Disease, at the University of Pittsburgh.
A risk calculator that more effectively identifies those at highest risk of converting might be a tool that could allow early intervention to be tested. Such a calculator has been in development for some years, and the most recent research suggests that it is nearing a degree of accuracy that is clinically meaningful (J Am Acad Child Adolesc Psychiatry. 2018;57:755-63).
Accuracy might improve further with the identification and incorporation of more predictive variables. High-risk features for conversion include a parent with bipolar disorder, particularly one with childhood onset, and specific clinical features, such as prominent episodes of mania.
“Once replicated, the risk calculator will be instrumental to predict personalized risk to develop bipolar disease,” Dr. Birmaher said. He compared it to risk calculators now in use in other fields of medicine, such as cancer and cardiovascular disease, which generate information used by patients and their physicians for treatment decisions.
In the most recent study with the risk calculator, which has been the topic of several previous publications, 140 children with a diagnosis of bipolar disorder not otherwise specified (BP-NOS) were assessed every 7 months for a median of 11.5 years. BP-NOS is the diagnosis of a prodromal syndrome that includes mood lability and other features of bipolar disorder but not at levels reaching DSM-5 diagnostic criteria. The primary outcome of the study was conversion from BP-NOS to bipolar I or II, which are DSM-5 categories.
At the end of follow-up, 53.6% of the population had converted to bipolar I or II, which is consistent with previous risk estimates in this population. In specific patients, the correlation between predicted and observed conversions was “excellent.” Furthermore, the risk calculator was reported to have provided “good” discrimination between converters and nonconverters.
The risk calculator already is accessible online (http://www.cabsresearch.pitt.edu/bpriskcalculator/). Dr. Birmaher invited clinicians to visit and “play around” with its features, but he also issued a warning. “Be careful because we need to further validate this, which we are doing now, to see if it’s truly accurate or not. If it is, it would be a very good tool for us,” he said.
There are many potential clinical applications of the risk calculator, but Dr. Birmaher emphasized its possible value in selecting at-risk patients for therapy studies. Although several therapy trials already have been conducted in high-risk children on the basis of clinical presentation alone, such as a double-blind trial in BP-NOS patients that associated aripiprazole with a reduction in mania (J Child Adolesc Psychopharmacol. 2017;27:864-74), Dr. Birmaher sees the risk calculator as potentially more precise in identifying candidates.
REPORTING FROM the PSYCHOPHARMACOLOGY UPDATE INSTITUTE
Tyranny by the numbers
“How come you retired?” I asked.
A few years my junior, Marty had taught in public school forever. “It was the MCAS,” he said. That’s the Massachusetts Comprehensive Assessment System, a standardized test meant to gauge student performance and teacher competence.
“They demanded that my students test at a fifth-grade level,” Marty said. “But they were all at a second-grade level.
“Plus, I had been teaching for thirty years, and some kid right out of college was telling me how to do my job. So I left.”
Of course, this tale will sound familiar to physicians. Pay for performance. Bean counters calling the shots. Dismissal of clinical experience as useless and self-serving.
A recent book lays it all out: Jerry Z. Muller’s The Tyranny of Metrics. This book is punchy, witty, and succinct – you can read it in a day. A historian of economics and culture, Muller shows the extent of what I had guessed at from chats with people in different fields. In all of these, if you don’t count it, it doesn’t count.
Metrics, it is assumed, are “hard” and “objective.” They must “replace judgment based on experience with standardized measurement.” Their promise is transparency, efficiency, accountability.
Muller began to study this when he became chair of his academic department. He thought his job was to nurture scholars and help students learn, only to find much of his time taken up with feeding often worthless data to remote administrators. He traces the metrical impulse, at root, to lack of trust. It’s not only doctors whom society doesn’t trust, but experts of all kinds.
Principal agents ... “employed in institutions are not to be trusted … their activity must be monitored and measured ... those measures need to be transparent to those without firsthand knowledge of the institutions ... and ... pecuniary rewards and punishments are the best way to motivate ‘agents.’ ”
What this analysis ignores, argues Muller, is that professionals respond not just to “extrinsic motivation[s]” (money) but to intrinsic ones: commitment to profession and clients, doing the right thing, making people happier and better, being recognized and honored by peers, doing interesting and stimulating work. When society denigrates and dismisses those considerations, professionals become demoralized. They leave, or they learn to game the system.
Muller gives many examples. Punish hospitals for readmissions within 30 days of discharge? Fine – readmit patients under “observation status” and call them outpatients. Dock hospitals for deaths within 30 days of leaving? Keep the respirator on for an extra day, and let the patient die on day 31. Risky case? Don’t operate. “Juking the stats” – arresting many small-fry drug pushers instead of focusing on the kingpins. Does U.S. News and World Report rank a college higher for classes with under 20 students? Schedule seminars with a maximum of 19. (My example, not Muller’s.) Teach to the MCAS (unless, like Marty, you decide that’s hopeless and just quit). Buff the numbers.
You know the drill. And if you need to learn it to succeed – or not be judged a failure – you’ll learn it.
Studies show that “pay for performance” often doesn’t work. Metric advocates ignore these and call for more studies. In Muller’s words, “Metric fixation, which aspires to imitate science, too often resembles faith.”
Muller argues with balance and nuance. He affirms that objective measurement has helped sweep away old dogmas no one had ever tested and culled markedly substandard teachers. But he shows that over the past 30 years just counting what you know how to count, counting things that cannot be counted, and privileging belief over disconfirming evidence has conferred on metrics “elements of a cult,” whose baleful effects doctors and others toiling in their professional vineyards know too well.
Faith in metrics will wane and its cult will pass away, though likely well after we have done so ourselves. At some point, so-called situated knowledge – what people who actually do something know – will again be valued.
In the meantime, please rate this column highly (give it a 6 on a scale of 1-5), and confirm that there are no barriers to your implementing its wisdom, which comes unsullied by any financial conflicts of interest.
And check out Muller’s book. You have nothing to lose but your chains.
Measurement without meaning is tyranny!
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.
“How come you retired?” I asked.
A few years my junior, Marty had taught in public school forever. “It was the MCAS,” he said. That’s the Massachusetts Comprehensive Assessment System, a standardized test meant to gauge student performance and teacher competence.
“They demanded that my students test at a fifth-grade level,” Marty said. “But they were all at a second-grade level.
“Plus, I had been teaching for thirty years, and some kid right out of college was telling me how to do my job. So I left.”
Of course, this tale will sound familiar to physicians. Pay for performance. Bean counters calling the shots. Dismissal of clinical experience as useless and self-serving.
A recent book lays it all out: Jerry Z. Muller’s The Tyranny of Metrics. This book is punchy, witty, and succinct – you can read it in a day. A historian of economics and culture, Muller shows the extent of what I had guessed at from chats with people in different fields. In all of these, if you don’t count it, it doesn’t count.
Metrics, it is assumed, are “hard” and “objective.” They must “replace judgment based on experience with standardized measurement.” Their promise is transparency, efficiency, accountability.
Muller began to study this when he became chair of his academic department. He thought his job was to nurture scholars and help students learn, only to find much of his time taken up with feeding often worthless data to remote administrators. He traces the metrical impulse, at root, to lack of trust. It’s not only doctors whom society doesn’t trust, but experts of all kinds.
Principal agents ... “employed in institutions are not to be trusted … their activity must be monitored and measured ... those measures need to be transparent to those without firsthand knowledge of the institutions ... and ... pecuniary rewards and punishments are the best way to motivate ‘agents.’ ”
What this analysis ignores, argues Muller, is that professionals respond not just to “extrinsic motivation[s]” (money) but to intrinsic ones: commitment to profession and clients, doing the right thing, making people happier and better, being recognized and honored by peers, doing interesting and stimulating work. When society denigrates and dismisses those considerations, professionals become demoralized. They leave, or they learn to game the system.
Muller gives many examples. Punish hospitals for readmissions within 30 days of discharge? Fine – readmit patients under “observation status” and call them outpatients. Dock hospitals for deaths within 30 days of leaving? Keep the respirator on for an extra day, and let the patient die on day 31. Risky case? Don’t operate. “Juking the stats” – arresting many small-fry drug pushers instead of focusing on the kingpins. Does U.S. News and World Report rank a college higher for classes with under 20 students? Schedule seminars with a maximum of 19. (My example, not Muller’s.) Teach to the MCAS (unless, like Marty, you decide that’s hopeless and just quit). Buff the numbers.
You know the drill. And if you need to learn it to succeed – or not be judged a failure – you’ll learn it.
Studies show that “pay for performance” often doesn’t work. Metric advocates ignore these and call for more studies. In Muller’s words, “Metric fixation, which aspires to imitate science, too often resembles faith.”
Muller argues with balance and nuance. He affirms that objective measurement has helped sweep away old dogmas no one had ever tested and culled markedly substandard teachers. But he shows that over the past 30 years just counting what you know how to count, counting things that cannot be counted, and privileging belief over disconfirming evidence has conferred on metrics “elements of a cult,” whose baleful effects doctors and others toiling in their professional vineyards know too well.
Faith in metrics will wane and its cult will pass away, though likely well after we have done so ourselves. At some point, so-called situated knowledge – what people who actually do something know – will again be valued.
In the meantime, please rate this column highly (give it a 6 on a scale of 1-5), and confirm that there are no barriers to your implementing its wisdom, which comes unsullied by any financial conflicts of interest.
And check out Muller’s book. You have nothing to lose but your chains.
Measurement without meaning is tyranny!
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.
“How come you retired?” I asked.
A few years my junior, Marty had taught in public school forever. “It was the MCAS,” he said. That’s the Massachusetts Comprehensive Assessment System, a standardized test meant to gauge student performance and teacher competence.
“They demanded that my students test at a fifth-grade level,” Marty said. “But they were all at a second-grade level.
“Plus, I had been teaching for thirty years, and some kid right out of college was telling me how to do my job. So I left.”
Of course, this tale will sound familiar to physicians. Pay for performance. Bean counters calling the shots. Dismissal of clinical experience as useless and self-serving.
A recent book lays it all out: Jerry Z. Muller’s The Tyranny of Metrics. This book is punchy, witty, and succinct – you can read it in a day. A historian of economics and culture, Muller shows the extent of what I had guessed at from chats with people in different fields. In all of these, if you don’t count it, it doesn’t count.
Metrics, it is assumed, are “hard” and “objective.” They must “replace judgment based on experience with standardized measurement.” Their promise is transparency, efficiency, accountability.
Muller began to study this when he became chair of his academic department. He thought his job was to nurture scholars and help students learn, only to find much of his time taken up with feeding often worthless data to remote administrators. He traces the metrical impulse, at root, to lack of trust. It’s not only doctors whom society doesn’t trust, but experts of all kinds.
Principal agents ... “employed in institutions are not to be trusted … their activity must be monitored and measured ... those measures need to be transparent to those without firsthand knowledge of the institutions ... and ... pecuniary rewards and punishments are the best way to motivate ‘agents.’ ”
What this analysis ignores, argues Muller, is that professionals respond not just to “extrinsic motivation[s]” (money) but to intrinsic ones: commitment to profession and clients, doing the right thing, making people happier and better, being recognized and honored by peers, doing interesting and stimulating work. When society denigrates and dismisses those considerations, professionals become demoralized. They leave, or they learn to game the system.
Muller gives many examples. Punish hospitals for readmissions within 30 days of discharge? Fine – readmit patients under “observation status” and call them outpatients. Dock hospitals for deaths within 30 days of leaving? Keep the respirator on for an extra day, and let the patient die on day 31. Risky case? Don’t operate. “Juking the stats” – arresting many small-fry drug pushers instead of focusing on the kingpins. Does U.S. News and World Report rank a college higher for classes with under 20 students? Schedule seminars with a maximum of 19. (My example, not Muller’s.) Teach to the MCAS (unless, like Marty, you decide that’s hopeless and just quit). Buff the numbers.
You know the drill. And if you need to learn it to succeed – or not be judged a failure – you’ll learn it.
Studies show that “pay for performance” often doesn’t work. Metric advocates ignore these and call for more studies. In Muller’s words, “Metric fixation, which aspires to imitate science, too often resembles faith.”
Muller argues with balance and nuance. He affirms that objective measurement has helped sweep away old dogmas no one had ever tested and culled markedly substandard teachers. But he shows that over the past 30 years just counting what you know how to count, counting things that cannot be counted, and privileging belief over disconfirming evidence has conferred on metrics “elements of a cult,” whose baleful effects doctors and others toiling in their professional vineyards know too well.
Faith in metrics will wane and its cult will pass away, though likely well after we have done so ourselves. At some point, so-called situated knowledge – what people who actually do something know – will again be valued.
In the meantime, please rate this column highly (give it a 6 on a scale of 1-5), and confirm that there are no barriers to your implementing its wisdom, which comes unsullied by any financial conflicts of interest.
And check out Muller’s book. You have nothing to lose but your chains.
Measurement without meaning is tyranny!
Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.
Aftermath
I cared for my first patient with leukemia my first month as a doctor. Actually, he would protest that characterization. Marty didn’t have leukemia anymore. After chemotherapy and a bone marrow transplant, he was a few years out with no evidence of disease. While his hematologist was hesitant to use the word “cured” until more time had passed, he had been in a lasting remission.
Except that was the chart version of Marty’s story, not his own. He was diagnosed as a college sophomore, left school for treatment, and then never went back. He was pulled from his friends and his life.
“I never thought I would be the guy living in my parents’ basement,” he told me. “No job. No friends. No girlfriend.”
And, the graft-versus-host disease was still affecting him. His skin chronically itched. The light bothered his eyes, so he couldn’t drive long distances. Insecure about his skin and his vision, he self-imposed limitations on his activities, which in turn limited his hobbies.
In medical literature, what Marty was going through is chalked up to issues in survivorship. Many patients experience some version of this story. And it’s often not the hematologist or oncologist, but primary care physicians, who are responsible for managing this challenging aftermath.
Primary care physicians are responsible for a lot. After a certain duration of remission, I’ve noticed we tell some of our hematology and oncology patients, “Congratulations! You’ve graduated our clinic. We are happy to see you back if you’d like. But really, your primary care physician can manage your health now.”
In addition to depression, there was anxiety, understandably centered on the tenuousness of his health. I remember how Marty would send urgent emails and call the office after each blood test. If anything came back abnormal, there came a slew of questions. The meaning behind them was clear: The questions were filled with a fear that it could be the leukemia coming back.
What he didn’t know was that I was scared, too. After all, I was an internal medicine resident, not a hematologist. Was I checking the right labs? Was I taking his concerns seriously enough? Behind the scenes, I checked myself by running things by his bone marrow transplant doctor on a regular basis. She guided me on guiding him.
I often thought that I couldn’t imagine what he was feeling. We were the same age, but our day-to-day concerns took a drastically different tone. We both took a deep interest in his blood work, but while I felt angst over taking responsibility for them, he worried about whether they signaled an impending death.
“If the leukemia does come back,” he told me one day, “I don’t think I want to treat it. I can’t deal with all that again.”
There were many times he wanted to give up, he told me, and it was only for his parents that he pushed through. But now, he said, if it came back and the odds of curing it were that much smaller, he couldn’t do it for his parents again. He would take his savings, travel the world, and not look back.
I listened. I felt I understood his values at that point. I could not disagree.
Looking back, I realize some of my best help to Marty was through paperwork. It wasn’t glamorous, but it was what Marty needed. The passport to putting his life back together included many notes from a doctor: One to get him back into school, another to live in a dorm room, another for accommodations for his vision during exams, another to participate in sports.
At the time, I still was in newfound awe of the power of my signature; suddenly, signing MD at the end of documents persuaded schools, employers, and others to provide necessary services for my patients. I couldn’t think of a better use of my signature than to help Marty get his life back.
At the end of my residency, when I broke the news that I wouldn’t be a primary care physician anymore, I tried to soften it by sharing that I would be staying at Stanford for a fellowship in hematology and oncology. I’d be around. When I casually suggested he could come by anytime to say hello, he said no, and I then realized my blunder. He didn’t want to see me in a cancer center. He had done his time there. That was not the place he wanted to be a patient, ever again.
This month Marty turned 30, and so did I. He occasionally sends me updates from school, which I always enjoy receiving. He is on a sports team; he is pursuing a degree in economics; he has friends. And, he remains in remission. It took a long time, but he is happy.
During our last visit together, Marty gave me a stuffed animal with the name of the college I had helped him go back to. It’s sitting on my bookshelf. It reminds me how to be there for patients during the aftermath, a time that can be easily overlooked as the hardest. It reminds me what matters.
Minor details of this story have been changed to protect privacy.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
I cared for my first patient with leukemia my first month as a doctor. Actually, he would protest that characterization. Marty didn’t have leukemia anymore. After chemotherapy and a bone marrow transplant, he was a few years out with no evidence of disease. While his hematologist was hesitant to use the word “cured” until more time had passed, he had been in a lasting remission.
Except that was the chart version of Marty’s story, not his own. He was diagnosed as a college sophomore, left school for treatment, and then never went back. He was pulled from his friends and his life.
“I never thought I would be the guy living in my parents’ basement,” he told me. “No job. No friends. No girlfriend.”
And, the graft-versus-host disease was still affecting him. His skin chronically itched. The light bothered his eyes, so he couldn’t drive long distances. Insecure about his skin and his vision, he self-imposed limitations on his activities, which in turn limited his hobbies.
In medical literature, what Marty was going through is chalked up to issues in survivorship. Many patients experience some version of this story. And it’s often not the hematologist or oncologist, but primary care physicians, who are responsible for managing this challenging aftermath.
Primary care physicians are responsible for a lot. After a certain duration of remission, I’ve noticed we tell some of our hematology and oncology patients, “Congratulations! You’ve graduated our clinic. We are happy to see you back if you’d like. But really, your primary care physician can manage your health now.”
In addition to depression, there was anxiety, understandably centered on the tenuousness of his health. I remember how Marty would send urgent emails and call the office after each blood test. If anything came back abnormal, there came a slew of questions. The meaning behind them was clear: The questions were filled with a fear that it could be the leukemia coming back.
What he didn’t know was that I was scared, too. After all, I was an internal medicine resident, not a hematologist. Was I checking the right labs? Was I taking his concerns seriously enough? Behind the scenes, I checked myself by running things by his bone marrow transplant doctor on a regular basis. She guided me on guiding him.
I often thought that I couldn’t imagine what he was feeling. We were the same age, but our day-to-day concerns took a drastically different tone. We both took a deep interest in his blood work, but while I felt angst over taking responsibility for them, he worried about whether they signaled an impending death.
“If the leukemia does come back,” he told me one day, “I don’t think I want to treat it. I can’t deal with all that again.”
There were many times he wanted to give up, he told me, and it was only for his parents that he pushed through. But now, he said, if it came back and the odds of curing it were that much smaller, he couldn’t do it for his parents again. He would take his savings, travel the world, and not look back.
I listened. I felt I understood his values at that point. I could not disagree.
Looking back, I realize some of my best help to Marty was through paperwork. It wasn’t glamorous, but it was what Marty needed. The passport to putting his life back together included many notes from a doctor: One to get him back into school, another to live in a dorm room, another for accommodations for his vision during exams, another to participate in sports.
At the time, I still was in newfound awe of the power of my signature; suddenly, signing MD at the end of documents persuaded schools, employers, and others to provide necessary services for my patients. I couldn’t think of a better use of my signature than to help Marty get his life back.
At the end of my residency, when I broke the news that I wouldn’t be a primary care physician anymore, I tried to soften it by sharing that I would be staying at Stanford for a fellowship in hematology and oncology. I’d be around. When I casually suggested he could come by anytime to say hello, he said no, and I then realized my blunder. He didn’t want to see me in a cancer center. He had done his time there. That was not the place he wanted to be a patient, ever again.
This month Marty turned 30, and so did I. He occasionally sends me updates from school, which I always enjoy receiving. He is on a sports team; he is pursuing a degree in economics; he has friends. And, he remains in remission. It took a long time, but he is happy.
During our last visit together, Marty gave me a stuffed animal with the name of the college I had helped him go back to. It’s sitting on my bookshelf. It reminds me how to be there for patients during the aftermath, a time that can be easily overlooked as the hardest. It reminds me what matters.
Minor details of this story have been changed to protect privacy.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
I cared for my first patient with leukemia my first month as a doctor. Actually, he would protest that characterization. Marty didn’t have leukemia anymore. After chemotherapy and a bone marrow transplant, he was a few years out with no evidence of disease. While his hematologist was hesitant to use the word “cured” until more time had passed, he had been in a lasting remission.
Except that was the chart version of Marty’s story, not his own. He was diagnosed as a college sophomore, left school for treatment, and then never went back. He was pulled from his friends and his life.
“I never thought I would be the guy living in my parents’ basement,” he told me. “No job. No friends. No girlfriend.”
And, the graft-versus-host disease was still affecting him. His skin chronically itched. The light bothered his eyes, so he couldn’t drive long distances. Insecure about his skin and his vision, he self-imposed limitations on his activities, which in turn limited his hobbies.
In medical literature, what Marty was going through is chalked up to issues in survivorship. Many patients experience some version of this story. And it’s often not the hematologist or oncologist, but primary care physicians, who are responsible for managing this challenging aftermath.
Primary care physicians are responsible for a lot. After a certain duration of remission, I’ve noticed we tell some of our hematology and oncology patients, “Congratulations! You’ve graduated our clinic. We are happy to see you back if you’d like. But really, your primary care physician can manage your health now.”
In addition to depression, there was anxiety, understandably centered on the tenuousness of his health. I remember how Marty would send urgent emails and call the office after each blood test. If anything came back abnormal, there came a slew of questions. The meaning behind them was clear: The questions were filled with a fear that it could be the leukemia coming back.
What he didn’t know was that I was scared, too. After all, I was an internal medicine resident, not a hematologist. Was I checking the right labs? Was I taking his concerns seriously enough? Behind the scenes, I checked myself by running things by his bone marrow transplant doctor on a regular basis. She guided me on guiding him.
I often thought that I couldn’t imagine what he was feeling. We were the same age, but our day-to-day concerns took a drastically different tone. We both took a deep interest in his blood work, but while I felt angst over taking responsibility for them, he worried about whether they signaled an impending death.
“If the leukemia does come back,” he told me one day, “I don’t think I want to treat it. I can’t deal with all that again.”
There were many times he wanted to give up, he told me, and it was only for his parents that he pushed through. But now, he said, if it came back and the odds of curing it were that much smaller, he couldn’t do it for his parents again. He would take his savings, travel the world, and not look back.
I listened. I felt I understood his values at that point. I could not disagree.
Looking back, I realize some of my best help to Marty was through paperwork. It wasn’t glamorous, but it was what Marty needed. The passport to putting his life back together included many notes from a doctor: One to get him back into school, another to live in a dorm room, another for accommodations for his vision during exams, another to participate in sports.
At the time, I still was in newfound awe of the power of my signature; suddenly, signing MD at the end of documents persuaded schools, employers, and others to provide necessary services for my patients. I couldn’t think of a better use of my signature than to help Marty get his life back.
At the end of my residency, when I broke the news that I wouldn’t be a primary care physician anymore, I tried to soften it by sharing that I would be staying at Stanford for a fellowship in hematology and oncology. I’d be around. When I casually suggested he could come by anytime to say hello, he said no, and I then realized my blunder. He didn’t want to see me in a cancer center. He had done his time there. That was not the place he wanted to be a patient, ever again.
This month Marty turned 30, and so did I. He occasionally sends me updates from school, which I always enjoy receiving. He is on a sports team; he is pursuing a degree in economics; he has friends. And, he remains in remission. It took a long time, but he is happy.
During our last visit together, Marty gave me a stuffed animal with the name of the college I had helped him go back to. It’s sitting on my bookshelf. It reminds me how to be there for patients during the aftermath, a time that can be easily overlooked as the hardest. It reminds me what matters.
Minor details of this story have been changed to protect privacy.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
Melatonin update, Part 1
Found in various plant and animal species, including humans, melatonin (N-acetyl-5-methoxytryptamine) is best known for its daily fluctuations in circulating levels that regulate circadian rhythms. But this ancient serotonin derivative, stimulated by beta-adrenergic receptors, is the primary neuroendocrine product of the pineal gland (discovered as such in 1917) in humans and a dynamic compound with diverse roles in human health levels of which decrease with age.1,2 Over the last quarter of a century, we have arrived at a much greater understanding of the varied biological functions of this highly lipophilic hormone, which is now recognized as the strongest endogenous antioxidant, particularly potent against hydroxyl radicals, the most harmful of reactive oxygen species, and known to protect mitochondria and DNA from direct oxidative harm.2-4 Directly or via its circadian impact, melatonin also affects skin as well as core body temperature.1 This column is a . Next month’s column will address some more of the activities of this dynamic hormone while concentrating on the interaction of melatonin and ultraviolet radiation.
Early studies
In the mid-1990s, Bangha et al. performed several studies in healthy human volunteers that demonstrated that topically applied melatonin suppressed UVB-induced erythema (with one study showing pre- and posttreatment as effective and a subsequent one showing only pretreatment as effective), and also found that melatonin appears to have the potential to accumulate in the stratum corneum with extended release into the blood system through cutaneous delivery.5-7
A randomized, double-blind study by Dreher et al. in 12 healthy adults (6 women and 6 men, all white, aged 29-49 years) considered the short-term photoprotective effects of topically applied vitamin C, vitamin E, and melatonin, alone or in combination, 30 minutes after UV exposure. A dose-dependent photoprotective effect was associated with melatonin, and photoprotective properties were enhanced when melatonin in was combined with vitamins C and E.8
The following year, Dreher et al. evaluated the short-term photoprotective effects of the same compounds in a randomized, double-blind, placebo-controlled human study. Each antioxidant was topically applied alone or in combination after UV exposure in a single application (immediately or 30 minutes after UV exposure) or in multiple applications 30 minutes, 1 hour, and 2 hours after UV exposure (totaling three applications). Interestingly, no photoprotective effects were seen. The researchers concluded that given the speed of cutaneous damage from UV radiation, antioxidants likely must be delivered at the appropriate site in sufficient doses at the outset of and during active oxidative harm.9
In 2004, Fischer et al. conducted a clinical study of 15 healthy volunteers to test the skin penetration activity of melatonin 0.01% in a cream and 0.01% and 0.03% in a solution. During a 24-hour period, researchers obtained blood samples for melatonin measurement prior to application at 9 a.m. as well as 1, 4, 8, and 24 hours after application. Preapplication serum melatonin levels ranged from 0.6 to 15.9 pg/mL. The mean serum value 24 hours later after application of the 0.01% melatonin cream was 9.0 pg/mL. For the 0.01% solution group, the mean melatonin level was 12.7 pg/mL 24 hours after application. Melatonin levels also substantially rose just 1 and 8 hours later in the 0.03% solution group, with cumulative melatonin measured as 7.1 pg/mL in the 0.01% cream group, 8.6 pg/mL in the 0.01% solution participants, and 15.7 pg/mL in the 0.03% group. The investigators concluded that as a strong lipophilic compound melatonin penetrates the skin with serum blood levels increasing in a dose- and galenic-dependent manner without prompting spikes above the physiological range.10
Wound healing and atopic dermatitis
In 2006, Sener et al. reported that topically applied and systemically administered melatonin was successful as a pressure ulcer treatment in rats.11 Four years later, in a study using a chronic wound model in rats with pinealectomy that suppressed basal melatonin, Ozler et al. found that systemic and topical melatonin treatment were equally effective in imparting wound healing effects.12
A study in mice conducted by Kim et al. at around the same time showed that topically applied melatonin, by reducing total IgE in serum and interleukin-4 and interferon-gamma production by activated CD4(+) T cells, inhibits atopic dermatitis–like skin lesion development engendered by 2,4-dinitrofluorobenzene (DNFB) treatment in NC/Nga mice.13
More recently, Abbaszadeh et al. have suggested that melatonin has the potential to enhance the therapeutic ratio in radiation oncology, and to be more effective at reducing skin damage in this setting when used in optimal and non-toxic doses.2
Pigmentation disorders
Melatonin and serotonin are thought to have potential to ameliorate or attenuate the spread of vitiligo.1 In addition, melatonin appears to have potential in the realm of hyperpigmentation treatment. Investigators have found that the combination of topical melatonin 5% and a daily dose of 3 g of oral melatonin over 120 days significantly reduces Melasma Area Severity Index scores in comparison to placebo; the improvement is attributed primarily to the use of topical melatonin.14,15
Androgenetic alopecia
In 2018, Hatem et al. designed nanostructured lipid carriers to better deliver melatonin in antioxidant oils to treat androgenic alopecia. They found that the carriers achieved a sustained release of 6 hours and raised the skin deposition of melatonin 4.5-fold in the stratum corneum, 7-fold in the epidermis, and 6.8-fold in the dermis compared with a melatonin solution. The nanostructured lipid carriers also improved on clinical results, compared to the melatonin formula, by increasing hair density and thickness and reducing hair loss in patients with androgenic alopecia.16
Conclusion
Studies in humans have shown that through systemic administration and, particularly, topical application. Demonstrated to be safe and effective, topically applied melatonin appears to warrant serious consideration as a skin-protective, anti-aging tool in the dermatologic armamentarium.
Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com.
References
1. Slominski AT et al. J Invest Dermatol. 2018 Mar;138(3):490-9.
2. Abbaszadeh A et al. J Biomed Phys Eng. 2017 Jun;7(2):127-136.
3. Fischer T et al. Hautarzt. 1999 Jan;50(1):5-11.
4. Scheuer C. Dan Med J. 2017 Jun;64(6). pii:B5358.
5. Bangha E et al. Arch Dermatol Res. 1996 Aug;288(9):522-6.
6. Bangha E et al. Dermatology. 1997;195(3):248-52.
7. Bangha E et al. Skin Pharmacol. 1997;10(5-6):298-302.
8. Dreher F et al. Br J Dermatol. 1998 Aug;139(2):332-9.
9. Dreher F et al. Dermatology. 1999;198(1):52-5.
10. Fischer TW et al. Skin Pharmacol Physiol. 2004 Jul-Aug;17(4):190-4.
11. Sener G et al. J Pineal Res. 2006 Apr;40(3):280-7.
12. Ozler M et al. Scand J Clin Lab Invest. 2010 Oct;70(6):447-52.
13. Kim TH et al. J Pineal Res. 2009 Nov;47(4):324-9.
14. Juhasz MLW et al. J Cosmet Dermatol. 2018 Dec;17(6):1144-57.
15. Hamadi SA, Mohammed MM, Aljaf AN, et al. The role of topical and oral melatonin in management of melasma patients. J Arab Univ Basic Appl Sci. 2009;8:30‐42.
16. Hatem S et al. Expert Opin Drug Deliv. 2018 Oct;15(10):927-35.
Found in various plant and animal species, including humans, melatonin (N-acetyl-5-methoxytryptamine) is best known for its daily fluctuations in circulating levels that regulate circadian rhythms. But this ancient serotonin derivative, stimulated by beta-adrenergic receptors, is the primary neuroendocrine product of the pineal gland (discovered as such in 1917) in humans and a dynamic compound with diverse roles in human health levels of which decrease with age.1,2 Over the last quarter of a century, we have arrived at a much greater understanding of the varied biological functions of this highly lipophilic hormone, which is now recognized as the strongest endogenous antioxidant, particularly potent against hydroxyl radicals, the most harmful of reactive oxygen species, and known to protect mitochondria and DNA from direct oxidative harm.2-4 Directly or via its circadian impact, melatonin also affects skin as well as core body temperature.1 This column is a . Next month’s column will address some more of the activities of this dynamic hormone while concentrating on the interaction of melatonin and ultraviolet radiation.
Early studies
In the mid-1990s, Bangha et al. performed several studies in healthy human volunteers that demonstrated that topically applied melatonin suppressed UVB-induced erythema (with one study showing pre- and posttreatment as effective and a subsequent one showing only pretreatment as effective), and also found that melatonin appears to have the potential to accumulate in the stratum corneum with extended release into the blood system through cutaneous delivery.5-7
A randomized, double-blind study by Dreher et al. in 12 healthy adults (6 women and 6 men, all white, aged 29-49 years) considered the short-term photoprotective effects of topically applied vitamin C, vitamin E, and melatonin, alone or in combination, 30 minutes after UV exposure. A dose-dependent photoprotective effect was associated with melatonin, and photoprotective properties were enhanced when melatonin in was combined with vitamins C and E.8
The following year, Dreher et al. evaluated the short-term photoprotective effects of the same compounds in a randomized, double-blind, placebo-controlled human study. Each antioxidant was topically applied alone or in combination after UV exposure in a single application (immediately or 30 minutes after UV exposure) or in multiple applications 30 minutes, 1 hour, and 2 hours after UV exposure (totaling three applications). Interestingly, no photoprotective effects were seen. The researchers concluded that given the speed of cutaneous damage from UV radiation, antioxidants likely must be delivered at the appropriate site in sufficient doses at the outset of and during active oxidative harm.9
In 2004, Fischer et al. conducted a clinical study of 15 healthy volunteers to test the skin penetration activity of melatonin 0.01% in a cream and 0.01% and 0.03% in a solution. During a 24-hour period, researchers obtained blood samples for melatonin measurement prior to application at 9 a.m. as well as 1, 4, 8, and 24 hours after application. Preapplication serum melatonin levels ranged from 0.6 to 15.9 pg/mL. The mean serum value 24 hours later after application of the 0.01% melatonin cream was 9.0 pg/mL. For the 0.01% solution group, the mean melatonin level was 12.7 pg/mL 24 hours after application. Melatonin levels also substantially rose just 1 and 8 hours later in the 0.03% solution group, with cumulative melatonin measured as 7.1 pg/mL in the 0.01% cream group, 8.6 pg/mL in the 0.01% solution participants, and 15.7 pg/mL in the 0.03% group. The investigators concluded that as a strong lipophilic compound melatonin penetrates the skin with serum blood levels increasing in a dose- and galenic-dependent manner without prompting spikes above the physiological range.10
Wound healing and atopic dermatitis
In 2006, Sener et al. reported that topically applied and systemically administered melatonin was successful as a pressure ulcer treatment in rats.11 Four years later, in a study using a chronic wound model in rats with pinealectomy that suppressed basal melatonin, Ozler et al. found that systemic and topical melatonin treatment were equally effective in imparting wound healing effects.12
A study in mice conducted by Kim et al. at around the same time showed that topically applied melatonin, by reducing total IgE in serum and interleukin-4 and interferon-gamma production by activated CD4(+) T cells, inhibits atopic dermatitis–like skin lesion development engendered by 2,4-dinitrofluorobenzene (DNFB) treatment in NC/Nga mice.13
More recently, Abbaszadeh et al. have suggested that melatonin has the potential to enhance the therapeutic ratio in radiation oncology, and to be more effective at reducing skin damage in this setting when used in optimal and non-toxic doses.2
Pigmentation disorders
Melatonin and serotonin are thought to have potential to ameliorate or attenuate the spread of vitiligo.1 In addition, melatonin appears to have potential in the realm of hyperpigmentation treatment. Investigators have found that the combination of topical melatonin 5% and a daily dose of 3 g of oral melatonin over 120 days significantly reduces Melasma Area Severity Index scores in comparison to placebo; the improvement is attributed primarily to the use of topical melatonin.14,15
Androgenetic alopecia
In 2018, Hatem et al. designed nanostructured lipid carriers to better deliver melatonin in antioxidant oils to treat androgenic alopecia. They found that the carriers achieved a sustained release of 6 hours and raised the skin deposition of melatonin 4.5-fold in the stratum corneum, 7-fold in the epidermis, and 6.8-fold in the dermis compared with a melatonin solution. The nanostructured lipid carriers also improved on clinical results, compared to the melatonin formula, by increasing hair density and thickness and reducing hair loss in patients with androgenic alopecia.16
Conclusion
Studies in humans have shown that through systemic administration and, particularly, topical application. Demonstrated to be safe and effective, topically applied melatonin appears to warrant serious consideration as a skin-protective, anti-aging tool in the dermatologic armamentarium.
Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com.
References
1. Slominski AT et al. J Invest Dermatol. 2018 Mar;138(3):490-9.
2. Abbaszadeh A et al. J Biomed Phys Eng. 2017 Jun;7(2):127-136.
3. Fischer T et al. Hautarzt. 1999 Jan;50(1):5-11.
4. Scheuer C. Dan Med J. 2017 Jun;64(6). pii:B5358.
5. Bangha E et al. Arch Dermatol Res. 1996 Aug;288(9):522-6.
6. Bangha E et al. Dermatology. 1997;195(3):248-52.
7. Bangha E et al. Skin Pharmacol. 1997;10(5-6):298-302.
8. Dreher F et al. Br J Dermatol. 1998 Aug;139(2):332-9.
9. Dreher F et al. Dermatology. 1999;198(1):52-5.
10. Fischer TW et al. Skin Pharmacol Physiol. 2004 Jul-Aug;17(4):190-4.
11. Sener G et al. J Pineal Res. 2006 Apr;40(3):280-7.
12. Ozler M et al. Scand J Clin Lab Invest. 2010 Oct;70(6):447-52.
13. Kim TH et al. J Pineal Res. 2009 Nov;47(4):324-9.
14. Juhasz MLW et al. J Cosmet Dermatol. 2018 Dec;17(6):1144-57.
15. Hamadi SA, Mohammed MM, Aljaf AN, et al. The role of topical and oral melatonin in management of melasma patients. J Arab Univ Basic Appl Sci. 2009;8:30‐42.
16. Hatem S et al. Expert Opin Drug Deliv. 2018 Oct;15(10):927-35.
Found in various plant and animal species, including humans, melatonin (N-acetyl-5-methoxytryptamine) is best known for its daily fluctuations in circulating levels that regulate circadian rhythms. But this ancient serotonin derivative, stimulated by beta-adrenergic receptors, is the primary neuroendocrine product of the pineal gland (discovered as such in 1917) in humans and a dynamic compound with diverse roles in human health levels of which decrease with age.1,2 Over the last quarter of a century, we have arrived at a much greater understanding of the varied biological functions of this highly lipophilic hormone, which is now recognized as the strongest endogenous antioxidant, particularly potent against hydroxyl radicals, the most harmful of reactive oxygen species, and known to protect mitochondria and DNA from direct oxidative harm.2-4 Directly or via its circadian impact, melatonin also affects skin as well as core body temperature.1 This column is a . Next month’s column will address some more of the activities of this dynamic hormone while concentrating on the interaction of melatonin and ultraviolet radiation.
Early studies
In the mid-1990s, Bangha et al. performed several studies in healthy human volunteers that demonstrated that topically applied melatonin suppressed UVB-induced erythema (with one study showing pre- and posttreatment as effective and a subsequent one showing only pretreatment as effective), and also found that melatonin appears to have the potential to accumulate in the stratum corneum with extended release into the blood system through cutaneous delivery.5-7
A randomized, double-blind study by Dreher et al. in 12 healthy adults (6 women and 6 men, all white, aged 29-49 years) considered the short-term photoprotective effects of topically applied vitamin C, vitamin E, and melatonin, alone or in combination, 30 minutes after UV exposure. A dose-dependent photoprotective effect was associated with melatonin, and photoprotective properties were enhanced when melatonin in was combined with vitamins C and E.8
The following year, Dreher et al. evaluated the short-term photoprotective effects of the same compounds in a randomized, double-blind, placebo-controlled human study. Each antioxidant was topically applied alone or in combination after UV exposure in a single application (immediately or 30 minutes after UV exposure) or in multiple applications 30 minutes, 1 hour, and 2 hours after UV exposure (totaling three applications). Interestingly, no photoprotective effects were seen. The researchers concluded that given the speed of cutaneous damage from UV radiation, antioxidants likely must be delivered at the appropriate site in sufficient doses at the outset of and during active oxidative harm.9
In 2004, Fischer et al. conducted a clinical study of 15 healthy volunteers to test the skin penetration activity of melatonin 0.01% in a cream and 0.01% and 0.03% in a solution. During a 24-hour period, researchers obtained blood samples for melatonin measurement prior to application at 9 a.m. as well as 1, 4, 8, and 24 hours after application. Preapplication serum melatonin levels ranged from 0.6 to 15.9 pg/mL. The mean serum value 24 hours later after application of the 0.01% melatonin cream was 9.0 pg/mL. For the 0.01% solution group, the mean melatonin level was 12.7 pg/mL 24 hours after application. Melatonin levels also substantially rose just 1 and 8 hours later in the 0.03% solution group, with cumulative melatonin measured as 7.1 pg/mL in the 0.01% cream group, 8.6 pg/mL in the 0.01% solution participants, and 15.7 pg/mL in the 0.03% group. The investigators concluded that as a strong lipophilic compound melatonin penetrates the skin with serum blood levels increasing in a dose- and galenic-dependent manner without prompting spikes above the physiological range.10
Wound healing and atopic dermatitis
In 2006, Sener et al. reported that topically applied and systemically administered melatonin was successful as a pressure ulcer treatment in rats.11 Four years later, in a study using a chronic wound model in rats with pinealectomy that suppressed basal melatonin, Ozler et al. found that systemic and topical melatonin treatment were equally effective in imparting wound healing effects.12
A study in mice conducted by Kim et al. at around the same time showed that topically applied melatonin, by reducing total IgE in serum and interleukin-4 and interferon-gamma production by activated CD4(+) T cells, inhibits atopic dermatitis–like skin lesion development engendered by 2,4-dinitrofluorobenzene (DNFB) treatment in NC/Nga mice.13
More recently, Abbaszadeh et al. have suggested that melatonin has the potential to enhance the therapeutic ratio in radiation oncology, and to be more effective at reducing skin damage in this setting when used in optimal and non-toxic doses.2
Pigmentation disorders
Melatonin and serotonin are thought to have potential to ameliorate or attenuate the spread of vitiligo.1 In addition, melatonin appears to have potential in the realm of hyperpigmentation treatment. Investigators have found that the combination of topical melatonin 5% and a daily dose of 3 g of oral melatonin over 120 days significantly reduces Melasma Area Severity Index scores in comparison to placebo; the improvement is attributed primarily to the use of topical melatonin.14,15
Androgenetic alopecia
In 2018, Hatem et al. designed nanostructured lipid carriers to better deliver melatonin in antioxidant oils to treat androgenic alopecia. They found that the carriers achieved a sustained release of 6 hours and raised the skin deposition of melatonin 4.5-fold in the stratum corneum, 7-fold in the epidermis, and 6.8-fold in the dermis compared with a melatonin solution. The nanostructured lipid carriers also improved on clinical results, compared to the melatonin formula, by increasing hair density and thickness and reducing hair loss in patients with androgenic alopecia.16
Conclusion
Studies in humans have shown that through systemic administration and, particularly, topical application. Demonstrated to be safe and effective, topically applied melatonin appears to warrant serious consideration as a skin-protective, anti-aging tool in the dermatologic armamentarium.
Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mdedge.com.
References
1. Slominski AT et al. J Invest Dermatol. 2018 Mar;138(3):490-9.
2. Abbaszadeh A et al. J Biomed Phys Eng. 2017 Jun;7(2):127-136.
3. Fischer T et al. Hautarzt. 1999 Jan;50(1):5-11.
4. Scheuer C. Dan Med J. 2017 Jun;64(6). pii:B5358.
5. Bangha E et al. Arch Dermatol Res. 1996 Aug;288(9):522-6.
6. Bangha E et al. Dermatology. 1997;195(3):248-52.
7. Bangha E et al. Skin Pharmacol. 1997;10(5-6):298-302.
8. Dreher F et al. Br J Dermatol. 1998 Aug;139(2):332-9.
9. Dreher F et al. Dermatology. 1999;198(1):52-5.
10. Fischer TW et al. Skin Pharmacol Physiol. 2004 Jul-Aug;17(4):190-4.
11. Sener G et al. J Pineal Res. 2006 Apr;40(3):280-7.
12. Ozler M et al. Scand J Clin Lab Invest. 2010 Oct;70(6):447-52.
13. Kim TH et al. J Pineal Res. 2009 Nov;47(4):324-9.
14. Juhasz MLW et al. J Cosmet Dermatol. 2018 Dec;17(6):1144-57.
15. Hamadi SA, Mohammed MM, Aljaf AN, et al. The role of topical and oral melatonin in management of melasma patients. J Arab Univ Basic Appl Sci. 2009;8:30‐42.
16. Hatem S et al. Expert Opin Drug Deliv. 2018 Oct;15(10):927-35.
Subclinical hypothyroidism: When to treat
Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.
Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.
HIGH TSH, NORMAL FREE T4 LEVELS
Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T4).1
The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T4 and triiodothyronine (T3) levels go down even a little, TSH levels go up a lot.2
TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.3
WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?
The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.3
In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.4 Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.5
On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.
Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.7 The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.7,8
It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.3 Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,9 although higher TSH cutoffs for treatment are advised in elderly patients.10 Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.11
Authors of the NHANES III8 and Hanford Thyroid Disease study12 have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.
SUBCLINICAL HYPOTHYROIDISM IS COMMON
In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.1,8,13 The prevalence is higher in women and increases with age.8 It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.14 Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.8
A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.10,15
A VARIETY OF CAUSES
The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,2 in which thyroid peroxidase antibodies are usually present.2,16
Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.
SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS
“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.17 And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,18 although it has been reported to resolve spontaneously in half of cases within 2 years,19 typically in patients with TSH values of 4 to 6 mIU/L.20 The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.18
Figure 1 shows the natural history of subclinical hypothyroidism.1
GUIDELINES FOR SCREENING DIFFER
Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.
Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.23
The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.24
The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.25
The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.26
The American Academy of Family Physicians recommends screening after age 60.18
The American College of Physicians recommends screening patients over age 50 who have symptoms.18
Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.24
CLINICAL PRESENTATION
About 70% of patients with subclinical hypothyroidism have no symptoms.13
Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.27,28
Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.13
The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.29–31
In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.31 An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.
ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY
INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING
The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.118 Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.
The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.118,119
Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.
When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.
If the TSH is high-normal
It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.
Pollock et al121 found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.
However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.
Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.
If TSH is mildly elevated
The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.2 The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.
The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.
If TSH is higher than 10 mIU/L
Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.122
- Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012; 379(9821):1142–1154. doi:10.1016/S0140-6736(11)60276-6
- Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc 2009; 84(1):65–71. doi:10.4065/84.1.65
- Laurberg P, Andersen S, Carle A, Karmisholt J, Knudsen N, Pedersen IB. The TSH upper reference limit: where are we at? Nat Rev Endocrinol 2011; 7(4):232–239. doi:10.1038/nrendo.2011.13
- Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab 2005; 90(9):5483–5488. doi:10.1210/jc.2005-0455
- Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE. National Health and Nutrition Examination Survey III thyroid-stimulating hormone (TSH)-thyroperoxidase antibody relationships demonstrate that TSH upper reference limits may be skewed by occult thyroid dysfunction. J Clin Endocrinol Metab 2007; 92(11):4236–4240. doi:10.1210/jc.2007-0287
- Fatourechi V, Klee GG, Grebe SK, et al. Effects of reducing the upper limit of normal TSH values. JAMA 2003; 290(24):3195–3196. doi:10.1001/jama.290.24.3195-a
- Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 2007; 92(12):4575–4582. doi:10.1210/jc.2007-1499
- Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87(2):489–499. doi:10.1210/jcem.87.2.8182
- Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 2014; 24(12):1670–1751. doi:10.1089/thy.2014.0028
- Hennessey JV, Espaillat R. Diagnosis and management of subclinical hypothyroidism in elderly adults: a review of the literature. J Am Geriatr Soc 2015; 63(8):1663–1673. doi:10.1111/jgs.13532
- Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis. J Clin Endocrinol Metab 2008; 93(8):2998–3007. doi:10.1210/jc.2008-0167
- Hamilton TE, Davis S, Onstad L, Kopecky KJ. Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism. J Clin Endocrinol Metab 2008; 93(4):1224–1230. doi:10.1210/jc.2006-2300
- Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160(4):526–534. pmid:10695693
- Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med 2006; 354(26):2783–2793. doi:10.1056/NEJMoa054022
- Negro R, Stagnaro-Green A. Diagnosis and management of subclinical hypothyroidism in pregnancy. BMJ 2014; 349:g4929. doi:10.1136/bmj.g4929
- Baumgartner C, Blum MR, Rodondi N. Subclinical hypothyroidism: summary of evidence in 2014. Swiss Med Wkly 2014; 144:w14058. doi:10.4414/smw.2014.14058
- Stedman TL. Stedman’s Medical Dictionary. 28th ed. Baltimore, MD: Lippincott Williams and Wilkins; 2006.
- Raza SA, Mahmood N. Subclinical hypothyroidism: controversies to consensus. Indian J Endocrinol Metab 2013; 17(suppl 3):S636–S642. doi:10.4103/2230-8210.123555
- Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab 2002; 87(7):3221–3226. doi:10.1210/jcem.87.7.8678
- Diez JJ, Iglesias P, Burman KD. Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2005; 90(7):4124–4127. doi:10.1210/jc.2005-0375
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- Hennessey JV, Klein I, Woeber KA, Cobin R, Garber JR. Aggressive case finding: a clinical strategy for the documentation of thyroid dysfunction. Ann Intern Med 2015; 163(4):311–312. doi:10.7326/M15-0762
- Rugge JB, Bougatsos C, Chou R. Screening and treatment of thyroid dysfunction: an evidence review for the US.Preventive Services Task Force. Ann Intern Med 2015; 162(1):35–45. doi:10.7326/M14-1456
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- Joffe RT, Pearce EN, Hennessey JV, Ryan JJ, Stern RA. Subclinical hypothyroidism, mood, and cognition in older adults: a review. Int J Geriatr Psychiatry 2013; 28(2):111–118. doi:10.1002/gps.3796
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- Andersen MN, Olsen AM, Madsen JC, et al. Levothyroxine substitution in patients with subclinical hypothyroidism and the risk of myocardial infarction and mortality. PLoS One 2015; 10(6):e0129793. doi:10.1371/journal.pone.0129793
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- Taddei S, Caraccio N, Virdis A, et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 2003; 88(8):3731–3737. doi:10.1210/jc.2003-030039
- Gao N, Zhang W, Zhang YZ, Yang Q, Chen SH. Carotid intima-media thickness in patients with subclinical hypothyroidism: a meta-analysis. Atherosclerosis 2013; 227(1):18–25. doi:10.1016/j.atherosclerosis.2012.10.070
- Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008; 29(1):76–131. doi:10.1210/er.2006-0043
- Chaker L, Baumgartner C, den Elzen WP, et al; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: an individual participant data analysis. J Clin Endocrinol Metab 2015; 100(6):2181–2191. doi:10.1210/jc.2015-1438
- Monzani F, Di Bello V, Caraccio N, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab 2001; 86(3):1110–1115. doi:10.1210/jcem.86.3.7291
- Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001; 358(9285):861-865. doi:10.1016/S0140-6736(01)06067-6
- Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med 2012; 172(10):811–817. doi:10.1001/archinternmed.2012.1159
- Pasqualetti G, Tognini S, Polini A, Caraccio N, Monzani F. Is subclinical hypothyroidism a cardiovascular risk factor in the elderly? J Clin Endocrinol Metab 2013; 98(6):2256–2266. doi:10.1210/jc.2012-3818
- Mooijaart SP, IEMO 80-plus Thyroid Trial Collaboration. Subclinical thyroid disorders. Lancet 2012; 380(9839):335. doi:10.1016/S0140-6736(12)61241-0
- Rodondi N, Bauer DC. Subclinical hypothyroidism and cardiovascular risk: how to end the controversy. J Clin Endocrinol Metab 2013; 98(6):2267–2269. doi:10.1210/jc.2013-1875
- Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005; 165(21):2460–2466. doi:10.1001/archinte.165.21.2460
- Rodondi N, Bauer DC, Cappola AR, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study. J Am Coll Cardiol 2008; 52(14):1152–1159. doi:10.1016/j.jacc.2008.07.009
- Haggerty JJ Jr, Garbutt JC, Evans DL, et al. Subclinical hypothyroidism: a review of neuropsychiatric aspects. Int J Psychiatry Med 1990; 20(2):193–208. doi:10.2190/ADLY-1UU0-1A8L-HPXY
- Baldini IM, Vita A, Mauri MC, et al. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry 1997; 21(6):925–935. pmid:9380789
- del Ser Quijano T, Delgado C, Martinez Espinosa S, Vazquez C. Cognitive deficiency in mild hypothyroidism. Neurologia 2000; 15(5):193–198. Spanish. pmid:10850118
- Correia N, Mullally S, Cooke G, et al. Evidence for a specific defect in hippocampal memory in overt and subclinical hypothyroidism. J Clin Endocrinol Metab 2009; 94(10):3789–3797. doi:10.1210/jc.2008-2702
- Aghili R, Khamseh ME, Malek M, et al. Changes of subtests of Wechsler memory scale and cognitive function in subjects with subclinical hypothyroidism following treatment with levothyroxine. Arch Med Sci 2012; 8(6):1096–1101. doi:10.5114/aoms.2012.32423
- Pasqualetti G, Pagano G, Rengo G, Ferrara N, Monzani F. Subclinical hypothyroidism and cognitive impairment: systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100(11):4240–4248. doi:10.1210/jc.2015-2046
- Christ-Crain M, Meier C, Huber PR, Staub J, Muller B. Effect of L-thyroxine replacement therapy on surrogate markers of skeletal and cardiac function in subclinical hypothyroidism. Endocrinologist 2004; 14(3):161–166. doi:10.1097/01.ten.0000127932.31710.4f
- Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid 2006; 16(4):375–380. doi:10.1089/thy.2006.16.375
- Reuters VS, Teixeira Pde F, Vigario PS, et al. Functional capacity and muscular abnormalities in subclinical hypothyroidism. Am J Med Sci 2009; 338(4):259–263. doi:10.1097/MAJ.0b013e3181af7c7c
- Mainenti MR, Vigario PS, Teixeira PF, Maia MD, Oliveira FP, Vaisman M. Effect of levothyroxine replacement on exercise performance in subclinical hypothyroidism. J Endocrinol Invest 2009; 32(5):470–473. doi:10.3275/6106
- Lankhaar JA, de Vries WR, Jansen JA, Zelissen PM, Backx FJ. Impact of overt and subclinical hypothyroidism on exercise tolerance: a systematic review. Res Q Exerc Sport 2014; 85(3):365–389. doi:10.1080/02701367.2014.930405
- Lee JS, Buzkova P, Fink HA, et al. Subclinical thyroid dysfunction and incident hip fracture in older adults. Arch Intern Med 2010; 170(21):1876–1883. doi:10.1001/archinternmed.2010.424
- Svare A, Nilsen TI, Asvold BO, et al. Does thyroid function influence fracture risk? Prospective data from the HUNT2 study, Norway. Eur J Endocrinol 2013; 169(6):845–852. doi:10.1530/EJE-13-0546
- Di Mase R, Cerbone M, Improda N, et al. Bone health in children with long-term idiopathic subclinical hypothyroidism. Ital J Pediatr 2012; 38:56. doi:10.1186/1824-7288-38-56
- Boelaert K. The association between serum TSH concentration and thyroid cancer. Endocr Relat Cancer 2009; 16(4):1065–1072. doi:10.1677/ERC-09-0150
- Haymart MR, Glinberg SL, Liu J, Sippel RS, Jaume JC, Chen H. Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension. Clin Endocrinol (Oxf) 2009; 71(3):434–439. doi:10.1111/j.1365-2265.2008.03489.x
- Fiore E, Vitti P. Serum TSH and risk of papillary thyroid cancer in nodular thyroid disease. J Clin Endocrinol Metab 2012; 97(4):1134–1145. doi:10.1210/jc.2011-2735
- Fiore E, Rago T, Provenzale MA, et al. L-thyroxine-treated patients with nodular goiter have lower serum TSH and lower frequency of papillary thyroid cancer: results of a cross-sectional study on 27,914 patients. Endocr Relat Cancer 2010; 17(1):231–239. doi:10.1677/ERC-09-0251
- Hercbergs AH, Ashur-Fabian O, Garfield D. Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 2010; 17(5):432–436. doi:10.1097/MED.0b013e32833d9710
- Thvilum M, Brandt F, Brix TH, Hegedus L. A review of the evidence for and against increased mortality in hypothyroidism. Nat Rev Endocrinol 2012; 8(7):417–424. doi:10.1038/nrendo.2012.29
- Stott DJ, Rodondi N, Kearney PM, et al; TRUST Study Group. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med 2017; 376(26):2534–2544. doi:10.1056/NEJMoa1603825
- Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril 2015; 104(3):545–753. doi:10.1016/j.fertnstert.2015.05.028
- Stagnaro-Green A, Abalovich M, Alexander E, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21(10):1081–1125. doi:10.1089/thy.2011.0087
- Goldsmith RE, Sturgis SH, Lerman J, Stanbury JB. The menstrual pattern in thyroid disease. J Clin Endocrinol Metab. 1952; 12(7):846-855. doi:10.1210/jcem-12-7-846
- Plowden TC, Schisterman EF, Sjaarda LA, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab 2016; 101(6):2358–2365. doi:10.1210/jc.2016-1049
- Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017; 27(3):315–389. doi:10.1089/thy.2016.0457
- Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006; 91(7):2587–2591. doi:10.1210/jc.2005-1603
- Panesar NS, Li CY, Rogers MS. Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 2001; 38(pt 4):329–332. doi:10.1258/0004563011900830
- Lepoutre T, Debieve F, Gruson D, Daumerie C. Reduction of miscarriages through universal screening and treatment of thyroid autoimmune diseases. Gynecol Obstet Invest 2012; 74(4):265–273. doi:10.1159/000343759
- De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97(8):2543–2565. doi:10.1210/jc.2011-2803
- Crawford NM, Steiner AZ. Thyroid autoimmunity and reproductive function. Semin Reprod Med 2016; 34(6):343–350. doi:10.1055/s-0036-1593485
- Maraka S, Ospina NM, O’Keeffe DT, et al. Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid 2016; 26(4):580–590. doi:10.1089/thy.2015.0418
- Wiles KS, Jarvis S, Nelson-Piercy C. Are we overtreating subclinical hypothyroidism in pregnancy? BMJ 2015; 351:h4726. doi:10.1136/bmj.h4726
- Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol 2012; 119(5):983–988. doi:10.1097/AOG.0b013e318250aeeb
- Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European Thyroid Association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014; 3(2):76–94. doi:10.1159/000362597
- Karakosta P, Alegakis D, Georgiou V, et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab 2012; 97(12):4464–4472. doi:10.1210/jc.2012-2540
- Toulis KA, Stagnaro-Green A, Negro R. Maternal subclinical hypothyroidsm and gestational diabetes mellitus: a meta-analysis. Endocr Pract 2014; 20(7):703–714. doi:10.4158/EP13440.RA
- van den Boogaard E, Vissenberg R, Land JA, et al. Significance of subclinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update 2011; 17(5):605–619. doi:10.1093/humupd/dmr024
- Wilson KL, Casey BM, McIntire DD, Halvorson LM, Cunningham FG. Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet Gynecol 2012; 119(2 Pt 1):315–320. doi:10.1097/AOG.0b013e318240de6a
- Ashoor G, Maiz N, Rotas M, Jawdat F, Nicolaides KH. Maternal thyroid function at 11 to 13 weeks of gestation and subsequent fetal death. Thyroid 2010; 20(9):989–993. doi:10.1089/thy.2010.0058
- Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105(2):239–245. doi:10.1097/01.AOG.0000152345.99421.22
- Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab 2010; 95(9):E44–E48. doi:10.1210/jc.2010-0340
- Su PY, Huang K, Hao JH, et al. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab 2011; 96(10):3234–3241. doi:10.1210/jc.2011-0274
- Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000; 7(3):127–130. doi:10.1136/jms.7.3.127
- Benhadi N, Wiersinga WM, Reitsma JB, Vrijkotte TG, Bonsel GJ. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 2009; 160(6):985–991. doi:10.1530/EJE-08-0953
- Korevaar TI, Medici M, de Rijke YB, et al. Ethnic differences in maternal thyroid parameters during pregnancy: the generation R study. J Clin Endocrinol Metab 2013; 98(9):3678–3686. doi:10.1210/jc.2013-2005
- Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008; 112(1):85–92. doi:10.1097/AOG.0b013e3181788dd7
- Li Y, Shan Z, Teng W, et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months. Clin Endocrinol (Oxf) 2010; 72(6):825–829. doi:10.1111/j.1365-2265.2009.03743.x
- Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341(8):549–555. doi:10.1056/NEJM199908193410801
- Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 2010; 95(9):4227–4234. doi:10.1210/jc.2010-0415
- Behrooz HG, Tohidi M, Mehrabi Y, Behrooz EG, Tehranidoost M, Azizi F. Subclinical hypothyroidism in pregnancy: intellectual development of offspring. Thyroid 2011; 21(10):1143–1147. doi:10.1089/thy.2011.0053
- Julvez J, Alvarez-Pedrerol M, Rebagliato M, et al. Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology 2013; 24(1):150–157. doi:10.1097/EDE.0b013e318276ccd3
- Casey BM, Thom EA, Peaceman AM, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 2017; 376(9):815–825. doi:10.1056/NEJMoa1606205
- Burns RB, Bates CK, Hartzband P, Smetana GW. Should we treat for subclinical hypothyroidism?: Grand rounds discussion from Beth Israel Deaconess Medical Center. Ann Intern Med 2016; 164(11):764–770. doi:10.7326/M16-0857
- Kucukler FK, Akbaba G, Arduc A, Simsek Y, Guler S. Evaluation of the common mistakes made by patients in the use of levothyroxine. Eur J Intern Med 2014; 25(9):e107–e108. doi:10.1016/j.ejim.2014.09.002
- McMillan M, Rotenberg KS, Vora K, et al. Comorbidities, concomitant medications, and diet as factors affecting levothyroxine therapy: results of the CONTROL surveillance project. Drugs R D 2016; 16(1):53–68. doi:10.1007/s40268-015-0116-6
- Pollock MA, Sturrock A, Marshall K, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: Randomised double blind placebo controlled crossover trial. BMJ 2001; 323(7318):891–895. pmid:11668132
- Peeters RP. Subclinical hypothyroidism. N Engl J Med 2017; 376(26):2556–2565. doi:10.1056/NEJMcp1611144
Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.
Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.
HIGH TSH, NORMAL FREE T4 LEVELS
Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T4).1
The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T4 and triiodothyronine (T3) levels go down even a little, TSH levels go up a lot.2
TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.3
WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?
The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.3
In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.4 Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.5
On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.
Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.7 The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.7,8
It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.3 Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,9 although higher TSH cutoffs for treatment are advised in elderly patients.10 Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.11
Authors of the NHANES III8 and Hanford Thyroid Disease study12 have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.
SUBCLINICAL HYPOTHYROIDISM IS COMMON
In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.1,8,13 The prevalence is higher in women and increases with age.8 It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.14 Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.8
A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.10,15
A VARIETY OF CAUSES
The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,2 in which thyroid peroxidase antibodies are usually present.2,16
Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.
SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS
“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.17 And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,18 although it has been reported to resolve spontaneously in half of cases within 2 years,19 typically in patients with TSH values of 4 to 6 mIU/L.20 The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.18
Figure 1 shows the natural history of subclinical hypothyroidism.1
GUIDELINES FOR SCREENING DIFFER
Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.
Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.23
The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.24
The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.25
The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.26
The American Academy of Family Physicians recommends screening after age 60.18
The American College of Physicians recommends screening patients over age 50 who have symptoms.18
Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.24
CLINICAL PRESENTATION
About 70% of patients with subclinical hypothyroidism have no symptoms.13
Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.27,28
Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.13
The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.29–31
In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.31 An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.
ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY
INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING
The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.118 Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.
The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.118,119
Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.
When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.
If the TSH is high-normal
It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.
Pollock et al121 found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.
However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.
Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.
If TSH is mildly elevated
The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.2 The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.
The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.
If TSH is higher than 10 mIU/L
Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.122
Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.
Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.
HIGH TSH, NORMAL FREE T4 LEVELS
Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T4).1
The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T4 and triiodothyronine (T3) levels go down even a little, TSH levels go up a lot.2
TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.3
WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?
The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.3
In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.4 Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.5
On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.
Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.7 The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.7,8
It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.3 Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,9 although higher TSH cutoffs for treatment are advised in elderly patients.10 Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.11
Authors of the NHANES III8 and Hanford Thyroid Disease study12 have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.
SUBCLINICAL HYPOTHYROIDISM IS COMMON
In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.1,8,13 The prevalence is higher in women and increases with age.8 It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.14 Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.8
A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.10,15
A VARIETY OF CAUSES
The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,2 in which thyroid peroxidase antibodies are usually present.2,16
Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.
SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS
“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.17 And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,18 although it has been reported to resolve spontaneously in half of cases within 2 years,19 typically in patients with TSH values of 4 to 6 mIU/L.20 The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.18
Figure 1 shows the natural history of subclinical hypothyroidism.1
GUIDELINES FOR SCREENING DIFFER
Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.
Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.23
The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.24
The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.25
The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.26
The American Academy of Family Physicians recommends screening after age 60.18
The American College of Physicians recommends screening patients over age 50 who have symptoms.18
Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.24
CLINICAL PRESENTATION
About 70% of patients with subclinical hypothyroidism have no symptoms.13
Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.27,28
Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.13
The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.29–31
In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.31 An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.
ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY
INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING
The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.118 Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.
The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.118,119
Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.
When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.
If the TSH is high-normal
It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.
Pollock et al121 found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.
However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.
Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.
If TSH is mildly elevated
The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.2 The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.
The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.
If TSH is higher than 10 mIU/L
Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.122
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- Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc 2009; 84(1):65–71. doi:10.4065/84.1.65
- Laurberg P, Andersen S, Carle A, Karmisholt J, Knudsen N, Pedersen IB. The TSH upper reference limit: where are we at? Nat Rev Endocrinol 2011; 7(4):232–239. doi:10.1038/nrendo.2011.13
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- Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 2007; 92(12):4575–4582. doi:10.1210/jc.2007-1499
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- Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 2014; 24(12):1670–1751. doi:10.1089/thy.2014.0028
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- Thvilum M, Brandt F, Brix TH, Hegedus L. A review of the evidence for and against increased mortality in hypothyroidism. Nat Rev Endocrinol 2012; 8(7):417–424. doi:10.1038/nrendo.2012.29
- Stott DJ, Rodondi N, Kearney PM, et al; TRUST Study Group. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med 2017; 376(26):2534–2544. doi:10.1056/NEJMoa1603825
- Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril 2015; 104(3):545–753. doi:10.1016/j.fertnstert.2015.05.028
- Stagnaro-Green A, Abalovich M, Alexander E, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21(10):1081–1125. doi:10.1089/thy.2011.0087
- Goldsmith RE, Sturgis SH, Lerman J, Stanbury JB. The menstrual pattern in thyroid disease. J Clin Endocrinol Metab. 1952; 12(7):846-855. doi:10.1210/jcem-12-7-846
- Plowden TC, Schisterman EF, Sjaarda LA, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab 2016; 101(6):2358–2365. doi:10.1210/jc.2016-1049
- Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017; 27(3):315–389. doi:10.1089/thy.2016.0457
- Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006; 91(7):2587–2591. doi:10.1210/jc.2005-1603
- Panesar NS, Li CY, Rogers MS. Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 2001; 38(pt 4):329–332. doi:10.1258/0004563011900830
- Lepoutre T, Debieve F, Gruson D, Daumerie C. Reduction of miscarriages through universal screening and treatment of thyroid autoimmune diseases. Gynecol Obstet Invest 2012; 74(4):265–273. doi:10.1159/000343759
- De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97(8):2543–2565. doi:10.1210/jc.2011-2803
- Crawford NM, Steiner AZ. Thyroid autoimmunity and reproductive function. Semin Reprod Med 2016; 34(6):343–350. doi:10.1055/s-0036-1593485
- Maraka S, Ospina NM, O’Keeffe DT, et al. Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid 2016; 26(4):580–590. doi:10.1089/thy.2015.0418
- Wiles KS, Jarvis S, Nelson-Piercy C. Are we overtreating subclinical hypothyroidism in pregnancy? BMJ 2015; 351:h4726. doi:10.1136/bmj.h4726
- Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol 2012; 119(5):983–988. doi:10.1097/AOG.0b013e318250aeeb
- Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European Thyroid Association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014; 3(2):76–94. doi:10.1159/000362597
- Karakosta P, Alegakis D, Georgiou V, et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab 2012; 97(12):4464–4472. doi:10.1210/jc.2012-2540
- Toulis KA, Stagnaro-Green A, Negro R. Maternal subclinical hypothyroidsm and gestational diabetes mellitus: a meta-analysis. Endocr Pract 2014; 20(7):703–714. doi:10.4158/EP13440.RA
- van den Boogaard E, Vissenberg R, Land JA, et al. Significance of subclinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update 2011; 17(5):605–619. doi:10.1093/humupd/dmr024
- Wilson KL, Casey BM, McIntire DD, Halvorson LM, Cunningham FG. Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet Gynecol 2012; 119(2 Pt 1):315–320. doi:10.1097/AOG.0b013e318240de6a
- Ashoor G, Maiz N, Rotas M, Jawdat F, Nicolaides KH. Maternal thyroid function at 11 to 13 weeks of gestation and subsequent fetal death. Thyroid 2010; 20(9):989–993. doi:10.1089/thy.2010.0058
- Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105(2):239–245. doi:10.1097/01.AOG.0000152345.99421.22
- Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab 2010; 95(9):E44–E48. doi:10.1210/jc.2010-0340
- Su PY, Huang K, Hao JH, et al. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab 2011; 96(10):3234–3241. doi:10.1210/jc.2011-0274
- Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000; 7(3):127–130. doi:10.1136/jms.7.3.127
- Benhadi N, Wiersinga WM, Reitsma JB, Vrijkotte TG, Bonsel GJ. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 2009; 160(6):985–991. doi:10.1530/EJE-08-0953
- Korevaar TI, Medici M, de Rijke YB, et al. Ethnic differences in maternal thyroid parameters during pregnancy: the generation R study. J Clin Endocrinol Metab 2013; 98(9):3678–3686. doi:10.1210/jc.2013-2005
- Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008; 112(1):85–92. doi:10.1097/AOG.0b013e3181788dd7
- Li Y, Shan Z, Teng W, et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months. Clin Endocrinol (Oxf) 2010; 72(6):825–829. doi:10.1111/j.1365-2265.2009.03743.x
- Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341(8):549–555. doi:10.1056/NEJM199908193410801
- Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 2010; 95(9):4227–4234. doi:10.1210/jc.2010-0415
- Behrooz HG, Tohidi M, Mehrabi Y, Behrooz EG, Tehranidoost M, Azizi F. Subclinical hypothyroidism in pregnancy: intellectual development of offspring. Thyroid 2011; 21(10):1143–1147. doi:10.1089/thy.2011.0053
- Julvez J, Alvarez-Pedrerol M, Rebagliato M, et al. Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology 2013; 24(1):150–157. doi:10.1097/EDE.0b013e318276ccd3
- Casey BM, Thom EA, Peaceman AM, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 2017; 376(9):815–825. doi:10.1056/NEJMoa1606205
- Burns RB, Bates CK, Hartzband P, Smetana GW. Should we treat for subclinical hypothyroidism?: Grand rounds discussion from Beth Israel Deaconess Medical Center. Ann Intern Med 2016; 164(11):764–770. doi:10.7326/M16-0857
- Kucukler FK, Akbaba G, Arduc A, Simsek Y, Guler S. Evaluation of the common mistakes made by patients in the use of levothyroxine. Eur J Intern Med 2014; 25(9):e107–e108. doi:10.1016/j.ejim.2014.09.002
- McMillan M, Rotenberg KS, Vora K, et al. Comorbidities, concomitant medications, and diet as factors affecting levothyroxine therapy: results of the CONTROL surveillance project. Drugs R D 2016; 16(1):53–68. doi:10.1007/s40268-015-0116-6
- Pollock MA, Sturrock A, Marshall K, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: Randomised double blind placebo controlled crossover trial. BMJ 2001; 323(7318):891–895. pmid:11668132
- Peeters RP. Subclinical hypothyroidism. N Engl J Med 2017; 376(26):2556–2565. doi:10.1056/NEJMcp1611144
KEY POINTS
- From 4% to 20% of adults have subclinical hypothyroidism, with a higher prevalence in women, older people, and those with thyroid autoimmunity.
- Subclinical hypothyroidism can progress to overt hypothyroidism, especially if antithyroid antibodies are present, and has been associated with adverse metabolic, cardiovascular, reproductive, maternal-fetal, neuromuscular, and cognitive abnormalities and lower quality of life.
- Some studies have suggested that levothyroxine therapy is beneficial, but others have not, possibly owing to variability in study designs, sample sizes, and patient populations.
- Further trials are needed to clearly demonstrate the clinical impact of subclinical hypothyroidism and the effect of levothyroxine therapy.
Managing malignant pleural effusion
Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,1–3 although prognosis varies considerably depending on the type and stage of the malignancy.
How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.
This article uses brief case presentations to review management strategies for malignant pleural effusion.
CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION
Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.4 Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.5 Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.6,7
A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION
An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.
Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.
What is the appropriate next step to manage this patient’s effusion?
Observation is reasonable
This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.5 For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.
It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.
If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.
A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE
A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.
How should this effusion be managed?
Indwelling pleural catheter placement
In a retrospective cohort study,8 malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.
In the absence of lung expansion, pleurodesis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.9
Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.
Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.
Indwelling pleural catheters are now initial therapy for many
Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.
Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.10–13
Davies et al14 randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.
Fysh et al15 also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.
Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).16 Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.17 And a systematic review18 found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.
Drainage rate may need to be moderated
Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.
A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS
A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.
One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.
What is the next step?
Chemical pleurodesis
Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,19 and practice patterns vary between institutions.
Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.19 However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.20,21
VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.
Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.
Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study22 comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).22 In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).23,24
A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS
A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.
On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.
His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.
What should be done for him?
Thoracentesis, repeat as needed
Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.25
Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.26 Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.
- Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ; BTS Pleural Disease Guideline Group. Management of a malignant pleural effusion: British Thoracic Society pleural disease guideline 2010. Thorax 2010; 65(suppl 2):ii32–ii40. doi:10.1136/thx.2010.136994
- Ruckdeschel JC. Management of malignant pleural effusions. Semin Oncol 1995; 22(2 suppl 3):58–63. pmid:7740322
- Bielsa S, Martín-Juan J, Porcel JM, Rodríguez-Panadero F. Diagnostic and prognostic implications of pleural adhesions in malignant effusions. J Thorac Oncol 2008; 3(11):1251–1256. doi:10.1097/JTO.0b013e318189f53d
- 35th Annual meeting of the European Association for the Study of Diabetes. Brussels, Belgium, 28 September–2 October, 1999. Abstracts. Diabetologia 1999;42(suppl 1):A1–A354. pmid:10505080
- Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J 2001; 18(2):402–419. pmid:11529302
- Sahn SA. Malignancy metastatic to the pleura. Clin Chest Med 1998; 19(2):351–361. pmid:9646986
- Sahn SA. Pleural diseases related to metastatic malignancies. Eur Respir J 1997; 10(8):1907–1913. pmid:9272937
- Anderson CB, Philpott GW, Ferguson TB. The treatment of malignant pleural effusions. Cancer 1974; 33(4):916–922. pmid:4362107
- Uzbeck MH, Almeida FA, Sarkiss MG, et al. Management of malignant pleural effusions. Adv Ther 2010; 27(6):334–347. doi:10.1007/S12325-010-0031-8
- Suzuki K, Servais EL, Rizk NP, et al. Palliation and pleurodesis in malignant pleural effusion: the role for tunneled pleural catheters. J Thorac Oncol 2011; 6(4):762–767. doi:10.1097/JTO.0b013e31820d614f
- Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest 2006; 129(2):362–368. doi:10.1378/chest.129.2.362
- Warren WH, Kalimi R, Khodadadian LM, Kim AW. Management of malignant pleural effusions using the Pleur(x) catheter. Ann Thorac Surg 2008; 85(3):1049–1055 doi:10.1016/j.athoracsur.2007.11.039
- Murthy SC, Okereke I, Mason DP, Rice TW. A simple solution for complicated pleural effusions. J Thorac Oncol 2006; 1(7):697–700. pmid:17409939
- Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA 2012; 307(22):2383–2389. doi:10.1001/jama.2012.5535
- Fysh ETH, Waterer GW, Kendall PA, et al. Indwelling pleural catheters reduce inpatient days over pleurodesis for malignant pleural effusion. Chest 2012; 142(2):394–400. doi:10.1378/chest.11-2657
- Olfert JA, Penz ED, Manns BJ, et al. Cost-effectiveness of indwelling pleural catheter compared with talc in malignant pleural effusion. Respirology 2017; 22(4):764–770. doi:10.1111/resp.12962
- Morel A, Mishra E, Medley L, et al. Chemotherapy should not be withheld from patients with an indwelling pleural catheter for malignant pleural effusion. Thorax 2011; 66(5):448–449. doi:10.1136/thx.2009.133504
- Van Meter MEM, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med 2011; 26(1):70–76. doi:10.1007/s11606-010-1472-0
- Lee YCG, Baumann MH, Maskell NA, et al. Pleurodesis practice for malignant pleural effusions in five English-speaking countries. Chest 2003; 124(6):2229–2238. pmid:14665505
- Villanueva AG, Gray AW Jr, Shahian DM, Williamson WA, Beamis JF Jr. Efficacy of short term versus long term tube thoracostomy drainage before tetracycline pleurodesis in the treatment of malignant pleural effusions. Thorax 1994; 49(1):23–25. pmid:7512285
- Sartori S, Tombesi P, Tassinari D, et al. Sonographically guided small-bore chest tubes and sonographic monitoring for rapid sclerotherapy of recurrent malignant pleural effusions. J Ultrasound Med 2004; 23(9):1171–1176. pmid:15328431
- Mineo TC, Sellitri F, Tacconi F, Ambrogi V. Quality of life and outcomes after nonintubated versus intubated video-thoracoscopic pleurodesis for malignant pleural effusion: comparison by a case-matched study. J Palliat Med 2014; 17(7):761–768. doi:10.1089/jpm.2013.0617
- Michaud G, Berkowitz DM, Ernst A. Pleuroscopy for diagnosis and therapy for pleural effusions. Chest 2010; 138(5):1242–1246. doi:10.1378/chest.10-1259
- Bhatnagar R, Maskell NA. Medical pleuroscopy. Clin Chest Med 2013; 34(3):487–500. doi:10.1016/j.ccm.2013.04.001
- Pilling JE, Dusmet ME, Ladas G, Goldstraw P. Prognostic factors for survival after surgical palliation of malignant pleural effusion. J Thorac Oncol 2010; 5(10):1544–1550. doi:10.1097/JTO.0b013e3181e95cb8
- Beyea A, Winzelberg G, Stafford RE. To drain or not to drain: an evidence-based approach to palliative procedures for the management of malignant pleural effusions. J Pain Symptom Manage 2012; 44(2):301–306. doi:10.1016/j.jpainsymman.2012.05.002
Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,1–3 although prognosis varies considerably depending on the type and stage of the malignancy.
How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.
This article uses brief case presentations to review management strategies for malignant pleural effusion.
CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION
Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.4 Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.5 Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.6,7
A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION
An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.
Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.
What is the appropriate next step to manage this patient’s effusion?
Observation is reasonable
This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.5 For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.
It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.
If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.
A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE
A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.
How should this effusion be managed?
Indwelling pleural catheter placement
In a retrospective cohort study,8 malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.
In the absence of lung expansion, pleurodesis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.9
Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.
Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.
Indwelling pleural catheters are now initial therapy for many
Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.
Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.10–13
Davies et al14 randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.
Fysh et al15 also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.
Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).16 Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.17 And a systematic review18 found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.
Drainage rate may need to be moderated
Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.
A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS
A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.
One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.
What is the next step?
Chemical pleurodesis
Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,19 and practice patterns vary between institutions.
Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.19 However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.20,21
VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.
Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.
Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study22 comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).22 In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).23,24
A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS
A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.
On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.
His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.
What should be done for him?
Thoracentesis, repeat as needed
Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.25
Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.26 Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.
Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,1–3 although prognosis varies considerably depending on the type and stage of the malignancy.
How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.
This article uses brief case presentations to review management strategies for malignant pleural effusion.
CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION
Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.4 Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.5 Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.6,7
A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION
An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.
Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.
What is the appropriate next step to manage this patient’s effusion?
Observation is reasonable
This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.5 For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.
It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.
If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.
A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE
A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.
How should this effusion be managed?
Indwelling pleural catheter placement
In a retrospective cohort study,8 malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.
In the absence of lung expansion, pleurodesis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.9
Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.
Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.
Indwelling pleural catheters are now initial therapy for many
Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.
Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.10–13
Davies et al14 randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.
Fysh et al15 also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.
Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).16 Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.17 And a systematic review18 found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.
Drainage rate may need to be moderated
Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.
A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS
A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.
One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.
What is the next step?
Chemical pleurodesis
Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,19 and practice patterns vary between institutions.
Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.19 However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.20,21
VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.
Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.
Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study22 comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).22 In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).23,24
A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS
A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.
On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.
His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.
What should be done for him?
Thoracentesis, repeat as needed
Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.25
Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.26 Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.
- Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ; BTS Pleural Disease Guideline Group. Management of a malignant pleural effusion: British Thoracic Society pleural disease guideline 2010. Thorax 2010; 65(suppl 2):ii32–ii40. doi:10.1136/thx.2010.136994
- Ruckdeschel JC. Management of malignant pleural effusions. Semin Oncol 1995; 22(2 suppl 3):58–63. pmid:7740322
- Bielsa S, Martín-Juan J, Porcel JM, Rodríguez-Panadero F. Diagnostic and prognostic implications of pleural adhesions in malignant effusions. J Thorac Oncol 2008; 3(11):1251–1256. doi:10.1097/JTO.0b013e318189f53d
- 35th Annual meeting of the European Association for the Study of Diabetes. Brussels, Belgium, 28 September–2 October, 1999. Abstracts. Diabetologia 1999;42(suppl 1):A1–A354. pmid:10505080
- Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J 2001; 18(2):402–419. pmid:11529302
- Sahn SA. Malignancy metastatic to the pleura. Clin Chest Med 1998; 19(2):351–361. pmid:9646986
- Sahn SA. Pleural diseases related to metastatic malignancies. Eur Respir J 1997; 10(8):1907–1913. pmid:9272937
- Anderson CB, Philpott GW, Ferguson TB. The treatment of malignant pleural effusions. Cancer 1974; 33(4):916–922. pmid:4362107
- Uzbeck MH, Almeida FA, Sarkiss MG, et al. Management of malignant pleural effusions. Adv Ther 2010; 27(6):334–347. doi:10.1007/S12325-010-0031-8
- Suzuki K, Servais EL, Rizk NP, et al. Palliation and pleurodesis in malignant pleural effusion: the role for tunneled pleural catheters. J Thorac Oncol 2011; 6(4):762–767. doi:10.1097/JTO.0b013e31820d614f
- Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest 2006; 129(2):362–368. doi:10.1378/chest.129.2.362
- Warren WH, Kalimi R, Khodadadian LM, Kim AW. Management of malignant pleural effusions using the Pleur(x) catheter. Ann Thorac Surg 2008; 85(3):1049–1055 doi:10.1016/j.athoracsur.2007.11.039
- Murthy SC, Okereke I, Mason DP, Rice TW. A simple solution for complicated pleural effusions. J Thorac Oncol 2006; 1(7):697–700. pmid:17409939
- Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA 2012; 307(22):2383–2389. doi:10.1001/jama.2012.5535
- Fysh ETH, Waterer GW, Kendall PA, et al. Indwelling pleural catheters reduce inpatient days over pleurodesis for malignant pleural effusion. Chest 2012; 142(2):394–400. doi:10.1378/chest.11-2657
- Olfert JA, Penz ED, Manns BJ, et al. Cost-effectiveness of indwelling pleural catheter compared with talc in malignant pleural effusion. Respirology 2017; 22(4):764–770. doi:10.1111/resp.12962
- Morel A, Mishra E, Medley L, et al. Chemotherapy should not be withheld from patients with an indwelling pleural catheter for malignant pleural effusion. Thorax 2011; 66(5):448–449. doi:10.1136/thx.2009.133504
- Van Meter MEM, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med 2011; 26(1):70–76. doi:10.1007/s11606-010-1472-0
- Lee YCG, Baumann MH, Maskell NA, et al. Pleurodesis practice for malignant pleural effusions in five English-speaking countries. Chest 2003; 124(6):2229–2238. pmid:14665505
- Villanueva AG, Gray AW Jr, Shahian DM, Williamson WA, Beamis JF Jr. Efficacy of short term versus long term tube thoracostomy drainage before tetracycline pleurodesis in the treatment of malignant pleural effusions. Thorax 1994; 49(1):23–25. pmid:7512285
- Sartori S, Tombesi P, Tassinari D, et al. Sonographically guided small-bore chest tubes and sonographic monitoring for rapid sclerotherapy of recurrent malignant pleural effusions. J Ultrasound Med 2004; 23(9):1171–1176. pmid:15328431
- Mineo TC, Sellitri F, Tacconi F, Ambrogi V. Quality of life and outcomes after nonintubated versus intubated video-thoracoscopic pleurodesis for malignant pleural effusion: comparison by a case-matched study. J Palliat Med 2014; 17(7):761–768. doi:10.1089/jpm.2013.0617
- Michaud G, Berkowitz DM, Ernst A. Pleuroscopy for diagnosis and therapy for pleural effusions. Chest 2010; 138(5):1242–1246. doi:10.1378/chest.10-1259
- Bhatnagar R, Maskell NA. Medical pleuroscopy. Clin Chest Med 2013; 34(3):487–500. doi:10.1016/j.ccm.2013.04.001
- Pilling JE, Dusmet ME, Ladas G, Goldstraw P. Prognostic factors for survival after surgical palliation of malignant pleural effusion. J Thorac Oncol 2010; 5(10):1544–1550. doi:10.1097/JTO.0b013e3181e95cb8
- Beyea A, Winzelberg G, Stafford RE. To drain or not to drain: an evidence-based approach to palliative procedures for the management of malignant pleural effusions. J Pain Symptom Manage 2012; 44(2):301–306. doi:10.1016/j.jpainsymman.2012.05.002
- Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ; BTS Pleural Disease Guideline Group. Management of a malignant pleural effusion: British Thoracic Society pleural disease guideline 2010. Thorax 2010; 65(suppl 2):ii32–ii40. doi:10.1136/thx.2010.136994
- Ruckdeschel JC. Management of malignant pleural effusions. Semin Oncol 1995; 22(2 suppl 3):58–63. pmid:7740322
- Bielsa S, Martín-Juan J, Porcel JM, Rodríguez-Panadero F. Diagnostic and prognostic implications of pleural adhesions in malignant effusions. J Thorac Oncol 2008; 3(11):1251–1256. doi:10.1097/JTO.0b013e318189f53d
- 35th Annual meeting of the European Association for the Study of Diabetes. Brussels, Belgium, 28 September–2 October, 1999. Abstracts. Diabetologia 1999;42(suppl 1):A1–A354. pmid:10505080
- Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J 2001; 18(2):402–419. pmid:11529302
- Sahn SA. Malignancy metastatic to the pleura. Clin Chest Med 1998; 19(2):351–361. pmid:9646986
- Sahn SA. Pleural diseases related to metastatic malignancies. Eur Respir J 1997; 10(8):1907–1913. pmid:9272937
- Anderson CB, Philpott GW, Ferguson TB. The treatment of malignant pleural effusions. Cancer 1974; 33(4):916–922. pmid:4362107
- Uzbeck MH, Almeida FA, Sarkiss MG, et al. Management of malignant pleural effusions. Adv Ther 2010; 27(6):334–347. doi:10.1007/S12325-010-0031-8
- Suzuki K, Servais EL, Rizk NP, et al. Palliation and pleurodesis in malignant pleural effusion: the role for tunneled pleural catheters. J Thorac Oncol 2011; 6(4):762–767. doi:10.1097/JTO.0b013e31820d614f
- Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest 2006; 129(2):362–368. doi:10.1378/chest.129.2.362
- Warren WH, Kalimi R, Khodadadian LM, Kim AW. Management of malignant pleural effusions using the Pleur(x) catheter. Ann Thorac Surg 2008; 85(3):1049–1055 doi:10.1016/j.athoracsur.2007.11.039
- Murthy SC, Okereke I, Mason DP, Rice TW. A simple solution for complicated pleural effusions. J Thorac Oncol 2006; 1(7):697–700. pmid:17409939
- Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA 2012; 307(22):2383–2389. doi:10.1001/jama.2012.5535
- Fysh ETH, Waterer GW, Kendall PA, et al. Indwelling pleural catheters reduce inpatient days over pleurodesis for malignant pleural effusion. Chest 2012; 142(2):394–400. doi:10.1378/chest.11-2657
- Olfert JA, Penz ED, Manns BJ, et al. Cost-effectiveness of indwelling pleural catheter compared with talc in malignant pleural effusion. Respirology 2017; 22(4):764–770. doi:10.1111/resp.12962
- Morel A, Mishra E, Medley L, et al. Chemotherapy should not be withheld from patients with an indwelling pleural catheter for malignant pleural effusion. Thorax 2011; 66(5):448–449. doi:10.1136/thx.2009.133504
- Van Meter MEM, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med 2011; 26(1):70–76. doi:10.1007/s11606-010-1472-0
- Lee YCG, Baumann MH, Maskell NA, et al. Pleurodesis practice for malignant pleural effusions in five English-speaking countries. Chest 2003; 124(6):2229–2238. pmid:14665505
- Villanueva AG, Gray AW Jr, Shahian DM, Williamson WA, Beamis JF Jr. Efficacy of short term versus long term tube thoracostomy drainage before tetracycline pleurodesis in the treatment of malignant pleural effusions. Thorax 1994; 49(1):23–25. pmid:7512285
- Sartori S, Tombesi P, Tassinari D, et al. Sonographically guided small-bore chest tubes and sonographic monitoring for rapid sclerotherapy of recurrent malignant pleural effusions. J Ultrasound Med 2004; 23(9):1171–1176. pmid:15328431
- Mineo TC, Sellitri F, Tacconi F, Ambrogi V. Quality of life and outcomes after nonintubated versus intubated video-thoracoscopic pleurodesis for malignant pleural effusion: comparison by a case-matched study. J Palliat Med 2014; 17(7):761–768. doi:10.1089/jpm.2013.0617
- Michaud G, Berkowitz DM, Ernst A. Pleuroscopy for diagnosis and therapy for pleural effusions. Chest 2010; 138(5):1242–1246. doi:10.1378/chest.10-1259
- Bhatnagar R, Maskell NA. Medical pleuroscopy. Clin Chest Med 2013; 34(3):487–500. doi:10.1016/j.ccm.2013.04.001
- Pilling JE, Dusmet ME, Ladas G, Goldstraw P. Prognostic factors for survival after surgical palliation of malignant pleural effusion. J Thorac Oncol 2010; 5(10):1544–1550. doi:10.1097/JTO.0b013e3181e95cb8
- Beyea A, Winzelberg G, Stafford RE. To drain or not to drain: an evidence-based approach to palliative procedures for the management of malignant pleural effusions. J Pain Symptom Manage 2012; 44(2):301–306. doi:10.1016/j.jpainsymman.2012.05.002
KEY POINTS
- Asymptomatic pleural effusion in patients currently on chemotherapy does not require treatment but should be monitored for progression.
- Indwelling pleural catheters are best used to treat effusion with lung collapse and are increasingly used as first-line therapy in other settings.
- Chemical or mechanical pleurodesis results in filling the pleural space to prevent further fluid accumulation and can be accomplished by one of several methods.
- For patients near the end of life, simple thoracentesis, repeated as needed, is a reasonable strategy.
Breast augmentation surgery: Clinical considerations
At present, 300,000 US women undergo breast augmentation surgery each year,1 making this the second most common aesthetic procedure in women (after liposuction),2–4 and making it extremely likely that clinicians will encounter women who have breast implants. In addition, approximately 110,000 women undergo breast reconstructive surgery after mastectomy, of whom more than 88,000 (81%) receive implants (2016 data).5
This review discusses the evolution of breast implants, their complications, and key considerations with regard to aesthetic and reconstructive breast surgery, as the principles are similar.
EVOLUTION OF IMPLANTS
Reports of breast augmentation surgery, also known as augmentation mammoplasty, date back to 1895, when a fatty tumor (lipoma) was successfully transplanted from a patient’s back to a breast defect in a mastectomy patient.2,3,6,7 In the 1930s, implantation of a glass ball into a patient’s breast marked the first implant-based breast augmentation.6 By 1954, attempts at breast augmentation using local dermal-fat flaps, adipose tissue, and even omentum were described.
Alloplastic materials gained popularity throughout the 1950s and 1960s and included polyurethane, polytetrafluoroethylene (Teflon), and other synthetics. Adverse reactions associated with alloplastic materials were plentiful: local tissue reactions, distortion of the breast mound, increased firmness, and discomfort all contributed to the eventual discontinuation of their use. The history of alloplastic breast augmentation also included epoxy resin, shellac, beeswax, paraffin, rubber, petroleum jelly, and liquefied silicone. Outcomes were not good, and many patients ultimately needed mastectomy.7
The first modern breast prosthesis was developed in 1961, and since then, implant composition and design have evolved significantly.8
From silicone to saline, and back again
The first silicone gel implants, introduced in the early 1960s,8–19 had high complication rates—some centers reported an incidence of capsular contracture of up to 70%.8,11 This is a foreign body reaction in which pathologic scar tissue encases the implant, causing it to distort, appear misshapen, harden, and even become painful.11 Attempts to minimize this reaction led to later generations of silicone implants with polyurethane shells.12
Inflatable implants filled with sterile saline solution were originally developed in France in 1965. Unlike silicone implants, saline implants have undergone minimal changes since their inception, and grew in popularity during the 1970s in view of the high rates of capsular contracture with silicone implants.8 However, saline implants have their own problems, and as they became increasingly popular, deflation and the unnatural feel of saline sparked a renewed interest in silicone gel.
By the late 1980s, the thinner-shelled generation of silicone implants displayed its own frustrating complications including implant rupture, capsular contracture, infection, and possible systemic and disseminated granulomatous disease. From 1992 to 2006, the US Food and Drug Administration (FDA) placed a moratorium on silicone implants due to concerns about a possible link with autoimmune and connective tissue diseases and the possible carcinogenic nature of silicone.
While silicone implants were prohibited in the United States, development continued abroad, and eventually the moratorium was lifted after several meta-analyses failed to reveal any link regarding the aforementioned concerns.13
Today, silicone gel implants dominate the world market.14 In the United States, approximately 60% of implants contain silicone gel filler, and trends are similar in Europe.7
Table 1 summarizes the evolution of silicone breast implants over the last 50 years.2,6,11,12Table 2 lists the advantages and disadvantages of silicone and saline breast implants.2,6,8,15
CURRENT IMPLANT OPTIONS
Currently, 3 companies (Allergan, Mentor, Sientra) manufacture and distribute breast implants and implant-associated products such as tissue expanders and sizers in the US market.6
Another company, Motiva, makes an implant that is available in Europe, Asia, and Australia, and the device is currently undergoing a 10-year clinical trial in the United States that began recruiting patients in 16 centers in April 2018.16 Pending final approval, the Cleveland Clinic Department of Plastic Surgery may be among the centers involved in the clinical trial of the Motiva implant. Innovations in the Motiva implant include a high-performance shell that maintains consistent strength and includes a proprietary barrier layer, improved silicone gel filler, 3-D imprinted surface texturing, and an implant shape that adapts with vertical and horizontal movement. It also contains radio-frequency identification transponders that can transmit data about the implant wirelessly.17–19
Surface (textured vs smooth)
Developed in the 1980s, texturing of the implant surface disrupts capsule formation around the prosthesis. Additionally, texturing stabilizes an anatomically shaped (teardrop) implant within the breast pocket, reducing malrotation.20,21
The first textured implants were covered with polyurethane foam, but they were ultimately withdrawn from the US market because of concern for in vivo degradation to carcinogenic compounds. The focus subsequently turned to texturing implant shells by mechanically creating pores of different sizes. Smooth implants, by contrast, are manufactured by repeatedly dipping the implant shell into liquid silicone.2
The capsular contraction rate has been shown to be lower with textured silicone than with smooth silicone (number needed to treat = 7–9), and evidence suggests a lower risk of needing a secondary procedure.21
Form-stable vs fluid-form
Silicone is a polymer. The physical properties of polymers vary greatly and depend on the length of the individual chains and the degree to which those chains are cross-linked. Liquid silicone contains short chains and sparse cross-linking, resulting in an oily compound well suited for lubrication. Silicone gel contains longer chains and more cross-linking and is therefore more viscous.
In “form-stable” implants, the silicone interior has sufficient chain length and cross-linking to retain the designed shape even at rest,2 but they require slightly larger incisions.7 “Fluid-form” refers to an implant with silicone filler with shorter chain length, less cross-linking, and more fluidity.6
Shell
As with silicone fillers, the properties of silicone implant shells also depend on chain length and cross-linking within the polymer. Silicone elastomer shells (Table 1) contain extensively cross-linked chains that impart a flexible yet rubbery character. Silicone elastomers can also be found in facial implants and tissue expanders.2
Implant shape (round vs anatomic)
The shape of an implant is determined by the gel distribution inside of it. To understand gel distribution and implant shape, one must understand the gel-shell ratio. This ratio increases as cohesivity of the filler increases, and it represents increased bonding of the gel filler to the shell and a preserved implant shape at rest.
The gel-shell ratio varies among manufacturers, and a less-viscous filler may be more prone to rippling or loss of upper pole fullness in some patients. For this reason, careful analysis, patient and implant selection, and discussion of complications remain paramount.2
No anatomically shaped implant is manufactured with a smooth shell, but rather with a textured shell that resists malrotation.6,15 However, in the United States, 95% of patients receive round implants.16
PATIENT ASSESSMENT
Before breast augmentation surgery, the surgeon assesses a number of factors—physical and psychosocial—and helps the patient choose a type and size of implant. The surgeon and patient also plan where the implants will be placed—ie, above or beneath the chest wall muscle—and where the incisions will be made. Every decision is made in close consultation with the patient, taking into account the patient’s desires and expectations, as well as what the patient’s anatomy allows. An integral component of this shared decision-making process is a discussion of the possible complications, and often photographs to better illustrate what to expect postoperatively.
Psychosocial factors
One must consider the patient’s psychology, motivations for surgery, and emotional stability. Here, we look for underlying body dysmorphic disorder; excessive or unusual encouragement to undergo the procedure by a spouse, friends, or others; a history of other aesthetic procedures; unrealistic expectations; and other factors influencing the desire to undergo this surgery.
Choosing an implant
Implant selection must take into account the patient’s height, weight,7 and overall body morphology: taller patients and those with wider hips or shoulders usually require larger implants. A reliable method for determining the appropriate implant must include the current breast shape, dimensions, volume, skin elasticity, soft-tissue thickness, and overall body habitus. Ultimately, the most important considerations include breast base diameter, implant volume,20 and soft-tissue envelope.
Preoperative sizing can involve placing sample implants within a brassiere so that the patient can preview possible outcomes. This method is particularly effective in minimizing dissatisfaction because it shares ownership of the decision-making process.15
A computerized implant selection program available in Europe suggests a “best-fit” implant based on a clinician’s measurements.7
Anatomic placement
Traditionally, plastic surgeons place breast implants either beneath the pectoralis major muscle (submuscular placement) or over the pectoralis8 but beneath the glandular breast parenchyma (subglandular placement) (Figure 2).7
Advantages of submuscular placement are a smoother transition of the upper breast pole from the chest wall and less rippling visible through the skin, due to the additional muscular coverage of the implant. Another advantage is that capsular contraction rates are lower with submuscular placement, likely due to possible contamination of implants by lactiferous ductal microbes when accessing the subglandular plane.14,20 Disadvantages are pronounced discomfort after surgery and animation deformities with muscle contraction, particularly in young, highly active patients.
A popular modification of submuscular placement involves creating a surgical dissection plane between the subglandular tissue and the pectoralis major fascia. This “dualplane” approach allows the parenchyma to retract superiorly and reduce breast ptosis.7
Incisions
Table 3 highlights important considerations with regard to incision location.15,20,21
ANTIBIOTICS
Many surgeons give a single prophylactic dose of antibiotic before surgery, a practice that some studies have shown to be effective in reducing the risk of infection.15 However, the benefit of routine postoperative use of antibiotics remains unsubstantiated15: postoperative antibiotic use does not appear to protect against infection, capsular contracture, or overall complications in primary or secondary breast augmentation surgery.20
PERIOPERATIVE PERIOD
At our institution, breast augmentation surgery is an ambulatory procedure—the patient goes home the same day unless circumstances such as pain control warrant admission. This is, however, according to surgeon preference, and differs on a case-by-case basis. General anesthesia is the standard of care.15
POSTOPERATIVE PERIOD
In the immediate postoperative period, patients are instructed to wear a surgical bra for up to 6 weeks to allow stable scarring. Early mobilization is encouraged.7,15 Depending on the patient’s situation, recovery, and healing, she may be out of work for about 1 week, sometimes more, sometimes less.
Additional instructions are surgeon-specific. However, the patient is instructed to avoid bathing, swimming, immersion in water, and wearing underwire brassieres that could impair healing of an inferior incision; instead, patients are often instructed to wear a surgical bra provided on the day of surgery until cleared in the clinic.
Showering is allowed the next day or the second day after surgery, and of course there is no driving while on narcotics. Additionally, patients are counseled extensively regarding hematoma formation and the signs and symptoms of infection.
Patients are typically seen in clinic 1 week after surgery.
The cost of surgery may be $5,000 to $6,000 but can vary significantly from center to center depending on who the patient sees and where, and whether the patient presents for breast reconstruction after cancer or repair of congenital anomalies, or in certain cases of transgender surgery. The patient is typically responsible for the fee, but again this depends on the patient, indications, and particular insurance concerns.
IMPLANT LONGEVITY AND RUPTURE
In the United States, implant rupture rates range from 1.1% to 17.7% at 6 to 10 years after primary augmentation, 2.9% to 14.7% after revision augmentation, 1.5% to 35.4% after primary breast reconstruction, and 0% to 19.6% after revision reconstruction.11
Unfortunately, the existence of multiple implant manufacturers, numerous implant generations, and poorly standardized screening protocols and reporting systems make the true rate of implant rupture difficult to assess without definitive imaging or implant retrieval.11
Damage from surgical instrumentation during implantation is the most common cause of silicone breast implant rupture (50% to 64% of cases).22 Other causes include underfilling and fold flaw from capsular contracture.
Leakage of silicone gel filler may be confined to the periprosthetic capsule (intracapsular rupture) or extend beyond and into the breast parenchyma (extracapsular rupture). One study reported that only 10% of intracapsular ruptures progressed extracapsularly, while 84% of patients with extracapsular involvement remained stable for up to 2 years,23 indicating that intracapsular rupture may not portend worsening disease.11
Implant rupture occurs silently in most cases, with no clinically detectable signs or symptoms. In other cases, patients may present with alterations in breast shape and size, sudden asymmetry, firmness, pronounced capsular contracture, contour irregularity, or pain.
Aside from physical examination, comprehensive diagnostic testing includes imaging—ultrasonography, mammography, computed tomography, and magnetic resonance imaging (MRI). Of these, MRI is the method of choice, with sensitivity and specificity exceeding 90% for detecting implant rupture.11 Classic findings on MRI include the “linguine” sign from a deflating implant shell, or the teardrop sign from implant sagging. Classic findings on ultrasonography include the “snowstorm” sign of extracapsular rupture and the “stepladder” sign of intracapsular rupture.
Mammography effectively detects free silicone in breast tissue with extracapsular rupture (25% of ruptures according to some studies)23; however, it cannot detect rupture within the implant capsule. As an aside, submuscular implant placement may interfere less with screening mammography than subglandular implants do.14,24
Current FDA recommendations to detect implant rupture encourage women with silicone breast implants to undergo screening 3 years after implantation and then every 2 years thereafter; no long-term monitoring is suggested for saline implants.15 Many plastic surgeons evaluate silicone breast implant patients every 1 to 2 years for contracture and rupture.8 Of note, capsular contracture impairs the effectiveness of ultrasonography and may require MRI confirmation.11
If implant rupture is confirmed, the current recommendation is to remove the implant and the capsule. Another implant may be placed depending on the patient’s preference. Rigorous washout remains a key feature of any surgical intervention for ruptured breast implants; however, in the event of extracapsular rupture, resection of silicone granulomas may also be required.11
Reoperation rates for primary breast augmentation surgery approach 20% and are even higher for secondary augmentation over a patient’s lifetime—the highest rate of all aesthetic procedures.7,14
CAPSULAR CONTRACTURE
Capsular contracture is the most common complication of breast augmentation,25 typically presenting within the first postoperative year,26,27 and the risk increases over time.28 It occurs with both silicone and saline breast implants.
In some studies, the incidence exceeded 4% in the first 2 years after surgery,29 and nearly 50% by 10 years.30 Other studies found rates of 0% to 20% over 13 years.20
The etiology is not well understood and is presumed to be multifactorial, with proposed mechanisms and factors that include bacterial contamination, surface texturing, the implant pocket selected, the incision type, drain placement, antibiotic use, and smoking.25
A meta-analysis from 17,000 implants found that the risk of capsular contracture was significantly higher when an implant was placed in a subglandular pocket than in a submuscular pocket,22,26 and that although texturing decreased capsular contracture compared with smooth implants, the effect was modest when a textured or smooth implant was placed in a submuscular location.28 With regard to incision location, studies have reported that the incidence of capsular contracture is highest with transaxillary and periareolar incisions, and lowest with inframammary incisions.20,21
The leading theory is that contamination of the implant (primarily from the mammary ducts) results in biofilm formation. Subclinical hematoma surrounding the implant may also provide key bacterial nutrients.20
Textured implants induce a greater inflammatory response in the capsular tissue, resulting in a thicker capsule; however, contracture rates remain lower with textured than with smooth implants.14,31 Interestingly, lower rates of capsular contracture have been observed with later-generation, cohesive-gel, form-stable implants than with those of earlier generations.12
Although more research is needed, silicone implants appear to confer a higher risk of capsular contracture than saline implants.14,20
Irrigating the breast pocket intraoperatively with triple antibiotic solution (bacitracin, cefazolin, and gentamicin) before placing the implant may decrease the capsular contracture rate.15,20
Treatments for capsular contracture include pocket modifications such as capsulotomy (making releasing, relaxing incisions in the scar capsule encasing the implant), capsulectomy (removing portions of or the entire capsule), and replacing the implant in the other pocket (ie, if the original implant was subglandular, the replacement is placed in the submuscular pocket). Patients who have contractures that fail to respond to these treatments may ultimately benefit from implant removal and autologous reconstruction (autoaugmentation) rather than implant replacement.32,33
ADDITIONAL COMPLICATIONS
Other complications include infection, malposition, rippling, seroma, hematoma, and sensory alterations.
Irrigation during the implantation procedure with a triple antibiotic solution consisting of bacitracin, gentamycin, and cephalexin in normal saline decreases infection and seroma rates.15,20,34
Some surgeons also choose to irrigate the pocket with a betadine solution, or to cleanse the skin with betadine and place sterile towels and redrape before inserting the implant. Additionally, many prefer using a sterile device much like a pastry funnel called a Keller funnel to insert the implant into the breast pocket.35
Infection is less common with cosmetic augmentations than with implant-based breast reconstruction, likely because of healthier, well-vascularized tissue in patients undergoing cosmetic surgery than in those undergoing mastectomy.14
Seroma is thought to be a consequence of texturing, and more so with macro- vs microtexturing. Though poorly understood, an association between texturing and double capsules has also been reported.12,20
After primary breast augmentation, 10-year follow-up rates of capsular contracture, seroma, rippling, and malposition vary across the 3 major silicone implant manufacturers.12 Hematoma and infection occur in less than 1% of primary augmentation patients.15
Malposition of the implant over time is less frequent with textured implants because of the higher coefficient of friction compared with smooth implants.6,8,15
Visible skin rippling may be a consequence of texturing and also of thin body habitus, eg, in patients with a body mass index less than 18.5 kg/m2. If the soft-tissue layer of the breast is thin, the natural rippling of smooth saline implant shells are more likely to show when placed in the subglandular pocket. Form-stable implants, by contrast, resist rippling.12,15
Large implants and extensive lateral dissection can cause alterations in nipple sensation and sensory loss within lower breast pole skin. Axillary incisions may traumatize or damage the intercostobrachial nerve, resulting in upper inner arm sensory aberrations.
Ultimately, the 10-year incidence of secondary surgery ranges from 0% to 36% and the 10-year incidence of capsular contracture ranges from 11% to 19%.15 Additional cosmetic complaints after augmentation with implants include enlargement of the areola and engorgement of breast veins.14
BREAST CANCER AND DETECTION
Patients with or without implants do not seem to differ with regard to breast cancer stage upon detection, tumor burden, recurrence, or survival. However, more patients with implants may present with palpable masses, invasive tumors, axillary metastasis, and falsely negative mammograms.
Breast implants may actually facilitate cancer detection on physical examination by providing a more dense or stable surface upon which to palpate the breast tissue. Although they do not necessarily impair mastectomy or breast reconstruction, they may result in an increased rate of revision surgery after breast conservation therapy.24,36 Mammography remains the standard of care for radiologic diagnosis but can be further supported by MRI and ultrasonography if necessary in patients with implants.
AUTOIMMUNE DISEASES
Although concerns persist, multiple studies have demonstrated the safety of fourth- and fifth-generation silicone breast implants with regard to autoimmune disease.7
In various clinical studies in mastectomy patients who underwent breast reconstruction with either silicone implants or autologous tissue, no difference was found with regard to the incidence of autoimmune diseases.2 Additionally, in meta-analyses of data from more than 87,000 women, no association was found between connective tissue disease and silicone breast implants.2,11 One study11,23 noted no increase in autoantibodies in patients with undamaged silicone implants vs patients who experienced rupture.
Studies have also demonstrated that in children born to mothers with breast implants, the risk of rheumatic disease, esophageal disorders, congenital malformations, and death during the perinatal period is comparable with that in controls.37 Another study, examining breastfeeding in women with silicone breast implants, showed no significant difference in silicon levels (used as a proxy for silicone) in breast milk compared with controls without implants; silicon levels were found to be significantly higher in cow’s milk and store-bought formulas.38
BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE-CELL LYMPHOMA
Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma that develops in tissue adjacent to breast implants. It typically presents as breast swelling 2 to 38 years (mean of 8 years) after implant insertion.39,40 The swelling may be secondary to periprosthetic seroma formation or, more rarely, palpable disease in the axilla. Patients occasionally complain of pain and, rarely, constitutional symptoms.20 BIA-ALCL is not a disease of the surrounding breast tissue, but rather of the fibrous periprosthetic capsule.21
Of note, there is no documented case involving smooth implants,41–43 but it may be related to fifth-generation textured implants.6 At present, it is not possible to definitively state which implant is associated with this condition; hence, more data are needed, and this association is currently under study.
The absolute risk of BIA-ALCL was reported in a Dutch study39 as 1 in 35,000 by age 50, 1 in 12,000 by age 70, and 1 in 7,000 by age 75, with a number needed to harm of 6,920. Overall lifetime risk was estimated at 1 in 30,000 for women with textured implants in a 2015 US study.40 In comparison, breast cancer risk is about 1 in 8 women. There is no apparent predilection for patients who underwent cosmetic augmentation vs reconstruction, or who received silicone vs saline implants.
The diagnosis is confirmed by ultrasonographically guided fine-needle aspiration of seroma fluid and subsequent immunohistochemical testing for CD30-positive and ALK-negative T lymphocytes. Other than positron-emission tomography for staging after diagnosis confirmation, imaging is ineffective. Expert opinion does not recommend routine screening unless the aforementioned symptoms arise.
Treatment involves implant removal and total capsulectomy, with samples sent for pathology study with cytokeratin staining.12 Of note, in all cases of BIA-ALCL in which the disease was limited to the circumscribed scar tissue of the breast capsule, complete surgical excision has proved curative, whereas incomplete capsulectomy portends a greater risk of recurrence and decreased survival.44
In cases of advanced or recurrent ALCL, diagnosed late or inappropriately, the National Comprehensive Cancer Network recommends a multidisciplinary approach involving adjuvant chemotherapy and radiation.44 Anecdotally, at our institution, we have recently treated several cases of advanced ALCL presenting with invasive chest wall masses with extirpative surgery and subsequent reconstruction with the assistance of our thoracic surgery colleagues, as well as the aforementioned multidisciplinary approach using adjuvant therapy.
The mechanism of this malignancy is currently under investigation, but the current theory implicates an exaggerated lymphoproliferative response to bacterial contamination of the capsule superimposed upon genetic factors in susceptible patients.42,43
National societies advise plastic surgeons to discuss the risk of BIA-ALCL with all patients at the time of breast augmentation consultation and to report all confirmed cases to the PROFILE registry (Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology).45
ARE PATIENTS HAPPIER AFTERWARD?
Studies have shown that after undergoing breast augmentation surgery, patients note improvement in body image, and satisfaction rates range from 85% to 95% with respect to self-confidence and body image.46 An evaluation of patient responses on the validated BREAST-Q Augmentation Questionnaire showed the following satisfaction rates: breasts 83%, psychosocial well-being 88%, and sexual functioning 81%.15
Although epidemiologic studies have reported higher suicide rates in women with cosmetic breast implants, this likely stems from preoperative psychological factors and underscores the role of psychiatric referral in patients with a mental health history or in those whom the surgeon deems it necessary.46
Several high-quality studies have demonstrated that quality of life and psychosocial functioning (including depression) markedly improve after breast augmentation surgery.47 Among a cohort of Norwegian patients, breast implant surgery resulted in improved motivation to perform daily activities, as well as improved quality of life from both a psychosocial and aesthetic perspective.48 Interestingly, a recent study reported that patients who underwent breast implant surgery alone reported greater satisfaction and psychosocial quality of life than patients who underwent combination breast augmentation and mastopexy (breast-lifting) surgery.49
Additional data are needed to refine our understanding of the complex interplay between psychosocial factors before and after surgery in patients seeking and undergoing breast augmentation procedures.
- Derby BM, Codner MA. Textured silicone breast implant use in primary augmentation: core data update and review. Plast Reconstr Surg 2015; 135(1):113–124. doi:10.1097/PRS.0000000000000832
- Maxwell GP, Gabriel A. Breast implant design. Gland Surg 2017; 6(2):148–153. doi:10.21037/gs.2016.11.09
- Gabriel A, Maxwell GP. The evolution of breast implants. Clin Plast Surg 2015; 42(4):399–404. doi:10.1016/j.cps.2015.06.015
- American Society of Plastic Surgeons. Procedural statistics trends 1992–2012. www.plasticsurgery.org/documents/News/Statistics/2012/plastic-surgery-statistics-full-report-2012.pdf. Accessed January 17, 2019.
- American Society of Plastic Surgeons. Plastic surgery statistics report 2016. www.plasticsurgery.org/documents/News/Statistics/2016/plastic-surgery-statistics-full-report-2016.pdf. Accessed January 17, 2019.
- Henderson PW, Nash D, Laskowski M, Grant RT. Objective comparison of commercially available breast implant devices. Aesthetic Plast Surg 2015; 39(5):724–732. doi:10.1007/s00266-015-0537-1
- Adams WP Jr, Mallucci P. Breast augmentation. Plast Reconstr Surg 2012; 130(4):597e–611e. doi:10.1097/PRS.0b013e318262f607
- Spear SL, Jespersen MR. Breast implants: saline or silicone? Aesthet Surg J 2010; 30(4):557–570. doi:10.1177/1090820X10380401
- Cronin TD, Gerow FJ. Augmentation mammaplasty: a new “natural feel” prosthesis. In: Transactions of the Third International Conference of Plastic Surgery: October 13–18, 1963, Washington, DC.
- Maxwell GP, Gabriel A. The evolution of breast implants. Plast Reconstr Surg 2014; 134(suppl 1):12S–17S. doi:10.1097/PRS.0000000000000348
- Hillard C, Fowler JD, Barta R, Cunningham B. Silicone breast implant rupture: a review. Gland Surg 2017; 6(2):163–168. doi:10.21037/gs.2016.09.12
- Derby BM, Codner MA. Textured silicone breast implant use in primary augmentation: core data update and review. Plast Reconstr Surg 2015; 135(1):113–124. doi:10.1097/PRS.0000000000000832
- Tugwell P, Wells G, Peterson J, et al. Do silicone breast implants cause rheumatologic disorders? A systematic review for a court-appointed national science panel. Arthritis Rheum 2001; 44(11):2477–2484. pmid:11710703
- Alpert BS, Lalonde DH. MOC-PS(SM) CME article: breast augmentation. Plast Reconstr Surg 2008; 121(suppl 4):1–7. doi:10.1097/01.prs.0000305933.31540.5d
- Hidalgo DA, Spector JA. Breast augmentation. Plast Reconstr Surg 2014; 133(4):567e–583e. doi:10.1097/PRS.0000000000000033
- ClinicalTrials.gov. Study of the safety and effectiveness of Motiva Implants®. https://clinicaltrials.gov/ct2/show/NCT03579901. Accessed January 17, 2019.
- Establishment Labs. Motiva Implants. https://motivaimplants.com/why-motiva/innovation-for-enhanced-safety/. Accessed January 17, 2019.
- Sforza M, Zaccheddu R, Alleruzzo A, et al. Preliminary 3-year evaluation of experience with silksurface and velvetsurface Motiva silicone breast implants: a single-center experience with 5813 consecutive breast augmentation cases. Aesthet Surg J 2018; 38(suppl 2):S62–S73. doi:10.1093/asj/sjx150
- Huemer GM, Wenny R, Aitzetmüller MM, Duscher D. Motiva ergonomix round silksurface silicone breast implants: outcome analysis of 100 primary breast augmentations over 3 years and technical considerations. Plast Reconstr Surg 2018; 141(6):831e–842e. doi:10.1097/PRS.0000000000004367
- Lista F, Ahmad J. Evidence-based medicine: augmentation mammaplasty. Plast Reconstr Surg 2013; 132(6):1684–1696. doi:10.1097/PRS.0b013e3182a80880
- Namnoum JD, Largent J, Kaplan HM, Oefelein MG, Brown MH. Primary breast augmentation clinical trial outcomes stratified by surgical incision, anatomical placement and implant device type. J Plast Reconstr Aesthet Surg 2013; 66(9):1165–1172. doi:10.1016/j.bjps.2013.04.046
- Handel N, Garcia ME, Wixtrom R. Breast implant rupture: causes, incidence, clinical impact, and management. Plast Reconstr Surg 2013; 132(5):1128–1137. doi:10.1097/PRS.0b013e3182a4c243
- Hölmich LR, Friis S, Fryzek JP, et al. Incidence of silicone breast implant rupture. Arch Surg 2003; 138(7):801–806. doi:10.1001/archsurg.138.7.801
- Mccarthy CM, Pusic AL, Disa JJ, Cordeiro PG, Cody HS 3rd, Mehrara B. Breast cancer in the previously augmented breast. Plast Reconstr Surg 2007; 119(1):49–58. doi:10.1097/01.prs.0000244748.38742.1f
- Egeberg A, Sørensen JA. The impact of breast implant location on the risk of capsular contraction. Ann Plast Surg 2016; 77(2):255–259. doi:10.1097/SAP.0000000000000227
- Wickman M. Rapid versus slow tissue expansion for breast reconstruction: a three-year follow-up. Plast Reconstr Surg 1995; 95(4):712–718. pmid:7892316
- Kjøller K, Hölmich LR, Jacobsen PH, et al. Epidemiological investigation of local complications after cosmetic breast implant surgery in Denmark. Ann Plast Surg 2002; 48(3):229–237. pmid:11862025
- Handel N, Jensen JA, Black Q, Waisman JR, Silverstein MJ. The fate of breast implants: a critical analysis of complications and outcomes. Plast Reconstr Surg 1995; 96(7):1521–1533. pmid:7480271
- Henriksen TF, Hölmich LR, Fryzek JP, et al. Incidence and severity of short-term complications after breast augmentation: results from a nationwide breast implant registry. Ann Plast Surg 2003; 51(6):531–539. doi:10.1097/01.sap.0000096446.44082.60
- Fernandes JR, Salinas HM, Broelsch GF, et al. Prevention of capsular contracture with photochemical tissue passivation. Plast Reconstr Surg 2014; 133(3):571–577. doi:10.1097/01.prs.0000438063.31043.79
- Wong CH, Samuel M, Tan BK, Song C. Capsular contracture in subglandular breast augmentation with textured versus smooth breast implants: a systematic review. Plast Reconstr Surg 2006; 118(5):1224–1236. doi:10.1097/01.prs.0000237013.50283.d2
- Gurunluoglu R, Sacak B, Arton J. Outcomes analysis of patients undergoing autoaugmentation after breast implant removal. Plast Reconstr Surg 2013; 132(2):304–315. doi:10.1097/PRS.0b013e31829e7d9e
- Gurunluoglu R, Shafighi M, Schwabegger A, Ninkovic M. Secondary breast reconstruction with deepithelialized free flaps from the lower abdomen for intractable capsular contracture and maintenance of breast volume. J Reconstr Microsurg 2005; 21(1):35–41. doi:10.1055/s-2005-862779
- Adams WP Jr, Rios JL, Smith SJ. Enhancing patient outcomes in aesthetic reconstructive breast surgery using triple antibiotic breast irrigation: six-year prospective clinical study. Plast Reconstru Surg 2006; 118(7 suppl):46S–52S. doi:10.1097/01.prs.0000185671.51993.7e
- Moyer HR, Ghazi B, Saunders N, Losken A. Contamination in smooth gel breast implant placement: testing a funnel versus digital insertion technique in a cadaver model. Aesthet Surg J 2012; 32(2):194–199. doi:10.1177/1090820X11434505
- Handel N. The effect of silicone implants on the diagnosis, prognosis, and treatment of breast cancer. Plast Reconstr Surg 2007; 120(7 suppl 1):81S–93S. doi:10.1097/01.prs.0000286578.94102.2b
- Kjøller K, Friis S, Lipworth L, Mclaughlin JK, Olsen JH. Adverse health outcomes in offspring of mothers with cosmetic breast implants: a review. Plast Reconstr Surg 2007; 120(7 suppl 1):129S–134S. doi:10.1097/01.prs.0000286571.93392.00
- Semple JL. Breast-feeding and silicone implants. Plast Reconstr Surg 2007; 120(7 suppl 1):123S–128S. doi:10.1097/01.prs.0000286579.27852.ed
- de Boer M, van leeuwen FE, Hauptmann M, et al. Breast implants and the risk of anaplastic large-cell lymphoma in the breast. JAMA Oncol 2018; 4(3):335–341. doi:10.1001/jamaoncol.2017.4510
- McCarthy CM, Horwitz SM. Association of breast implants with anaplastic large-cell lymphoma. JAMA Oncol 2018; 4(3):341–342. doi:10.1001/jamaoncol.2017.4467
- American Society of Plastic Surgeons. BIA-ALCL physician resources. www.plasticsurgery.org/for-medical-professionals/health-policy/bia-alcl-physician-resources. Accessed December 17, 2018.
- The American Society for Aesthetic Plastic Surgery, Inc. Member FAQs: latest information on ALCL. www.surgery.org/sites/default/files/Member-FAQs_1.pdf. Accessed January 17, 2019.
- The American Society of Plastic Surgeons. BIA-ALCL resources: summary and quick facts. www.plasticsurgery.org/for-medical-professionals/health-policy/bia-alcl-summary-and-quick-facts. Accessed January 17, 2019.
- National Comprehensive Cancer Network. T-cell lymphomas. www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf.
- The Plastic Surgery Foundation PROFILE Registry. www.thepsf.org/research/registries/profile. Accessed January 17, 2019.
- Sarwer DB. The psychological aspects of cosmetic breast augmentation. Plast Reconstr Surg 2007; 120(7 suppl 1):110S–117S. doi:10.1097/01.prs.0000286591.05612.72
- Rohrich RJ, Adams WP, Potter JK. A review of psychological outcomes and suicide in aesthetic breast augmentation. Plast Reconstr Surg 2007; 119(1):401–408. doi:10.1097/01.prs.0000245342.06662.00
- Kalaaji A, Bjertness CB, Nordahl C, Olafsen K. Survey of breast implant patients: characteristics, depression rate, and quality of life. Aesthet Surg J 2013; 33(2):252–257. doi:10.1177/1090820X12473106
- Kalaaji A, Dreyer S, Brinkmann J, Maric I, Nordahl C, Olafsen K. Quality of life after breast enlargement with implants versus augmentation mastopexy: a comparative study. Aesthet Surg J 2018; 38(12):1304–1315. doi:10.1093/asj/sjy047
At present, 300,000 US women undergo breast augmentation surgery each year,1 making this the second most common aesthetic procedure in women (after liposuction),2–4 and making it extremely likely that clinicians will encounter women who have breast implants. In addition, approximately 110,000 women undergo breast reconstructive surgery after mastectomy, of whom more than 88,000 (81%) receive implants (2016 data).5
This review discusses the evolution of breast implants, their complications, and key considerations with regard to aesthetic and reconstructive breast surgery, as the principles are similar.
EVOLUTION OF IMPLANTS
Reports of breast augmentation surgery, also known as augmentation mammoplasty, date back to 1895, when a fatty tumor (lipoma) was successfully transplanted from a patient’s back to a breast defect in a mastectomy patient.2,3,6,7 In the 1930s, implantation of a glass ball into a patient’s breast marked the first implant-based breast augmentation.6 By 1954, attempts at breast augmentation using local dermal-fat flaps, adipose tissue, and even omentum were described.
Alloplastic materials gained popularity throughout the 1950s and 1960s and included polyurethane, polytetrafluoroethylene (Teflon), and other synthetics. Adverse reactions associated with alloplastic materials were plentiful: local tissue reactions, distortion of the breast mound, increased firmness, and discomfort all contributed to the eventual discontinuation of their use. The history of alloplastic breast augmentation also included epoxy resin, shellac, beeswax, paraffin, rubber, petroleum jelly, and liquefied silicone. Outcomes were not good, and many patients ultimately needed mastectomy.7
The first modern breast prosthesis was developed in 1961, and since then, implant composition and design have evolved significantly.8
From silicone to saline, and back again
The first silicone gel implants, introduced in the early 1960s,8–19 had high complication rates—some centers reported an incidence of capsular contracture of up to 70%.8,11 This is a foreign body reaction in which pathologic scar tissue encases the implant, causing it to distort, appear misshapen, harden, and even become painful.11 Attempts to minimize this reaction led to later generations of silicone implants with polyurethane shells.12
Inflatable implants filled with sterile saline solution were originally developed in France in 1965. Unlike silicone implants, saline implants have undergone minimal changes since their inception, and grew in popularity during the 1970s in view of the high rates of capsular contracture with silicone implants.8 However, saline implants have their own problems, and as they became increasingly popular, deflation and the unnatural feel of saline sparked a renewed interest in silicone gel.
By the late 1980s, the thinner-shelled generation of silicone implants displayed its own frustrating complications including implant rupture, capsular contracture, infection, and possible systemic and disseminated granulomatous disease. From 1992 to 2006, the US Food and Drug Administration (FDA) placed a moratorium on silicone implants due to concerns about a possible link with autoimmune and connective tissue diseases and the possible carcinogenic nature of silicone.
While silicone implants were prohibited in the United States, development continued abroad, and eventually the moratorium was lifted after several meta-analyses failed to reveal any link regarding the aforementioned concerns.13
Today, silicone gel implants dominate the world market.14 In the United States, approximately 60% of implants contain silicone gel filler, and trends are similar in Europe.7
Table 1 summarizes the evolution of silicone breast implants over the last 50 years.2,6,11,12Table 2 lists the advantages and disadvantages of silicone and saline breast implants.2,6,8,15
CURRENT IMPLANT OPTIONS
Currently, 3 companies (Allergan, Mentor, Sientra) manufacture and distribute breast implants and implant-associated products such as tissue expanders and sizers in the US market.6
Another company, Motiva, makes an implant that is available in Europe, Asia, and Australia, and the device is currently undergoing a 10-year clinical trial in the United States that began recruiting patients in 16 centers in April 2018.16 Pending final approval, the Cleveland Clinic Department of Plastic Surgery may be among the centers involved in the clinical trial of the Motiva implant. Innovations in the Motiva implant include a high-performance shell that maintains consistent strength and includes a proprietary barrier layer, improved silicone gel filler, 3-D imprinted surface texturing, and an implant shape that adapts with vertical and horizontal movement. It also contains radio-frequency identification transponders that can transmit data about the implant wirelessly.17–19
Surface (textured vs smooth)
Developed in the 1980s, texturing of the implant surface disrupts capsule formation around the prosthesis. Additionally, texturing stabilizes an anatomically shaped (teardrop) implant within the breast pocket, reducing malrotation.20,21
The first textured implants were covered with polyurethane foam, but they were ultimately withdrawn from the US market because of concern for in vivo degradation to carcinogenic compounds. The focus subsequently turned to texturing implant shells by mechanically creating pores of different sizes. Smooth implants, by contrast, are manufactured by repeatedly dipping the implant shell into liquid silicone.2
The capsular contraction rate has been shown to be lower with textured silicone than with smooth silicone (number needed to treat = 7–9), and evidence suggests a lower risk of needing a secondary procedure.21
Form-stable vs fluid-form
Silicone is a polymer. The physical properties of polymers vary greatly and depend on the length of the individual chains and the degree to which those chains are cross-linked. Liquid silicone contains short chains and sparse cross-linking, resulting in an oily compound well suited for lubrication. Silicone gel contains longer chains and more cross-linking and is therefore more viscous.
In “form-stable” implants, the silicone interior has sufficient chain length and cross-linking to retain the designed shape even at rest,2 but they require slightly larger incisions.7 “Fluid-form” refers to an implant with silicone filler with shorter chain length, less cross-linking, and more fluidity.6
Shell
As with silicone fillers, the properties of silicone implant shells also depend on chain length and cross-linking within the polymer. Silicone elastomer shells (Table 1) contain extensively cross-linked chains that impart a flexible yet rubbery character. Silicone elastomers can also be found in facial implants and tissue expanders.2
Implant shape (round vs anatomic)
The shape of an implant is determined by the gel distribution inside of it. To understand gel distribution and implant shape, one must understand the gel-shell ratio. This ratio increases as cohesivity of the filler increases, and it represents increased bonding of the gel filler to the shell and a preserved implant shape at rest.
The gel-shell ratio varies among manufacturers, and a less-viscous filler may be more prone to rippling or loss of upper pole fullness in some patients. For this reason, careful analysis, patient and implant selection, and discussion of complications remain paramount.2
No anatomically shaped implant is manufactured with a smooth shell, but rather with a textured shell that resists malrotation.6,15 However, in the United States, 95% of patients receive round implants.16
PATIENT ASSESSMENT
Before breast augmentation surgery, the surgeon assesses a number of factors—physical and psychosocial—and helps the patient choose a type and size of implant. The surgeon and patient also plan where the implants will be placed—ie, above or beneath the chest wall muscle—and where the incisions will be made. Every decision is made in close consultation with the patient, taking into account the patient’s desires and expectations, as well as what the patient’s anatomy allows. An integral component of this shared decision-making process is a discussion of the possible complications, and often photographs to better illustrate what to expect postoperatively.
Psychosocial factors
One must consider the patient’s psychology, motivations for surgery, and emotional stability. Here, we look for underlying body dysmorphic disorder; excessive or unusual encouragement to undergo the procedure by a spouse, friends, or others; a history of other aesthetic procedures; unrealistic expectations; and other factors influencing the desire to undergo this surgery.
Choosing an implant
Implant selection must take into account the patient’s height, weight,7 and overall body morphology: taller patients and those with wider hips or shoulders usually require larger implants. A reliable method for determining the appropriate implant must include the current breast shape, dimensions, volume, skin elasticity, soft-tissue thickness, and overall body habitus. Ultimately, the most important considerations include breast base diameter, implant volume,20 and soft-tissue envelope.
Preoperative sizing can involve placing sample implants within a brassiere so that the patient can preview possible outcomes. This method is particularly effective in minimizing dissatisfaction because it shares ownership of the decision-making process.15
A computerized implant selection program available in Europe suggests a “best-fit” implant based on a clinician’s measurements.7
Anatomic placement
Traditionally, plastic surgeons place breast implants either beneath the pectoralis major muscle (submuscular placement) or over the pectoralis8 but beneath the glandular breast parenchyma (subglandular placement) (Figure 2).7
Advantages of submuscular placement are a smoother transition of the upper breast pole from the chest wall and less rippling visible through the skin, due to the additional muscular coverage of the implant. Another advantage is that capsular contraction rates are lower with submuscular placement, likely due to possible contamination of implants by lactiferous ductal microbes when accessing the subglandular plane.14,20 Disadvantages are pronounced discomfort after surgery and animation deformities with muscle contraction, particularly in young, highly active patients.
A popular modification of submuscular placement involves creating a surgical dissection plane between the subglandular tissue and the pectoralis major fascia. This “dualplane” approach allows the parenchyma to retract superiorly and reduce breast ptosis.7
Incisions
Table 3 highlights important considerations with regard to incision location.15,20,21
ANTIBIOTICS
Many surgeons give a single prophylactic dose of antibiotic before surgery, a practice that some studies have shown to be effective in reducing the risk of infection.15 However, the benefit of routine postoperative use of antibiotics remains unsubstantiated15: postoperative antibiotic use does not appear to protect against infection, capsular contracture, or overall complications in primary or secondary breast augmentation surgery.20
PERIOPERATIVE PERIOD
At our institution, breast augmentation surgery is an ambulatory procedure—the patient goes home the same day unless circumstances such as pain control warrant admission. This is, however, according to surgeon preference, and differs on a case-by-case basis. General anesthesia is the standard of care.15
POSTOPERATIVE PERIOD
In the immediate postoperative period, patients are instructed to wear a surgical bra for up to 6 weeks to allow stable scarring. Early mobilization is encouraged.7,15 Depending on the patient’s situation, recovery, and healing, she may be out of work for about 1 week, sometimes more, sometimes less.
Additional instructions are surgeon-specific. However, the patient is instructed to avoid bathing, swimming, immersion in water, and wearing underwire brassieres that could impair healing of an inferior incision; instead, patients are often instructed to wear a surgical bra provided on the day of surgery until cleared in the clinic.
Showering is allowed the next day or the second day after surgery, and of course there is no driving while on narcotics. Additionally, patients are counseled extensively regarding hematoma formation and the signs and symptoms of infection.
Patients are typically seen in clinic 1 week after surgery.
The cost of surgery may be $5,000 to $6,000 but can vary significantly from center to center depending on who the patient sees and where, and whether the patient presents for breast reconstruction after cancer or repair of congenital anomalies, or in certain cases of transgender surgery. The patient is typically responsible for the fee, but again this depends on the patient, indications, and particular insurance concerns.
IMPLANT LONGEVITY AND RUPTURE
In the United States, implant rupture rates range from 1.1% to 17.7% at 6 to 10 years after primary augmentation, 2.9% to 14.7% after revision augmentation, 1.5% to 35.4% after primary breast reconstruction, and 0% to 19.6% after revision reconstruction.11
Unfortunately, the existence of multiple implant manufacturers, numerous implant generations, and poorly standardized screening protocols and reporting systems make the true rate of implant rupture difficult to assess without definitive imaging or implant retrieval.11
Damage from surgical instrumentation during implantation is the most common cause of silicone breast implant rupture (50% to 64% of cases).22 Other causes include underfilling and fold flaw from capsular contracture.
Leakage of silicone gel filler may be confined to the periprosthetic capsule (intracapsular rupture) or extend beyond and into the breast parenchyma (extracapsular rupture). One study reported that only 10% of intracapsular ruptures progressed extracapsularly, while 84% of patients with extracapsular involvement remained stable for up to 2 years,23 indicating that intracapsular rupture may not portend worsening disease.11
Implant rupture occurs silently in most cases, with no clinically detectable signs or symptoms. In other cases, patients may present with alterations in breast shape and size, sudden asymmetry, firmness, pronounced capsular contracture, contour irregularity, or pain.
Aside from physical examination, comprehensive diagnostic testing includes imaging—ultrasonography, mammography, computed tomography, and magnetic resonance imaging (MRI). Of these, MRI is the method of choice, with sensitivity and specificity exceeding 90% for detecting implant rupture.11 Classic findings on MRI include the “linguine” sign from a deflating implant shell, or the teardrop sign from implant sagging. Classic findings on ultrasonography include the “snowstorm” sign of extracapsular rupture and the “stepladder” sign of intracapsular rupture.
Mammography effectively detects free silicone in breast tissue with extracapsular rupture (25% of ruptures according to some studies)23; however, it cannot detect rupture within the implant capsule. As an aside, submuscular implant placement may interfere less with screening mammography than subglandular implants do.14,24
Current FDA recommendations to detect implant rupture encourage women with silicone breast implants to undergo screening 3 years after implantation and then every 2 years thereafter; no long-term monitoring is suggested for saline implants.15 Many plastic surgeons evaluate silicone breast implant patients every 1 to 2 years for contracture and rupture.8 Of note, capsular contracture impairs the effectiveness of ultrasonography and may require MRI confirmation.11
If implant rupture is confirmed, the current recommendation is to remove the implant and the capsule. Another implant may be placed depending on the patient’s preference. Rigorous washout remains a key feature of any surgical intervention for ruptured breast implants; however, in the event of extracapsular rupture, resection of silicone granulomas may also be required.11
Reoperation rates for primary breast augmentation surgery approach 20% and are even higher for secondary augmentation over a patient’s lifetime—the highest rate of all aesthetic procedures.7,14
CAPSULAR CONTRACTURE
Capsular contracture is the most common complication of breast augmentation,25 typically presenting within the first postoperative year,26,27 and the risk increases over time.28 It occurs with both silicone and saline breast implants.
In some studies, the incidence exceeded 4% in the first 2 years after surgery,29 and nearly 50% by 10 years.30 Other studies found rates of 0% to 20% over 13 years.20
The etiology is not well understood and is presumed to be multifactorial, with proposed mechanisms and factors that include bacterial contamination, surface texturing, the implant pocket selected, the incision type, drain placement, antibiotic use, and smoking.25
A meta-analysis from 17,000 implants found that the risk of capsular contracture was significantly higher when an implant was placed in a subglandular pocket than in a submuscular pocket,22,26 and that although texturing decreased capsular contracture compared with smooth implants, the effect was modest when a textured or smooth implant was placed in a submuscular location.28 With regard to incision location, studies have reported that the incidence of capsular contracture is highest with transaxillary and periareolar incisions, and lowest with inframammary incisions.20,21
The leading theory is that contamination of the implant (primarily from the mammary ducts) results in biofilm formation. Subclinical hematoma surrounding the implant may also provide key bacterial nutrients.20
Textured implants induce a greater inflammatory response in the capsular tissue, resulting in a thicker capsule; however, contracture rates remain lower with textured than with smooth implants.14,31 Interestingly, lower rates of capsular contracture have been observed with later-generation, cohesive-gel, form-stable implants than with those of earlier generations.12
Although more research is needed, silicone implants appear to confer a higher risk of capsular contracture than saline implants.14,20
Irrigating the breast pocket intraoperatively with triple antibiotic solution (bacitracin, cefazolin, and gentamicin) before placing the implant may decrease the capsular contracture rate.15,20
Treatments for capsular contracture include pocket modifications such as capsulotomy (making releasing, relaxing incisions in the scar capsule encasing the implant), capsulectomy (removing portions of or the entire capsule), and replacing the implant in the other pocket (ie, if the original implant was subglandular, the replacement is placed in the submuscular pocket). Patients who have contractures that fail to respond to these treatments may ultimately benefit from implant removal and autologous reconstruction (autoaugmentation) rather than implant replacement.32,33
ADDITIONAL COMPLICATIONS
Other complications include infection, malposition, rippling, seroma, hematoma, and sensory alterations.
Irrigation during the implantation procedure with a triple antibiotic solution consisting of bacitracin, gentamycin, and cephalexin in normal saline decreases infection and seroma rates.15,20,34
Some surgeons also choose to irrigate the pocket with a betadine solution, or to cleanse the skin with betadine and place sterile towels and redrape before inserting the implant. Additionally, many prefer using a sterile device much like a pastry funnel called a Keller funnel to insert the implant into the breast pocket.35
Infection is less common with cosmetic augmentations than with implant-based breast reconstruction, likely because of healthier, well-vascularized tissue in patients undergoing cosmetic surgery than in those undergoing mastectomy.14
Seroma is thought to be a consequence of texturing, and more so with macro- vs microtexturing. Though poorly understood, an association between texturing and double capsules has also been reported.12,20
After primary breast augmentation, 10-year follow-up rates of capsular contracture, seroma, rippling, and malposition vary across the 3 major silicone implant manufacturers.12 Hematoma and infection occur in less than 1% of primary augmentation patients.15
Malposition of the implant over time is less frequent with textured implants because of the higher coefficient of friction compared with smooth implants.6,8,15
Visible skin rippling may be a consequence of texturing and also of thin body habitus, eg, in patients with a body mass index less than 18.5 kg/m2. If the soft-tissue layer of the breast is thin, the natural rippling of smooth saline implant shells are more likely to show when placed in the subglandular pocket. Form-stable implants, by contrast, resist rippling.12,15
Large implants and extensive lateral dissection can cause alterations in nipple sensation and sensory loss within lower breast pole skin. Axillary incisions may traumatize or damage the intercostobrachial nerve, resulting in upper inner arm sensory aberrations.
Ultimately, the 10-year incidence of secondary surgery ranges from 0% to 36% and the 10-year incidence of capsular contracture ranges from 11% to 19%.15 Additional cosmetic complaints after augmentation with implants include enlargement of the areola and engorgement of breast veins.14
BREAST CANCER AND DETECTION
Patients with or without implants do not seem to differ with regard to breast cancer stage upon detection, tumor burden, recurrence, or survival. However, more patients with implants may present with palpable masses, invasive tumors, axillary metastasis, and falsely negative mammograms.
Breast implants may actually facilitate cancer detection on physical examination by providing a more dense or stable surface upon which to palpate the breast tissue. Although they do not necessarily impair mastectomy or breast reconstruction, they may result in an increased rate of revision surgery after breast conservation therapy.24,36 Mammography remains the standard of care for radiologic diagnosis but can be further supported by MRI and ultrasonography if necessary in patients with implants.
AUTOIMMUNE DISEASES
Although concerns persist, multiple studies have demonstrated the safety of fourth- and fifth-generation silicone breast implants with regard to autoimmune disease.7
In various clinical studies in mastectomy patients who underwent breast reconstruction with either silicone implants or autologous tissue, no difference was found with regard to the incidence of autoimmune diseases.2 Additionally, in meta-analyses of data from more than 87,000 women, no association was found between connective tissue disease and silicone breast implants.2,11 One study11,23 noted no increase in autoantibodies in patients with undamaged silicone implants vs patients who experienced rupture.
Studies have also demonstrated that in children born to mothers with breast implants, the risk of rheumatic disease, esophageal disorders, congenital malformations, and death during the perinatal period is comparable with that in controls.37 Another study, examining breastfeeding in women with silicone breast implants, showed no significant difference in silicon levels (used as a proxy for silicone) in breast milk compared with controls without implants; silicon levels were found to be significantly higher in cow’s milk and store-bought formulas.38
BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE-CELL LYMPHOMA
Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma that develops in tissue adjacent to breast implants. It typically presents as breast swelling 2 to 38 years (mean of 8 years) after implant insertion.39,40 The swelling may be secondary to periprosthetic seroma formation or, more rarely, palpable disease in the axilla. Patients occasionally complain of pain and, rarely, constitutional symptoms.20 BIA-ALCL is not a disease of the surrounding breast tissue, but rather of the fibrous periprosthetic capsule.21
Of note, there is no documented case involving smooth implants,41–43 but it may be related to fifth-generation textured implants.6 At present, it is not possible to definitively state which implant is associated with this condition; hence, more data are needed, and this association is currently under study.
The absolute risk of BIA-ALCL was reported in a Dutch study39 as 1 in 35,000 by age 50, 1 in 12,000 by age 70, and 1 in 7,000 by age 75, with a number needed to harm of 6,920. Overall lifetime risk was estimated at 1 in 30,000 for women with textured implants in a 2015 US study.40 In comparison, breast cancer risk is about 1 in 8 women. There is no apparent predilection for patients who underwent cosmetic augmentation vs reconstruction, or who received silicone vs saline implants.
The diagnosis is confirmed by ultrasonographically guided fine-needle aspiration of seroma fluid and subsequent immunohistochemical testing for CD30-positive and ALK-negative T lymphocytes. Other than positron-emission tomography for staging after diagnosis confirmation, imaging is ineffective. Expert opinion does not recommend routine screening unless the aforementioned symptoms arise.
Treatment involves implant removal and total capsulectomy, with samples sent for pathology study with cytokeratin staining.12 Of note, in all cases of BIA-ALCL in which the disease was limited to the circumscribed scar tissue of the breast capsule, complete surgical excision has proved curative, whereas incomplete capsulectomy portends a greater risk of recurrence and decreased survival.44
In cases of advanced or recurrent ALCL, diagnosed late or inappropriately, the National Comprehensive Cancer Network recommends a multidisciplinary approach involving adjuvant chemotherapy and radiation.44 Anecdotally, at our institution, we have recently treated several cases of advanced ALCL presenting with invasive chest wall masses with extirpative surgery and subsequent reconstruction with the assistance of our thoracic surgery colleagues, as well as the aforementioned multidisciplinary approach using adjuvant therapy.
The mechanism of this malignancy is currently under investigation, but the current theory implicates an exaggerated lymphoproliferative response to bacterial contamination of the capsule superimposed upon genetic factors in susceptible patients.42,43
National societies advise plastic surgeons to discuss the risk of BIA-ALCL with all patients at the time of breast augmentation consultation and to report all confirmed cases to the PROFILE registry (Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology).45
ARE PATIENTS HAPPIER AFTERWARD?
Studies have shown that after undergoing breast augmentation surgery, patients note improvement in body image, and satisfaction rates range from 85% to 95% with respect to self-confidence and body image.46 An evaluation of patient responses on the validated BREAST-Q Augmentation Questionnaire showed the following satisfaction rates: breasts 83%, psychosocial well-being 88%, and sexual functioning 81%.15
Although epidemiologic studies have reported higher suicide rates in women with cosmetic breast implants, this likely stems from preoperative psychological factors and underscores the role of psychiatric referral in patients with a mental health history or in those whom the surgeon deems it necessary.46
Several high-quality studies have demonstrated that quality of life and psychosocial functioning (including depression) markedly improve after breast augmentation surgery.47 Among a cohort of Norwegian patients, breast implant surgery resulted in improved motivation to perform daily activities, as well as improved quality of life from both a psychosocial and aesthetic perspective.48 Interestingly, a recent study reported that patients who underwent breast implant surgery alone reported greater satisfaction and psychosocial quality of life than patients who underwent combination breast augmentation and mastopexy (breast-lifting) surgery.49
Additional data are needed to refine our understanding of the complex interplay between psychosocial factors before and after surgery in patients seeking and undergoing breast augmentation procedures.
At present, 300,000 US women undergo breast augmentation surgery each year,1 making this the second most common aesthetic procedure in women (after liposuction),2–4 and making it extremely likely that clinicians will encounter women who have breast implants. In addition, approximately 110,000 women undergo breast reconstructive surgery after mastectomy, of whom more than 88,000 (81%) receive implants (2016 data).5
This review discusses the evolution of breast implants, their complications, and key considerations with regard to aesthetic and reconstructive breast surgery, as the principles are similar.
EVOLUTION OF IMPLANTS
Reports of breast augmentation surgery, also known as augmentation mammoplasty, date back to 1895, when a fatty tumor (lipoma) was successfully transplanted from a patient’s back to a breast defect in a mastectomy patient.2,3,6,7 In the 1930s, implantation of a glass ball into a patient’s breast marked the first implant-based breast augmentation.6 By 1954, attempts at breast augmentation using local dermal-fat flaps, adipose tissue, and even omentum were described.
Alloplastic materials gained popularity throughout the 1950s and 1960s and included polyurethane, polytetrafluoroethylene (Teflon), and other synthetics. Adverse reactions associated with alloplastic materials were plentiful: local tissue reactions, distortion of the breast mound, increased firmness, and discomfort all contributed to the eventual discontinuation of their use. The history of alloplastic breast augmentation also included epoxy resin, shellac, beeswax, paraffin, rubber, petroleum jelly, and liquefied silicone. Outcomes were not good, and many patients ultimately needed mastectomy.7
The first modern breast prosthesis was developed in 1961, and since then, implant composition and design have evolved significantly.8
From silicone to saline, and back again
The first silicone gel implants, introduced in the early 1960s,8–19 had high complication rates—some centers reported an incidence of capsular contracture of up to 70%.8,11 This is a foreign body reaction in which pathologic scar tissue encases the implant, causing it to distort, appear misshapen, harden, and even become painful.11 Attempts to minimize this reaction led to later generations of silicone implants with polyurethane shells.12
Inflatable implants filled with sterile saline solution were originally developed in France in 1965. Unlike silicone implants, saline implants have undergone minimal changes since their inception, and grew in popularity during the 1970s in view of the high rates of capsular contracture with silicone implants.8 However, saline implants have their own problems, and as they became increasingly popular, deflation and the unnatural feel of saline sparked a renewed interest in silicone gel.
By the late 1980s, the thinner-shelled generation of silicone implants displayed its own frustrating complications including implant rupture, capsular contracture, infection, and possible systemic and disseminated granulomatous disease. From 1992 to 2006, the US Food and Drug Administration (FDA) placed a moratorium on silicone implants due to concerns about a possible link with autoimmune and connective tissue diseases and the possible carcinogenic nature of silicone.
While silicone implants were prohibited in the United States, development continued abroad, and eventually the moratorium was lifted after several meta-analyses failed to reveal any link regarding the aforementioned concerns.13
Today, silicone gel implants dominate the world market.14 In the United States, approximately 60% of implants contain silicone gel filler, and trends are similar in Europe.7
Table 1 summarizes the evolution of silicone breast implants over the last 50 years.2,6,11,12Table 2 lists the advantages and disadvantages of silicone and saline breast implants.2,6,8,15
CURRENT IMPLANT OPTIONS
Currently, 3 companies (Allergan, Mentor, Sientra) manufacture and distribute breast implants and implant-associated products such as tissue expanders and sizers in the US market.6
Another company, Motiva, makes an implant that is available in Europe, Asia, and Australia, and the device is currently undergoing a 10-year clinical trial in the United States that began recruiting patients in 16 centers in April 2018.16 Pending final approval, the Cleveland Clinic Department of Plastic Surgery may be among the centers involved in the clinical trial of the Motiva implant. Innovations in the Motiva implant include a high-performance shell that maintains consistent strength and includes a proprietary barrier layer, improved silicone gel filler, 3-D imprinted surface texturing, and an implant shape that adapts with vertical and horizontal movement. It also contains radio-frequency identification transponders that can transmit data about the implant wirelessly.17–19
Surface (textured vs smooth)
Developed in the 1980s, texturing of the implant surface disrupts capsule formation around the prosthesis. Additionally, texturing stabilizes an anatomically shaped (teardrop) implant within the breast pocket, reducing malrotation.20,21
The first textured implants were covered with polyurethane foam, but they were ultimately withdrawn from the US market because of concern for in vivo degradation to carcinogenic compounds. The focus subsequently turned to texturing implant shells by mechanically creating pores of different sizes. Smooth implants, by contrast, are manufactured by repeatedly dipping the implant shell into liquid silicone.2
The capsular contraction rate has been shown to be lower with textured silicone than with smooth silicone (number needed to treat = 7–9), and evidence suggests a lower risk of needing a secondary procedure.21
Form-stable vs fluid-form
Silicone is a polymer. The physical properties of polymers vary greatly and depend on the length of the individual chains and the degree to which those chains are cross-linked. Liquid silicone contains short chains and sparse cross-linking, resulting in an oily compound well suited for lubrication. Silicone gel contains longer chains and more cross-linking and is therefore more viscous.
In “form-stable” implants, the silicone interior has sufficient chain length and cross-linking to retain the designed shape even at rest,2 but they require slightly larger incisions.7 “Fluid-form” refers to an implant with silicone filler with shorter chain length, less cross-linking, and more fluidity.6
Shell
As with silicone fillers, the properties of silicone implant shells also depend on chain length and cross-linking within the polymer. Silicone elastomer shells (Table 1) contain extensively cross-linked chains that impart a flexible yet rubbery character. Silicone elastomers can also be found in facial implants and tissue expanders.2
Implant shape (round vs anatomic)
The shape of an implant is determined by the gel distribution inside of it. To understand gel distribution and implant shape, one must understand the gel-shell ratio. This ratio increases as cohesivity of the filler increases, and it represents increased bonding of the gel filler to the shell and a preserved implant shape at rest.
The gel-shell ratio varies among manufacturers, and a less-viscous filler may be more prone to rippling or loss of upper pole fullness in some patients. For this reason, careful analysis, patient and implant selection, and discussion of complications remain paramount.2
No anatomically shaped implant is manufactured with a smooth shell, but rather with a textured shell that resists malrotation.6,15 However, in the United States, 95% of patients receive round implants.16
PATIENT ASSESSMENT
Before breast augmentation surgery, the surgeon assesses a number of factors—physical and psychosocial—and helps the patient choose a type and size of implant. The surgeon and patient also plan where the implants will be placed—ie, above or beneath the chest wall muscle—and where the incisions will be made. Every decision is made in close consultation with the patient, taking into account the patient’s desires and expectations, as well as what the patient’s anatomy allows. An integral component of this shared decision-making process is a discussion of the possible complications, and often photographs to better illustrate what to expect postoperatively.
Psychosocial factors
One must consider the patient’s psychology, motivations for surgery, and emotional stability. Here, we look for underlying body dysmorphic disorder; excessive or unusual encouragement to undergo the procedure by a spouse, friends, or others; a history of other aesthetic procedures; unrealistic expectations; and other factors influencing the desire to undergo this surgery.
Choosing an implant
Implant selection must take into account the patient’s height, weight,7 and overall body morphology: taller patients and those with wider hips or shoulders usually require larger implants. A reliable method for determining the appropriate implant must include the current breast shape, dimensions, volume, skin elasticity, soft-tissue thickness, and overall body habitus. Ultimately, the most important considerations include breast base diameter, implant volume,20 and soft-tissue envelope.
Preoperative sizing can involve placing sample implants within a brassiere so that the patient can preview possible outcomes. This method is particularly effective in minimizing dissatisfaction because it shares ownership of the decision-making process.15
A computerized implant selection program available in Europe suggests a “best-fit” implant based on a clinician’s measurements.7
Anatomic placement
Traditionally, plastic surgeons place breast implants either beneath the pectoralis major muscle (submuscular placement) or over the pectoralis8 but beneath the glandular breast parenchyma (subglandular placement) (Figure 2).7
Advantages of submuscular placement are a smoother transition of the upper breast pole from the chest wall and less rippling visible through the skin, due to the additional muscular coverage of the implant. Another advantage is that capsular contraction rates are lower with submuscular placement, likely due to possible contamination of implants by lactiferous ductal microbes when accessing the subglandular plane.14,20 Disadvantages are pronounced discomfort after surgery and animation deformities with muscle contraction, particularly in young, highly active patients.
A popular modification of submuscular placement involves creating a surgical dissection plane between the subglandular tissue and the pectoralis major fascia. This “dualplane” approach allows the parenchyma to retract superiorly and reduce breast ptosis.7
Incisions
Table 3 highlights important considerations with regard to incision location.15,20,21
ANTIBIOTICS
Many surgeons give a single prophylactic dose of antibiotic before surgery, a practice that some studies have shown to be effective in reducing the risk of infection.15 However, the benefit of routine postoperative use of antibiotics remains unsubstantiated15: postoperative antibiotic use does not appear to protect against infection, capsular contracture, or overall complications in primary or secondary breast augmentation surgery.20
PERIOPERATIVE PERIOD
At our institution, breast augmentation surgery is an ambulatory procedure—the patient goes home the same day unless circumstances such as pain control warrant admission. This is, however, according to surgeon preference, and differs on a case-by-case basis. General anesthesia is the standard of care.15
POSTOPERATIVE PERIOD
In the immediate postoperative period, patients are instructed to wear a surgical bra for up to 6 weeks to allow stable scarring. Early mobilization is encouraged.7,15 Depending on the patient’s situation, recovery, and healing, she may be out of work for about 1 week, sometimes more, sometimes less.
Additional instructions are surgeon-specific. However, the patient is instructed to avoid bathing, swimming, immersion in water, and wearing underwire brassieres that could impair healing of an inferior incision; instead, patients are often instructed to wear a surgical bra provided on the day of surgery until cleared in the clinic.
Showering is allowed the next day or the second day after surgery, and of course there is no driving while on narcotics. Additionally, patients are counseled extensively regarding hematoma formation and the signs and symptoms of infection.
Patients are typically seen in clinic 1 week after surgery.
The cost of surgery may be $5,000 to $6,000 but can vary significantly from center to center depending on who the patient sees and where, and whether the patient presents for breast reconstruction after cancer or repair of congenital anomalies, or in certain cases of transgender surgery. The patient is typically responsible for the fee, but again this depends on the patient, indications, and particular insurance concerns.
IMPLANT LONGEVITY AND RUPTURE
In the United States, implant rupture rates range from 1.1% to 17.7% at 6 to 10 years after primary augmentation, 2.9% to 14.7% after revision augmentation, 1.5% to 35.4% after primary breast reconstruction, and 0% to 19.6% after revision reconstruction.11
Unfortunately, the existence of multiple implant manufacturers, numerous implant generations, and poorly standardized screening protocols and reporting systems make the true rate of implant rupture difficult to assess without definitive imaging or implant retrieval.11
Damage from surgical instrumentation during implantation is the most common cause of silicone breast implant rupture (50% to 64% of cases).22 Other causes include underfilling and fold flaw from capsular contracture.
Leakage of silicone gel filler may be confined to the periprosthetic capsule (intracapsular rupture) or extend beyond and into the breast parenchyma (extracapsular rupture). One study reported that only 10% of intracapsular ruptures progressed extracapsularly, while 84% of patients with extracapsular involvement remained stable for up to 2 years,23 indicating that intracapsular rupture may not portend worsening disease.11
Implant rupture occurs silently in most cases, with no clinically detectable signs or symptoms. In other cases, patients may present with alterations in breast shape and size, sudden asymmetry, firmness, pronounced capsular contracture, contour irregularity, or pain.
Aside from physical examination, comprehensive diagnostic testing includes imaging—ultrasonography, mammography, computed tomography, and magnetic resonance imaging (MRI). Of these, MRI is the method of choice, with sensitivity and specificity exceeding 90% for detecting implant rupture.11 Classic findings on MRI include the “linguine” sign from a deflating implant shell, or the teardrop sign from implant sagging. Classic findings on ultrasonography include the “snowstorm” sign of extracapsular rupture and the “stepladder” sign of intracapsular rupture.
Mammography effectively detects free silicone in breast tissue with extracapsular rupture (25% of ruptures according to some studies)23; however, it cannot detect rupture within the implant capsule. As an aside, submuscular implant placement may interfere less with screening mammography than subglandular implants do.14,24
Current FDA recommendations to detect implant rupture encourage women with silicone breast implants to undergo screening 3 years after implantation and then every 2 years thereafter; no long-term monitoring is suggested for saline implants.15 Many plastic surgeons evaluate silicone breast implant patients every 1 to 2 years for contracture and rupture.8 Of note, capsular contracture impairs the effectiveness of ultrasonography and may require MRI confirmation.11
If implant rupture is confirmed, the current recommendation is to remove the implant and the capsule. Another implant may be placed depending on the patient’s preference. Rigorous washout remains a key feature of any surgical intervention for ruptured breast implants; however, in the event of extracapsular rupture, resection of silicone granulomas may also be required.11
Reoperation rates for primary breast augmentation surgery approach 20% and are even higher for secondary augmentation over a patient’s lifetime—the highest rate of all aesthetic procedures.7,14
CAPSULAR CONTRACTURE
Capsular contracture is the most common complication of breast augmentation,25 typically presenting within the first postoperative year,26,27 and the risk increases over time.28 It occurs with both silicone and saline breast implants.
In some studies, the incidence exceeded 4% in the first 2 years after surgery,29 and nearly 50% by 10 years.30 Other studies found rates of 0% to 20% over 13 years.20
The etiology is not well understood and is presumed to be multifactorial, with proposed mechanisms and factors that include bacterial contamination, surface texturing, the implant pocket selected, the incision type, drain placement, antibiotic use, and smoking.25
A meta-analysis from 17,000 implants found that the risk of capsular contracture was significantly higher when an implant was placed in a subglandular pocket than in a submuscular pocket,22,26 and that although texturing decreased capsular contracture compared with smooth implants, the effect was modest when a textured or smooth implant was placed in a submuscular location.28 With regard to incision location, studies have reported that the incidence of capsular contracture is highest with transaxillary and periareolar incisions, and lowest with inframammary incisions.20,21
The leading theory is that contamination of the implant (primarily from the mammary ducts) results in biofilm formation. Subclinical hematoma surrounding the implant may also provide key bacterial nutrients.20
Textured implants induce a greater inflammatory response in the capsular tissue, resulting in a thicker capsule; however, contracture rates remain lower with textured than with smooth implants.14,31 Interestingly, lower rates of capsular contracture have been observed with later-generation, cohesive-gel, form-stable implants than with those of earlier generations.12
Although more research is needed, silicone implants appear to confer a higher risk of capsular contracture than saline implants.14,20
Irrigating the breast pocket intraoperatively with triple antibiotic solution (bacitracin, cefazolin, and gentamicin) before placing the implant may decrease the capsular contracture rate.15,20
Treatments for capsular contracture include pocket modifications such as capsulotomy (making releasing, relaxing incisions in the scar capsule encasing the implant), capsulectomy (removing portions of or the entire capsule), and replacing the implant in the other pocket (ie, if the original implant was subglandular, the replacement is placed in the submuscular pocket). Patients who have contractures that fail to respond to these treatments may ultimately benefit from implant removal and autologous reconstruction (autoaugmentation) rather than implant replacement.32,33
ADDITIONAL COMPLICATIONS
Other complications include infection, malposition, rippling, seroma, hematoma, and sensory alterations.
Irrigation during the implantation procedure with a triple antibiotic solution consisting of bacitracin, gentamycin, and cephalexin in normal saline decreases infection and seroma rates.15,20,34
Some surgeons also choose to irrigate the pocket with a betadine solution, or to cleanse the skin with betadine and place sterile towels and redrape before inserting the implant. Additionally, many prefer using a sterile device much like a pastry funnel called a Keller funnel to insert the implant into the breast pocket.35
Infection is less common with cosmetic augmentations than with implant-based breast reconstruction, likely because of healthier, well-vascularized tissue in patients undergoing cosmetic surgery than in those undergoing mastectomy.14
Seroma is thought to be a consequence of texturing, and more so with macro- vs microtexturing. Though poorly understood, an association between texturing and double capsules has also been reported.12,20
After primary breast augmentation, 10-year follow-up rates of capsular contracture, seroma, rippling, and malposition vary across the 3 major silicone implant manufacturers.12 Hematoma and infection occur in less than 1% of primary augmentation patients.15
Malposition of the implant over time is less frequent with textured implants because of the higher coefficient of friction compared with smooth implants.6,8,15
Visible skin rippling may be a consequence of texturing and also of thin body habitus, eg, in patients with a body mass index less than 18.5 kg/m2. If the soft-tissue layer of the breast is thin, the natural rippling of smooth saline implant shells are more likely to show when placed in the subglandular pocket. Form-stable implants, by contrast, resist rippling.12,15
Large implants and extensive lateral dissection can cause alterations in nipple sensation and sensory loss within lower breast pole skin. Axillary incisions may traumatize or damage the intercostobrachial nerve, resulting in upper inner arm sensory aberrations.
Ultimately, the 10-year incidence of secondary surgery ranges from 0% to 36% and the 10-year incidence of capsular contracture ranges from 11% to 19%.15 Additional cosmetic complaints after augmentation with implants include enlargement of the areola and engorgement of breast veins.14
BREAST CANCER AND DETECTION
Patients with or without implants do not seem to differ with regard to breast cancer stage upon detection, tumor burden, recurrence, or survival. However, more patients with implants may present with palpable masses, invasive tumors, axillary metastasis, and falsely negative mammograms.
Breast implants may actually facilitate cancer detection on physical examination by providing a more dense or stable surface upon which to palpate the breast tissue. Although they do not necessarily impair mastectomy or breast reconstruction, they may result in an increased rate of revision surgery after breast conservation therapy.24,36 Mammography remains the standard of care for radiologic diagnosis but can be further supported by MRI and ultrasonography if necessary in patients with implants.
AUTOIMMUNE DISEASES
Although concerns persist, multiple studies have demonstrated the safety of fourth- and fifth-generation silicone breast implants with regard to autoimmune disease.7
In various clinical studies in mastectomy patients who underwent breast reconstruction with either silicone implants or autologous tissue, no difference was found with regard to the incidence of autoimmune diseases.2 Additionally, in meta-analyses of data from more than 87,000 women, no association was found between connective tissue disease and silicone breast implants.2,11 One study11,23 noted no increase in autoantibodies in patients with undamaged silicone implants vs patients who experienced rupture.
Studies have also demonstrated that in children born to mothers with breast implants, the risk of rheumatic disease, esophageal disorders, congenital malformations, and death during the perinatal period is comparable with that in controls.37 Another study, examining breastfeeding in women with silicone breast implants, showed no significant difference in silicon levels (used as a proxy for silicone) in breast milk compared with controls without implants; silicon levels were found to be significantly higher in cow’s milk and store-bought formulas.38
BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE-CELL LYMPHOMA
Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma that develops in tissue adjacent to breast implants. It typically presents as breast swelling 2 to 38 years (mean of 8 years) after implant insertion.39,40 The swelling may be secondary to periprosthetic seroma formation or, more rarely, palpable disease in the axilla. Patients occasionally complain of pain and, rarely, constitutional symptoms.20 BIA-ALCL is not a disease of the surrounding breast tissue, but rather of the fibrous periprosthetic capsule.21
Of note, there is no documented case involving smooth implants,41–43 but it may be related to fifth-generation textured implants.6 At present, it is not possible to definitively state which implant is associated with this condition; hence, more data are needed, and this association is currently under study.
The absolute risk of BIA-ALCL was reported in a Dutch study39 as 1 in 35,000 by age 50, 1 in 12,000 by age 70, and 1 in 7,000 by age 75, with a number needed to harm of 6,920. Overall lifetime risk was estimated at 1 in 30,000 for women with textured implants in a 2015 US study.40 In comparison, breast cancer risk is about 1 in 8 women. There is no apparent predilection for patients who underwent cosmetic augmentation vs reconstruction, or who received silicone vs saline implants.
The diagnosis is confirmed by ultrasonographically guided fine-needle aspiration of seroma fluid and subsequent immunohistochemical testing for CD30-positive and ALK-negative T lymphocytes. Other than positron-emission tomography for staging after diagnosis confirmation, imaging is ineffective. Expert opinion does not recommend routine screening unless the aforementioned symptoms arise.
Treatment involves implant removal and total capsulectomy, with samples sent for pathology study with cytokeratin staining.12 Of note, in all cases of BIA-ALCL in which the disease was limited to the circumscribed scar tissue of the breast capsule, complete surgical excision has proved curative, whereas incomplete capsulectomy portends a greater risk of recurrence and decreased survival.44
In cases of advanced or recurrent ALCL, diagnosed late or inappropriately, the National Comprehensive Cancer Network recommends a multidisciplinary approach involving adjuvant chemotherapy and radiation.44 Anecdotally, at our institution, we have recently treated several cases of advanced ALCL presenting with invasive chest wall masses with extirpative surgery and subsequent reconstruction with the assistance of our thoracic surgery colleagues, as well as the aforementioned multidisciplinary approach using adjuvant therapy.
The mechanism of this malignancy is currently under investigation, but the current theory implicates an exaggerated lymphoproliferative response to bacterial contamination of the capsule superimposed upon genetic factors in susceptible patients.42,43
National societies advise plastic surgeons to discuss the risk of BIA-ALCL with all patients at the time of breast augmentation consultation and to report all confirmed cases to the PROFILE registry (Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology).45
ARE PATIENTS HAPPIER AFTERWARD?
Studies have shown that after undergoing breast augmentation surgery, patients note improvement in body image, and satisfaction rates range from 85% to 95% with respect to self-confidence and body image.46 An evaluation of patient responses on the validated BREAST-Q Augmentation Questionnaire showed the following satisfaction rates: breasts 83%, psychosocial well-being 88%, and sexual functioning 81%.15
Although epidemiologic studies have reported higher suicide rates in women with cosmetic breast implants, this likely stems from preoperative psychological factors and underscores the role of psychiatric referral in patients with a mental health history or in those whom the surgeon deems it necessary.46
Several high-quality studies have demonstrated that quality of life and psychosocial functioning (including depression) markedly improve after breast augmentation surgery.47 Among a cohort of Norwegian patients, breast implant surgery resulted in improved motivation to perform daily activities, as well as improved quality of life from both a psychosocial and aesthetic perspective.48 Interestingly, a recent study reported that patients who underwent breast implant surgery alone reported greater satisfaction and psychosocial quality of life than patients who underwent combination breast augmentation and mastopexy (breast-lifting) surgery.49
Additional data are needed to refine our understanding of the complex interplay between psychosocial factors before and after surgery in patients seeking and undergoing breast augmentation procedures.
- Derby BM, Codner MA. Textured silicone breast implant use in primary augmentation: core data update and review. Plast Reconstr Surg 2015; 135(1):113–124. doi:10.1097/PRS.0000000000000832
- Maxwell GP, Gabriel A. Breast implant design. Gland Surg 2017; 6(2):148–153. doi:10.21037/gs.2016.11.09
- Gabriel A, Maxwell GP. The evolution of breast implants. Clin Plast Surg 2015; 42(4):399–404. doi:10.1016/j.cps.2015.06.015
- American Society of Plastic Surgeons. Procedural statistics trends 1992–2012. www.plasticsurgery.org/documents/News/Statistics/2012/plastic-surgery-statistics-full-report-2012.pdf. Accessed January 17, 2019.
- American Society of Plastic Surgeons. Plastic surgery statistics report 2016. www.plasticsurgery.org/documents/News/Statistics/2016/plastic-surgery-statistics-full-report-2016.pdf. Accessed January 17, 2019.
- Henderson PW, Nash D, Laskowski M, Grant RT. Objective comparison of commercially available breast implant devices. Aesthetic Plast Surg 2015; 39(5):724–732. doi:10.1007/s00266-015-0537-1
- Adams WP Jr, Mallucci P. Breast augmentation. Plast Reconstr Surg 2012; 130(4):597e–611e. doi:10.1097/PRS.0b013e318262f607
- Spear SL, Jespersen MR. Breast implants: saline or silicone? Aesthet Surg J 2010; 30(4):557–570. doi:10.1177/1090820X10380401
- Cronin TD, Gerow FJ. Augmentation mammaplasty: a new “natural feel” prosthesis. In: Transactions of the Third International Conference of Plastic Surgery: October 13–18, 1963, Washington, DC.
- Maxwell GP, Gabriel A. The evolution of breast implants. Plast Reconstr Surg 2014; 134(suppl 1):12S–17S. doi:10.1097/PRS.0000000000000348
- Hillard C, Fowler JD, Barta R, Cunningham B. Silicone breast implant rupture: a review. Gland Surg 2017; 6(2):163–168. doi:10.21037/gs.2016.09.12
- Derby BM, Codner MA. Textured silicone breast implant use in primary augmentation: core data update and review. Plast Reconstr Surg 2015; 135(1):113–124. doi:10.1097/PRS.0000000000000832
- Tugwell P, Wells G, Peterson J, et al. Do silicone breast implants cause rheumatologic disorders? A systematic review for a court-appointed national science panel. Arthritis Rheum 2001; 44(11):2477–2484. pmid:11710703
- Alpert BS, Lalonde DH. MOC-PS(SM) CME article: breast augmentation. Plast Reconstr Surg 2008; 121(suppl 4):1–7. doi:10.1097/01.prs.0000305933.31540.5d
- Hidalgo DA, Spector JA. Breast augmentation. Plast Reconstr Surg 2014; 133(4):567e–583e. doi:10.1097/PRS.0000000000000033
- ClinicalTrials.gov. Study of the safety and effectiveness of Motiva Implants®. https://clinicaltrials.gov/ct2/show/NCT03579901. Accessed January 17, 2019.
- Establishment Labs. Motiva Implants. https://motivaimplants.com/why-motiva/innovation-for-enhanced-safety/. Accessed January 17, 2019.
- Sforza M, Zaccheddu R, Alleruzzo A, et al. Preliminary 3-year evaluation of experience with silksurface and velvetsurface Motiva silicone breast implants: a single-center experience with 5813 consecutive breast augmentation cases. Aesthet Surg J 2018; 38(suppl 2):S62–S73. doi:10.1093/asj/sjx150
- Huemer GM, Wenny R, Aitzetmüller MM, Duscher D. Motiva ergonomix round silksurface silicone breast implants: outcome analysis of 100 primary breast augmentations over 3 years and technical considerations. Plast Reconstr Surg 2018; 141(6):831e–842e. doi:10.1097/PRS.0000000000004367
- Lista F, Ahmad J. Evidence-based medicine: augmentation mammaplasty. Plast Reconstr Surg 2013; 132(6):1684–1696. doi:10.1097/PRS.0b013e3182a80880
- Namnoum JD, Largent J, Kaplan HM, Oefelein MG, Brown MH. Primary breast augmentation clinical trial outcomes stratified by surgical incision, anatomical placement and implant device type. J Plast Reconstr Aesthet Surg 2013; 66(9):1165–1172. doi:10.1016/j.bjps.2013.04.046
- Handel N, Garcia ME, Wixtrom R. Breast implant rupture: causes, incidence, clinical impact, and management. Plast Reconstr Surg 2013; 132(5):1128–1137. doi:10.1097/PRS.0b013e3182a4c243
- Hölmich LR, Friis S, Fryzek JP, et al. Incidence of silicone breast implant rupture. Arch Surg 2003; 138(7):801–806. doi:10.1001/archsurg.138.7.801
- Mccarthy CM, Pusic AL, Disa JJ, Cordeiro PG, Cody HS 3rd, Mehrara B. Breast cancer in the previously augmented breast. Plast Reconstr Surg 2007; 119(1):49–58. doi:10.1097/01.prs.0000244748.38742.1f
- Egeberg A, Sørensen JA. The impact of breast implant location on the risk of capsular contraction. Ann Plast Surg 2016; 77(2):255–259. doi:10.1097/SAP.0000000000000227
- Wickman M. Rapid versus slow tissue expansion for breast reconstruction: a three-year follow-up. Plast Reconstr Surg 1995; 95(4):712–718. pmid:7892316
- Kjøller K, Hölmich LR, Jacobsen PH, et al. Epidemiological investigation of local complications after cosmetic breast implant surgery in Denmark. Ann Plast Surg 2002; 48(3):229–237. pmid:11862025
- Handel N, Jensen JA, Black Q, Waisman JR, Silverstein MJ. The fate of breast implants: a critical analysis of complications and outcomes. Plast Reconstr Surg 1995; 96(7):1521–1533. pmid:7480271
- Henriksen TF, Hölmich LR, Fryzek JP, et al. Incidence and severity of short-term complications after breast augmentation: results from a nationwide breast implant registry. Ann Plast Surg 2003; 51(6):531–539. doi:10.1097/01.sap.0000096446.44082.60
- Fernandes JR, Salinas HM, Broelsch GF, et al. Prevention of capsular contracture with photochemical tissue passivation. Plast Reconstr Surg 2014; 133(3):571–577. doi:10.1097/01.prs.0000438063.31043.79
- Wong CH, Samuel M, Tan BK, Song C. Capsular contracture in subglandular breast augmentation with textured versus smooth breast implants: a systematic review. Plast Reconstr Surg 2006; 118(5):1224–1236. doi:10.1097/01.prs.0000237013.50283.d2
- Gurunluoglu R, Sacak B, Arton J. Outcomes analysis of patients undergoing autoaugmentation after breast implant removal. Plast Reconstr Surg 2013; 132(2):304–315. doi:10.1097/PRS.0b013e31829e7d9e
- Gurunluoglu R, Shafighi M, Schwabegger A, Ninkovic M. Secondary breast reconstruction with deepithelialized free flaps from the lower abdomen for intractable capsular contracture and maintenance of breast volume. J Reconstr Microsurg 2005; 21(1):35–41. doi:10.1055/s-2005-862779
- Adams WP Jr, Rios JL, Smith SJ. Enhancing patient outcomes in aesthetic reconstructive breast surgery using triple antibiotic breast irrigation: six-year prospective clinical study. Plast Reconstru Surg 2006; 118(7 suppl):46S–52S. doi:10.1097/01.prs.0000185671.51993.7e
- Moyer HR, Ghazi B, Saunders N, Losken A. Contamination in smooth gel breast implant placement: testing a funnel versus digital insertion technique in a cadaver model. Aesthet Surg J 2012; 32(2):194–199. doi:10.1177/1090820X11434505
- Handel N. The effect of silicone implants on the diagnosis, prognosis, and treatment of breast cancer. Plast Reconstr Surg 2007; 120(7 suppl 1):81S–93S. doi:10.1097/01.prs.0000286578.94102.2b
- Kjøller K, Friis S, Lipworth L, Mclaughlin JK, Olsen JH. Adverse health outcomes in offspring of mothers with cosmetic breast implants: a review. Plast Reconstr Surg 2007; 120(7 suppl 1):129S–134S. doi:10.1097/01.prs.0000286571.93392.00
- Semple JL. Breast-feeding and silicone implants. Plast Reconstr Surg 2007; 120(7 suppl 1):123S–128S. doi:10.1097/01.prs.0000286579.27852.ed
- de Boer M, van leeuwen FE, Hauptmann M, et al. Breast implants and the risk of anaplastic large-cell lymphoma in the breast. JAMA Oncol 2018; 4(3):335–341. doi:10.1001/jamaoncol.2017.4510
- McCarthy CM, Horwitz SM. Association of breast implants with anaplastic large-cell lymphoma. JAMA Oncol 2018; 4(3):341–342. doi:10.1001/jamaoncol.2017.4467
- American Society of Plastic Surgeons. BIA-ALCL physician resources. www.plasticsurgery.org/for-medical-professionals/health-policy/bia-alcl-physician-resources. Accessed December 17, 2018.
- The American Society for Aesthetic Plastic Surgery, Inc. Member FAQs: latest information on ALCL. www.surgery.org/sites/default/files/Member-FAQs_1.pdf. Accessed January 17, 2019.
- The American Society of Plastic Surgeons. BIA-ALCL resources: summary and quick facts. www.plasticsurgery.org/for-medical-professionals/health-policy/bia-alcl-summary-and-quick-facts. Accessed January 17, 2019.
- National Comprehensive Cancer Network. T-cell lymphomas. www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf.
- The Plastic Surgery Foundation PROFILE Registry. www.thepsf.org/research/registries/profile. Accessed January 17, 2019.
- Sarwer DB. The psychological aspects of cosmetic breast augmentation. Plast Reconstr Surg 2007; 120(7 suppl 1):110S–117S. doi:10.1097/01.prs.0000286591.05612.72
- Rohrich RJ, Adams WP, Potter JK. A review of psychological outcomes and suicide in aesthetic breast augmentation. Plast Reconstr Surg 2007; 119(1):401–408. doi:10.1097/01.prs.0000245342.06662.00
- Kalaaji A, Bjertness CB, Nordahl C, Olafsen K. Survey of breast implant patients: characteristics, depression rate, and quality of life. Aesthet Surg J 2013; 33(2):252–257. doi:10.1177/1090820X12473106
- Kalaaji A, Dreyer S, Brinkmann J, Maric I, Nordahl C, Olafsen K. Quality of life after breast enlargement with implants versus augmentation mastopexy: a comparative study. Aesthet Surg J 2018; 38(12):1304–1315. doi:10.1093/asj/sjy047
- Derby BM, Codner MA. Textured silicone breast implant use in primary augmentation: core data update and review. Plast Reconstr Surg 2015; 135(1):113–124. doi:10.1097/PRS.0000000000000832
- Maxwell GP, Gabriel A. Breast implant design. Gland Surg 2017; 6(2):148–153. doi:10.21037/gs.2016.11.09
- Gabriel A, Maxwell GP. The evolution of breast implants. Clin Plast Surg 2015; 42(4):399–404. doi:10.1016/j.cps.2015.06.015
- American Society of Plastic Surgeons. Procedural statistics trends 1992–2012. www.plasticsurgery.org/documents/News/Statistics/2012/plastic-surgery-statistics-full-report-2012.pdf. Accessed January 17, 2019.
- American Society of Plastic Surgeons. Plastic surgery statistics report 2016. www.plasticsurgery.org/documents/News/Statistics/2016/plastic-surgery-statistics-full-report-2016.pdf. Accessed January 17, 2019.
- Henderson PW, Nash D, Laskowski M, Grant RT. Objective comparison of commercially available breast implant devices. Aesthetic Plast Surg 2015; 39(5):724–732. doi:10.1007/s00266-015-0537-1
- Adams WP Jr, Mallucci P. Breast augmentation. Plast Reconstr Surg 2012; 130(4):597e–611e. doi:10.1097/PRS.0b013e318262f607
- Spear SL, Jespersen MR. Breast implants: saline or silicone? Aesthet Surg J 2010; 30(4):557–570. doi:10.1177/1090820X10380401
- Cronin TD, Gerow FJ. Augmentation mammaplasty: a new “natural feel” prosthesis. In: Transactions of the Third International Conference of Plastic Surgery: October 13–18, 1963, Washington, DC.
- Maxwell GP, Gabriel A. The evolution of breast implants. Plast Reconstr Surg 2014; 134(suppl 1):12S–17S. doi:10.1097/PRS.0000000000000348
- Hillard C, Fowler JD, Barta R, Cunningham B. Silicone breast implant rupture: a review. Gland Surg 2017; 6(2):163–168. doi:10.21037/gs.2016.09.12
- Derby BM, Codner MA. Textured silicone breast implant use in primary augmentation: core data update and review. Plast Reconstr Surg 2015; 135(1):113–124. doi:10.1097/PRS.0000000000000832
- Tugwell P, Wells G, Peterson J, et al. Do silicone breast implants cause rheumatologic disorders? A systematic review for a court-appointed national science panel. Arthritis Rheum 2001; 44(11):2477–2484. pmid:11710703
- Alpert BS, Lalonde DH. MOC-PS(SM) CME article: breast augmentation. Plast Reconstr Surg 2008; 121(suppl 4):1–7. doi:10.1097/01.prs.0000305933.31540.5d
- Hidalgo DA, Spector JA. Breast augmentation. Plast Reconstr Surg 2014; 133(4):567e–583e. doi:10.1097/PRS.0000000000000033
- ClinicalTrials.gov. Study of the safety and effectiveness of Motiva Implants®. https://clinicaltrials.gov/ct2/show/NCT03579901. Accessed January 17, 2019.
- Establishment Labs. Motiva Implants. https://motivaimplants.com/why-motiva/innovation-for-enhanced-safety/. Accessed January 17, 2019.
- Sforza M, Zaccheddu R, Alleruzzo A, et al. Preliminary 3-year evaluation of experience with silksurface and velvetsurface Motiva silicone breast implants: a single-center experience with 5813 consecutive breast augmentation cases. Aesthet Surg J 2018; 38(suppl 2):S62–S73. doi:10.1093/asj/sjx150
- Huemer GM, Wenny R, Aitzetmüller MM, Duscher D. Motiva ergonomix round silksurface silicone breast implants: outcome analysis of 100 primary breast augmentations over 3 years and technical considerations. Plast Reconstr Surg 2018; 141(6):831e–842e. doi:10.1097/PRS.0000000000004367
- Lista F, Ahmad J. Evidence-based medicine: augmentation mammaplasty. Plast Reconstr Surg 2013; 132(6):1684–1696. doi:10.1097/PRS.0b013e3182a80880
- Namnoum JD, Largent J, Kaplan HM, Oefelein MG, Brown MH. Primary breast augmentation clinical trial outcomes stratified by surgical incision, anatomical placement and implant device type. J Plast Reconstr Aesthet Surg 2013; 66(9):1165–1172. doi:10.1016/j.bjps.2013.04.046
- Handel N, Garcia ME, Wixtrom R. Breast implant rupture: causes, incidence, clinical impact, and management. Plast Reconstr Surg 2013; 132(5):1128–1137. doi:10.1097/PRS.0b013e3182a4c243
- Hölmich LR, Friis S, Fryzek JP, et al. Incidence of silicone breast implant rupture. Arch Surg 2003; 138(7):801–806. doi:10.1001/archsurg.138.7.801
- Mccarthy CM, Pusic AL, Disa JJ, Cordeiro PG, Cody HS 3rd, Mehrara B. Breast cancer in the previously augmented breast. Plast Reconstr Surg 2007; 119(1):49–58. doi:10.1097/01.prs.0000244748.38742.1f
- Egeberg A, Sørensen JA. The impact of breast implant location on the risk of capsular contraction. Ann Plast Surg 2016; 77(2):255–259. doi:10.1097/SAP.0000000000000227
- Wickman M. Rapid versus slow tissue expansion for breast reconstruction: a three-year follow-up. Plast Reconstr Surg 1995; 95(4):712–718. pmid:7892316
- Kjøller K, Hölmich LR, Jacobsen PH, et al. Epidemiological investigation of local complications after cosmetic breast implant surgery in Denmark. Ann Plast Surg 2002; 48(3):229–237. pmid:11862025
- Handel N, Jensen JA, Black Q, Waisman JR, Silverstein MJ. The fate of breast implants: a critical analysis of complications and outcomes. Plast Reconstr Surg 1995; 96(7):1521–1533. pmid:7480271
- Henriksen TF, Hölmich LR, Fryzek JP, et al. Incidence and severity of short-term complications after breast augmentation: results from a nationwide breast implant registry. Ann Plast Surg 2003; 51(6):531–539. doi:10.1097/01.sap.0000096446.44082.60
- Fernandes JR, Salinas HM, Broelsch GF, et al. Prevention of capsular contracture with photochemical tissue passivation. Plast Reconstr Surg 2014; 133(3):571–577. doi:10.1097/01.prs.0000438063.31043.79
- Wong CH, Samuel M, Tan BK, Song C. Capsular contracture in subglandular breast augmentation with textured versus smooth breast implants: a systematic review. Plast Reconstr Surg 2006; 118(5):1224–1236. doi:10.1097/01.prs.0000237013.50283.d2
- Gurunluoglu R, Sacak B, Arton J. Outcomes analysis of patients undergoing autoaugmentation after breast implant removal. Plast Reconstr Surg 2013; 132(2):304–315. doi:10.1097/PRS.0b013e31829e7d9e
- Gurunluoglu R, Shafighi M, Schwabegger A, Ninkovic M. Secondary breast reconstruction with deepithelialized free flaps from the lower abdomen for intractable capsular contracture and maintenance of breast volume. J Reconstr Microsurg 2005; 21(1):35–41. doi:10.1055/s-2005-862779
- Adams WP Jr, Rios JL, Smith SJ. Enhancing patient outcomes in aesthetic reconstructive breast surgery using triple antibiotic breast irrigation: six-year prospective clinical study. Plast Reconstru Surg 2006; 118(7 suppl):46S–52S. doi:10.1097/01.prs.0000185671.51993.7e
- Moyer HR, Ghazi B, Saunders N, Losken A. Contamination in smooth gel breast implant placement: testing a funnel versus digital insertion technique in a cadaver model. Aesthet Surg J 2012; 32(2):194–199. doi:10.1177/1090820X11434505
- Handel N. The effect of silicone implants on the diagnosis, prognosis, and treatment of breast cancer. Plast Reconstr Surg 2007; 120(7 suppl 1):81S–93S. doi:10.1097/01.prs.0000286578.94102.2b
- Kjøller K, Friis S, Lipworth L, Mclaughlin JK, Olsen JH. Adverse health outcomes in offspring of mothers with cosmetic breast implants: a review. Plast Reconstr Surg 2007; 120(7 suppl 1):129S–134S. doi:10.1097/01.prs.0000286571.93392.00
- Semple JL. Breast-feeding and silicone implants. Plast Reconstr Surg 2007; 120(7 suppl 1):123S–128S. doi:10.1097/01.prs.0000286579.27852.ed
- de Boer M, van leeuwen FE, Hauptmann M, et al. Breast implants and the risk of anaplastic large-cell lymphoma in the breast. JAMA Oncol 2018; 4(3):335–341. doi:10.1001/jamaoncol.2017.4510
- McCarthy CM, Horwitz SM. Association of breast implants with anaplastic large-cell lymphoma. JAMA Oncol 2018; 4(3):341–342. doi:10.1001/jamaoncol.2017.4467
- American Society of Plastic Surgeons. BIA-ALCL physician resources. www.plasticsurgery.org/for-medical-professionals/health-policy/bia-alcl-physician-resources. Accessed December 17, 2018.
- The American Society for Aesthetic Plastic Surgery, Inc. Member FAQs: latest information on ALCL. www.surgery.org/sites/default/files/Member-FAQs_1.pdf. Accessed January 17, 2019.
- The American Society of Plastic Surgeons. BIA-ALCL resources: summary and quick facts. www.plasticsurgery.org/for-medical-professionals/health-policy/bia-alcl-summary-and-quick-facts. Accessed January 17, 2019.
- National Comprehensive Cancer Network. T-cell lymphomas. www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf.
- The Plastic Surgery Foundation PROFILE Registry. www.thepsf.org/research/registries/profile. Accessed January 17, 2019.
- Sarwer DB. The psychological aspects of cosmetic breast augmentation. Plast Reconstr Surg 2007; 120(7 suppl 1):110S–117S. doi:10.1097/01.prs.0000286591.05612.72
- Rohrich RJ, Adams WP, Potter JK. A review of psychological outcomes and suicide in aesthetic breast augmentation. Plast Reconstr Surg 2007; 119(1):401–408. doi:10.1097/01.prs.0000245342.06662.00
- Kalaaji A, Bjertness CB, Nordahl C, Olafsen K. Survey of breast implant patients: characteristics, depression rate, and quality of life. Aesthet Surg J 2013; 33(2):252–257. doi:10.1177/1090820X12473106
- Kalaaji A, Dreyer S, Brinkmann J, Maric I, Nordahl C, Olafsen K. Quality of life after breast enlargement with implants versus augmentation mastopexy: a comparative study. Aesthet Surg J 2018; 38(12):1304–1315. doi:10.1093/asj/sjy047
KEY POINTS
- Nearly 300,000 breast augmentation surgeries are performed annually, making this the second most common aesthetic procedure in US women (after liposuction).
- Today, silicone gel implants dominate the world market, and in the United States, approximately 60% of implants contain silicone gel filler.
- Capsular contracture is the most common complication of breast augmentation, typically presenting within the first postoperative year and with increasing risk over time. It occurs with both silicone and saline breast implants.
- Numerous studies have demonstrated the safety of silicone breast implants with regard to autoimmune disease incidence. However, the risk of associated anaplastic large-cell lymphoma must be discussed at every consultation, and confirmed cases should be reported to a national registry.
Heart failure guidelines: What you need to know about the 2017 focused update
In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) jointly released a focused update1 of the 2013 ACC/AHA guideline for managing heart failure.2 This is the second focused update of the 2013 guidelines; the first update,3 in 2016, covered 2 new drugs (sacubitril-valsartan and ivabradine) for chronic stage C heart failure with reduced ejection fraction (HFrEF).
Rather than focus on new medication classes, this second update provides recommendations regarding:
- Preventing the progression to left ventricular dysfunction or heart failure in patients at high risk (stage A) through screening with B-type natriuretic peptide (BNP) and aiming for more aggressive blood pressure control
- Inpatient biomarker use
- Medications in heart failure with preserved ejection fraction (HFpEF, or diastolic heart failure)
- Blood pressure targets in stage C heart failure
- Managing important comorbidities such as iron deficiency and sleep-disordered breathing to decrease morbidity, improve functional capacity, and enhance quality of life.
These guidelines and the data that underlie them are explored below. We also discuss potential applications to the management of hospitalization for acute decompensated heart failure (ADHF).
COMMON, COSTLY, AND DEBILITATING
Heart failure—defined by the ACC/AHA as the complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood—remains one of the most common, costly, and debilitating diseases in the United States.2 Based on National Health and Nutrition Examination Survey data from 2011 to 2014, an estimated 6.5 million US adults have it, with projections of more than 8 million by 2030.4,5 More than 960,000 new cases are thought to occur annually, with a lifetime risk of developing it of roughly 20% to 45%.6
Despite ever-growing familiarity and some significant strides in management, the death rate in this syndrome is substantial. After admissions for heart failure (which number 1 million per year), the mortality rate is roughly 10% at 1 year and 40% at 5 years.6 Also staggering are the associated costs, with $30.7 billion attributed to heart failure in 2012 and a projected $69.7 billion annually by 2030.5 Thus, we must direct efforts not only to treatment, but also to prevention.
Preventive efforts would target patients with ACC/AHA stage A heart failure—those at high risk for developing but currently without evidence of structural heart disease or heart failure symptoms (Table 1).7 This group may represent up to one-third of the US adult population, or 75 million people, when including the well-recognized risk factors of coronary artery disease, hypertension, diabetes mellitus, and chronic kidney disease in those without left ventricular dysfunction or heart failure.8
BIOMARKERS FOR PREVENTION
Past ACC/AHA heart failure guidelines2 have included recommendations on the use of biomarkers to aid in diagnosis and prognosis and, to a lesser degree, to guide treatment of heart failure. Largely based on 2 trials (see below), the 2017 guidelines go further, issuing a recommendation on the use of natriuretic peptide biomarkers in a screening strategy to prompt early intervention and prevent the progression to clinical heart failure in high-risk patients (stage A heart failure).
The PONTIAC trial
The NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease (PONTIAC) trial9 randomized 300 outpatients with type 2 diabetes mellitus and an elevated N-terminal proBNP (NT-proBNP) level (> 125 pg/mL) to standard medical care vs standard care plus intensive up-titration of renin-angiotensin system antagonists and beta-blockers in a cardiac clinic over 2 years.
Earlier studies10 had shown NT-proBNP levels to have predictive value for cardiac events in diabetic patients, while the neurohormonal treatments were thought to have an established record of preventing primary and secondary cardiovascular events. In PONTIAC, a significant reduction was seen in the primary end point of hospitalization or death due to cardiac disease (hazard ratio [HR] 0.351, P = .044), as well as in the secondary end point of hospitalization due to heart failure (P < .05), in the aggressive-intervention group. These results laid the foundation for the larger St. Vincent’s Screening to Prevent Heart Failure (STOP-HF) trial.11
The STOP-HF trial
The STOP-HF trial randomized 1,235 outpatients who were at high risk but without left ventricular dysfunction or heart failure symptoms (stage A) to annual screening alone vs annual screening plus BNP testing, in which a BNP level higher than 50 pg/mL triggered echocardiography and evaluation by a cardiologist who would then assist with medications.11
Eligible patients were over age 40 and had 1 or more of the following risk factors:
- Diabetes mellitus
- Hypertension
- Hypercholesterolemia
- Obesity (body mass index > 30 kg/m2)
- Vascular disease (coronary, cerebral, or peripheral arterial disease)
- Arrhythmia requiring treatment
- Moderate to severe valvular disease.
After a mean follow-up of 4.3 years, the primary end point, ie, asymptomatic left ventricular dysfunction with or without newly diagnosed heart failure, was found in 9.7% of the control group and in only 5.9% of the intervention group with BNP screening, a 42% relative risk reduction (P = .013).
Similarly, the incidence of secondary end points of emergency hospitalization for a cardiovascular event (arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis or embolization, or heart failure) was also lower at 45.2 vs 24.4 per 1,000 patient-years, a 46% relative risk reduction.
An important difference in medications between the 2 groups was an increase in subsequently prescribed renin-angiotensin-aldosterone system therapy, mainly consisting of angiotensin II receptor blockers (ARBs), in those with elevated BNP in the intervention group. Notably, blood pressure was about the same in the 2 groups.11
Although these findings are encouraging, larger studies are needed, as the lack of blinding, low event rates, and small absolute risk reduction make the results difficult to generalize.
New or modified recommendations for screening
Employing this novel prevention strategy in the extremely large number of patients with stage A heart failure, thought to be up to one-third of the US adult population, may serve as a way to best direct and utilize limited medical resources.8
BIOMARKERS FOR PROGNOSIS OR ADDED RISK STRATIFICATION
The 2013 guidelines2 recognized that a significant body of work had accumulated showing that natriuretic peptide levels can predict outcomes in both chronic and acute heart failure. Thus, in both conditions, the guidelines contained separate class Ia recommendations to obtain a natriuretic peptide level, troponin level, or both to establish prognosis or disease severity.
The 2017 update1 underscores the importance of timing in measuring natriuretic peptide levels during admission for ADHF, with emphasis on obtaining them at admission and at discharge for acute and postdischarge prognosis. The completely new class IIa recommendation to obtain a predischarge natriuretic peptide level for postdischarge prognosis was based on a number of observational studies, some of which we explore below.
The ELAN-HF meta-analysis
The European Collaboration on Acute Decompensated Heart Failure (ELAN-HF)12 performed a meta-analysis to develop a discharge prognostication score for ADHF that included both absolute level and percent change in natriuretic peptide levels at the time of discharge.
Using data from 7 prospective cohorts totaling 1,301 patients, the authors found that incorporation of these values into a subsequently validated risk model led to significant improvements in the ability to predict the end points of all-cause mortality and the combined end point of all-cause mortality or first readmission for a cardiovascular reason within 180 days.
The OPTIMIZE-HF retrospective analysis
Data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) were retrospectively analyzed13 to determine whether postdischarge outcomes were best predicted by natriuretic peptide levels at admission or discharge or by the relative change in natriuretic peptide level. More than 7,000 patients age 65 or older, in 220 hospitals, were included, and Cox prediction models were compared using clinical variables alone or in combination with the natriuretic peptide levels.
The model that included the discharge natriuretic peptide level was found to be the most predictive, with a c-index of 0.693 for predicting mortality and a c-index of 0.606 for mortality or rehospitalization at 1 year.
New or modified recommendations on biomarkers for prognosis
The 2017 update1 modified the earlier recommendation to obtain a natriuretic peptide or troponin level or both at admission for ADHF to establish prognosis. This now has a class Ia recommendation, emphasizing that such levels be obtained on admission. In addition, a new class IIa recommendation is made to obtain a predischarge natriuretic peptide level for postdischarge prognosis. The former class Ia recommendation to obtain a natriuretic peptide level in chronic heart failure to establish prognosis or disease severity remains unchanged.
Also worth noting is what the 2017 update does not recommend in regard to obtaining biomarker levels. It emphasizes that many patients, particularly those with advanced (stage D) heart failure, have a poor prognosis that is well established with or without biomarker levels. Additionally, there are many cardiac and noncardiac causes of natriuretic peptide elevation; thus, clinical judgment remains paramount.
The 2017 update1 also cautions against setting targets of percent change in or absolute levels of natriuretic peptide at discharge despite observational and retrospective studies demonstrating better outcomes when levels are reduced, as treating for any specific target has never been studied in a large prospective study. Thus, doing so may result in unintended harm. Rather, clinical judgment and optimization of guideline-directed management and therapy are encouraged (Table 2).
PHARMACOLOGIC TREATMENT FOR STAGE C HFpEF
Although the 2013 guidelines2 contain many class I recommendations for various medications in chronic HFrEF, not a single such recommendation is found for chronic HFpEF. A review by Okwuosa et al7 covered HFrEF, including the most recent additions on which the 2016 update was based, sacubitril-valsartan and ivabradine. The 2016 update was similarly devoid of recommendations regarding specific medications in HFpEF, leaving only the 2013 class IIb recommendation to consider using an ARB to decrease hospitalizations in HFpEF.
Evidence behind this recommendation came from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity program’s randomized controlled trial in 3,025 patients with New York Heart Association (NYHA) class II to IV heart failure and left ventricular ejection fraction over 40%, who were treated with candesartan or placebo.14 Over a median follow-up of 36.6 months, there was no significant difference in the primary composite outcome of cardiovascular death or admission for heart failure, but significantly fewer patients in the candesartan arm were admitted (230 vs 270, P = .017). Thus the recommendation.
Although this finding was encouraging, it was clear that no blockbuster drug for HFpEF had been identified. Considering that roughly half of all heart failure patients have preserved ejection fraction, the discovery of such a drug for HFpEF would be met with much excitement.15 Subsequently, other medication classes have been evaluated in the hope of benefit, allowing the 2017 update to provide specific recommendations for aldosterone antagonists, nitrates, and phosphodiesterase-5 inhibitors in HFpEF.
ALDOSTERONE ANTAGONISTS FOR HFpEF
Mineralocorticoid receptor antagonists had previously been shown to significantly reduce morbidity and mortality rates in patients with HFrEF.16 In addition to aldosterone’s effects on sodium retention and many other pathophysiologic mechanisms relating to heart failure, this hormone is also known to play a role in promoting myocardial fibrosis.17 Accordingly, some have wondered whether aldosterone antagonists could improve diastolic dysfunction, and perhaps outcomes, in HFpEF.
The Aldo-DHF trial
The Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial investigated whether the aldosterone antagonist spironolactone would improve diastolic function or maximal exercise capacity in chronic HFpEF.18 It randomized 422 ambulatory patients with NYHA stage II or III heart failure, preserved left ventricular ejection fraction (≥ 50%), and echocardiographic evidence of diastolic dysfunction to receive spironolactone 25 mg daily or placebo.
Although no significant difference was seen in maximal exercise capacity, follow-up over 1 year nevertheless showed significant improvement in echocardiographic diastolic dysfunction (E/e') and perhaps reverse remodeling (decreased left ventricular mass index). These improvements spurred larger trials powered to detect whether clinical outcomes could also be improved.
The TOPCAT trial
The Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial19 was a large, multicenter, international, double-blind, placebo-controlled trial that investigated whether spironolactone could improve clinical outcomes in HFpEF. It randomized 3,445 patients with symptomatic heart failure and left ventricular ejection fraction of 45% or more to spironolactone 15 to 45 mg daily or placebo.
The effect on a composite primary outcome of death from cardiovascular cause, aborted cardiac arrest, or hospitalization for heart failure was evaluated over a mean follow-up of 3.3 years, with only a small (HR 0.89), nonclinically significant reduction evident. Those in the spironolactone group did have a significantly lower incidence of hospitalization for heart failure (12.0% vs 14.2%, P = .04).
Although the results were disappointing in this essentially negative trial, significant regional variations evident on post hoc analysis prompted further investigation and much controversy since the trial’s publication in 2014.
Participants came in roughly equal proportions from the Americas (United States, Canada, Brazil, and Argentina—51%) and from Russia and Georgia (49%), but outcomes between the two groups were markedly different. Concern was first raised when immediate review discovered a 4-fold lower rate of the primary outcome in the placebo groups from Russia and Georgia (8.4%), a rate in fact similar to that in patients without heart failure.19 This led to further exploration that identified other red flags that called into question the data integrity from the non-American sites.20
Not only did patients receiving spironolactone in Russia and Georgia not experience the reduction in clinical outcomes seen in their American counterparts, they also did not manifest the expected elevations in potassium and creatinine, and spironolactone metabolites were undetectable in almost one-third of patients.21
These findings prompted a post hoc analysis that included only the 51% (1,767 patients) of the study population coming from the Americas; in this subgroup, treatment with spironolactone was associated with a statistically significant 18% relative risk reduction in the primary composite outcome, a 26% reduction in cardiovascular mortality, and an 18% reduction in hospitalization for heart failure.20
New or modified recommendations on aldosterone receptor antagonists
Nitrates and phosphodiesterase-5 inhibitors
Earlier studies indicated that long-acting nitrates are prescribed in 15% to 50% of patients with HFpEF, perhaps based on extrapolation from studies in HFrEF suggesting that they might improve exercise intolerance.22 Some have speculated that the hemodynamic effects of nitrates, such as decreasing pulmonary congestion, might improve exercise intolerance in those with the stiff ventricles of HFpEF as well, prompting further study.
The NEAT-HFpEF trial
The Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction (NEAT-HFpEF) trial22 investigated whether extended-release isosorbide mononitrate would increase daily activity levels in patients with HFpEF. This double-blind, crossover study randomized 110 patients with HFpEF (ejection fraction ≥ 50%) and persistent dyspnea to escalating doses of isosorbide mononitrate or placebo over 6 weeks, then to the other arm for another 6 weeks. Daily activity levels during the 120-mg phase were measured with a continuously worn accelerometer.
No beneficial effect of nitrates was evident, with a nonsignificant trend towards decreased activity levels, a significant decrease in hours of activity per day (–0.30 hours, P = .02), and no change in the other secondary end points such as quality-of-life score, 6-minute walk distance, or natriuretic peptide level.
Suggested explanations for these negative findings include the possibility of rapid dose escalation leading to increased subtle side effects (headache, dizziness, fatigue) that, in turn, decreased activity. Additionally, given the imprecise diagnostic criteria for HFpEF, difficulties with patient selection may have led to inclusion of a large number of patients without elevated left-sided filling pressures.23
The RELAX trial
The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction (RELAX) trial24 investigated whether the phosphodiesterase-5 inhibitor sildenafil would improve exercise capacity in HFpEF. Improvements in both exercise capacity and clinical outcomes had already been seen in earlier trials in patients with pulmonary hypertension, as well as in those with HFrEF.25 A smaller study in HFpEF patients with pulmonary hypertension was also encouraging.26
Thus, it was disappointing that, after randomizing 216 outpatients with HFpEF to sildenafil or placebo for 24 weeks, no benefit was seen in the primary end point of change in peak oxygen consumption or in secondary end points of change in 6-minute walk distance or composite clinical score. Unlike in NEAT-HFpEF, patients here were required to have elevated natriuretic peptide levels or elevated invasively measured filling pressures.
The study authors speculated that pulmonary arterial hypertension and right ventricular systolic failure might need to be significant for patients with HFpEF to benefit from phosphodiesterase-5 inhibitors, with their known effects of dilation of pulmonary vasculature and increasing contractility of the right ventricle.24
New or modified recommendations on nitrates or phosphodiesterase-5 drugs
Given these disappointing results, the 2017 update provides a class III (no benefit) recommendation against the routine use of nitrates or phosphodiesterase-5 inhibitors to improve exercise tolerance or quality of life in HFpEF, citing them as ineffective (Table 3).1
IRON DEFICIENCY IN HEART FAILURE
Not only is iron deficiency present in roughly 50% of patients with symptomatic heart failure (stage C and D HFrEF),27 it is also associated with increased heart failure symptoms such as fatigue and exercise intolerance,28 reduced functional capacity, decreased quality of life, and increased mortality.
Notably, this association exists regardless of the hemoglobin level.29 In fact, even in those without heart failure or anemia, iron deficiency alone results in worsened aerobic performance, exercise intolerance, and increased fatigue.30 Conversely, improvement in symptoms, exercise tolerance, and cognition have been shown with repletion of iron stores in such patients.31
At the time of the 2013 guidelines, only a single large trial of intravenous iron in HFrEF and iron deficiency had been carried out (see below), and although the results were promising, it was felt that the evidence base on which to make recommendations was inadequate. Thus, recommendations were deferred until more data could be obtained.
Of note, in all the trials discussed below, iron deficiency was diagnosed in the setting of heart failure as ferritin less than 100 mg/mL (absolute iron deficiency) or as ferritin 100 to 300 mg/mL with transferrin saturation less than 20% (relative deficiency).32
The CONFIRM-HF trial
As in the Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial,33 the subsequent Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination With Chronic Heart Failure (CONFIRM-HF) trial34 involved the intravenous infusion of iron (ferric carboxymaltose) in outpatients with symptomatic HFrEF and iron deficiency. It showed that benefits remained evident with a more objective primary end point (change in 6-minute walk test distance at 24 weeks), and that such benefits were sustained, as seen in numerous secondary end points related to functional capacity at 52 weeks. Benefits in CONFIRM-HF were evident independently from anemia, specifically whether hemoglobin was under or over 12 g/dL.
Although these results were promising, it remained unclear whether such improvements could be obtained with a much easier to administer, more readily available, and less expensive oral iron formulation.
The IRONOUT-HF trial
The Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT-HF) trial35 investigated whether oral, rather than intravenous, iron supplementation could improve peak exercise capacity in patients with HFrEF and iron deficiency. This double-blind, placebo-controlled trial randomized 225 patients with NYHA class II to IV HFrEF and iron deficiency to treatment with oral iron polysaccharide (150 mg twice daily) or placebo for 16 weeks.
Contrary to the supportive findings above, no significant change was seen in the primary end point of change in peak oxygen uptake or in any of the secondary end points (change in 6-minute walk, quality of life). Also, despite a 15-fold increase in the amount of iron administered in oral form compared with intravenously, little change was evident in the indices of iron stores over the course of the study, with only a 3% increase in transferrin saturation and an 11 ng/mL increase in ferritin. The intravenous trials resulted in a 4-fold greater increase in transferrin saturation and a 20-fold greater increase in ferritin.36
What keeps heart failure patients from absorbing oral iron? It is unclear why oral iron administration in HFrEF, such as in IRONOUT-HF, seems to be so ineffective, but hepcidin—a protein hormone made by the liver that shuts down intestinal iron absorption and iron release from macrophages—may play a central role.37 When iron stores are adequate, hepcidin is upregulated to prevent iron overload. However, hepcidin is also increased in inflammatory states, and chronic heart failure is often associated with inflammation.
With this in mind, the IRONOUT-HF investigators measured baseline hepcidin levels at the beginning and at the end of the 16 weeks and found that high baseline hepcidin levels predicted poorer response to oral iron. Other inflammatory mediators, such as interleukin 6, may also play a role.38,39 Unlike oral iron formulations such as iron polysaccharide, intravenous iron (ferric carboxymaltose) bypasses these regulatory mechanisms, which may partly explain its much more significant effect on the indices of iron stores and outcomes.
New or modified recommendations on iron
The 2017 update1 makes recommendations regarding iron deficiency and anemia in heart failure for the first time.
A class IIb recommendation states that it might be reasonable to treat NYHA class II and III heart failure patients with iron deficiency with intravenous iron to improve functional status and quality of life. A strong recommendation has been deferred until more is known about morbidity and mortality effects from adequately powered trials, some of which are under way and explored further below.
The 2017 update also withholds any recommendations regarding oral iron supplementation in heart failure, citing an uncertain evidence base. Certainly, the subsequent IRONOUT-HF trial does not lend enthusiasm for this approach.
Lastly, given the lack of benefit coupled with the increased risk of thromboembolic events evident in a trial of darbepoetin alfa vs placebo in non-iron deficiency-related anemia in HFrEF,40,41 the 2017 update provides a class III (no benefit) recommendation against using erythropoietin-stimulating agents in heart failure and anemia.
HYPERTENSION IN HEART FAILURE
The 2013 guidelines for the management of heart failure simply provided a class I recommendation to control hypertension and lipid disorders in accordance with contemporary guidelines to lower the risk of heart failure.1
SPRINT
The Systolic Blood Pressure Intervention Trial (SPRINT)42 sought to determine whether a lower systolic blood pressure target (120 vs 140 mm Hg) would reduce clinical events in patients at high risk for cardiovascular events but without diabetes mellitus. Patients at high risk were defined as over age 75, or with known vascular disease, chronic kidney disease, or a Framingham Risk Score higher than 15%. This multicenter, open-label controlled trial randomized 9,361 patients to intensive treatment (goal systolic blood pressure < 120 mm Hg) or standard treatment (goal systolic blood pressure < 140 mm Hg).
SPRINT was stopped early at a median follow-up of 3.26 years when a 25% relative risk reduction in the primary composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes became evident in the intensive-treatment group (1.65% vs 2.19% per year, HR 0.75, P < .0001).
All-cause mortality was also lower in the intensive-treatment group (HR 0.73, P = .003), while the incidence of serious adverse events (hypotension, syncope, electrolyte abnormalities, acute kidney injury, and noninjurious falls) was only slightly higher (38.3% vs 37.1%, P = .25). Most pertinent, a significant 38% relative risk reduction in heart failure and a 43% relative risk reduction in cardiovascular events were also evident.
Of note, blood pressure measurements were taken as the average of 3 measurements obtained by an automated cuff taken after the patient had been sitting quietly alone in a room for 5 minutes.
New or modified recommendations on hypertension in heart failure
Given the impressive 25% relative risk reduction in myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes in SPRINT,42 the 2017 update1 incorporated the intensive targets of SPRINT into its recommendations. However, to compensate for what are expected to be higher blood pressures obtained in real-world clinical practice as opposed to the near-perfect conditions used in SPRINT, a slightly higher blood pressure goal of less than 130/80 mm Hg was set.
Although not specifically included in SPRINT, given the lack of trial data on specific blood pressure targets in HFrEF and the decreased cardiovascular events noted above, a class I (level of evidence C, expert opinion) recommendation to target a goal systolic blood pressure less than 130 mm Hg in stage C HFrEF with hypertension is also given. Standard guideline-directed medications in the treatment of HFrEF are to be used (Table 4).
Similarly, a new class I (level of evidence C, expert opinion) recommendation is given for hypertension in HFpEF to target a systolic blood pressure of less than 130 mm Hg, with special mention to first manage any element of volume overload with diuretics. Other than avoiding nitrates (unless used for angina) and phosphodiesterase inhibitors, it is noted that few data exist to guide the choice of antihypertensive further, although perhaps renin-angiotensin-aldosterone system inhibition, especially aldosterone antagonists, may be considered. These recommendations are fully in line with the 2017 ACC/AHA high blood pressure clinical practice guidelines,43 ie, that renin-angiotensin-aldosterone system inhibition with an angiotensin-converting enzyme (ACE) inhibitor or ARB and especially mineralocorticoid receptor antagonists would be the preferred choice (Table 4).
SLEEP-DISORDERED BREATHING IN HEART FAILURE
Sleep-disordered breathing, either obstructive sleep apnea (OSA) or central sleep apnea, is quite commonly associated with symptomatic HFrEF.44 Whereas OSA is found in roughly 18% and central sleep apnea in 1% of the general population, sleep-disordered breathing is found in nearly 60% of patients with HFrEF, with some studies showing a nearly equal proportion of OSA and central sleep apnea.45 A similar prevalence is seen in HFpEF, although with a much higher proportion of OSA.46 Central sleep apnea tends to be a marker of more severe heart failure, as it is strongly associated with severe cardiac systolic dysfunction and worse functional capacity.47
Not surprisingly, the underlying mechanism of central sleep apnea is quite different from that of OSA. Whereas OSA predominantly occurs because of repeated obstruction of the pharynx due to nocturnal pharyngeal muscle relaxation, no such airway patency issues or strained breathing patterns exist in central sleep apnea. Central sleep apnea, which can manifest as Cheyne-Stokes respirations, is thought to occur due to an abnormal ventilatory control system with complex pathophysiology such as altered sensitivity of central chemoreceptors to carbon dioxide, interplay of pulmonary congestion, subsequent hyperventilation, and prolonged circulation times due to reduced cardiac output.48
What the two types of sleep-disordered breathing have in common is an association with negative health outcomes. Both appear to induce inflammation and sympathetic nervous system activity via oxidative stress from intermittent nocturnal hypoxemia and hypercapnea.49 OSA was already known to be associated with significant morbidity and mortality rates in the general population,50 and central sleep apnea had been identified as an independent predictor of mortality in HFrEF.51
At the time of the 2013 guidelines, only small or observational studies with limited results had been done evaluating treatment effects of continuous positive airway pressure therapy (CPAP) on OSA and central sleep apnea. Given the relative paucity of data, only a single class IIa recommendation stating that CPAP could be beneficial to increase left ventricular ejection fraction and functional status in concomitant sleep apnea and heart failure was given in 2013. However, many larger trials were under way,52–59 some with surprising results such as a significant increase in cardiovascular and all-cause mortality (Table 5).54
New or modified recommendations on sleep-disordered breathing
Given the common association with heart failure (60%)45 and the marked variation in response to treatment, including potential for harm with adaptive servo-ventilation and central sleep apnea, a class IIa recommendation is made stating that it is reasonable to obtain a formal sleep study in any patient with symptomatic (NYHA class II–IV) heart failure.1
Due to the potential for harm with adaptive servo-ventilation in patients with central sleep apnea and NYHA class II to IV HFrEF, a class III (harm) recommendation is made against its use.
Largely based on the results of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial,56 a class IIb, level of evidence B-R (moderate, based on randomized trials) recommendation is given, stating that the use of CPAP in those with OSA and known cardiovascular disease may be reasonable to improve sleep quality and reduce daytime sleepiness.
POTENTIAL APPLICATIONS IN ACUTE DECOMPENSATED HEART FAILURE
Although the 2017 update1 is directed mostly toward managing chronic heart failure, it is worth considering how it might apply to the management of ADHF.
SHOULD WE USE BIOMARFER TARGETS TO GUIDE THERAPY IN ADHF?
The 2017 update1 does offer direct recommendations regarding the use of biomarker levels during admissions for ADHF. Mainly, they emphasize that the admission biomarker levels provide valuable information regarding acute prognosis and risk stratification (class I recommendation), while natriuretic peptide levels just before discharge provide the same for the postdischarge timeframe (class IIa recommendation).
The update also explicitly cautions against using a natriuretic peptide level-guided treatment strategy, such as setting targets for predischarge absolute level or percent change in level of natriuretic peptides during admissions for ADHF. Although observational and retrospective studies have shown better outcomes when levels are reduced at discharge, treating for any specific inpatient target has never been tested in any large, prospective study; thus, doing so could result in unintended harm.
So what do we know?
McQuade et al systematic review
McQuade et al57 performed a systematic review of more than 40 ADHF trials, which showed that, indeed, patients who achieved a target absolute natriuretic peptide level (BNP ≤ 250 pg/mL) or percent reduction (≥ 30%) at time of discharge had significantly improved outcomes such as reduced postdischarge all-cause mortality and rehospitalization rates. However, these were mostly prospective cohort studies that did not use any type of natriuretic peptide level-guided treatment protocol, leaving it unclear whether such a strategy could positively influence outcomes.
For this reason, both McQuade et al57 and, in an accompanying editorial, Felker et al58 called for properly designed, randomized controlled trials to investigate such a strategy. Felker noted that only 2 such phase II trials in ADHF have been completed,59,60 with unconvincing results.
PRIMA II
The Multicenter, Randomized Clinical Trial to Study the Impact of In-hospital Guidance for Acute Decompensated Heart Failure Treatment by a Predefined NT-ProBNP Target on the Reduction of Readmission and Mortality Rates (PRIMA II)60 randomized patients to natriuretic peptide level-guided treatment or standard care during admission for ADHF.
Many participants (60%) reached the predetermined target of 30% reduction in natriuretic peptide levels at the time of clinical stabilization and randomization; 405 patients were randomized. Patients in the natriuretic peptide level-guided treatment group underwent a prespecified treatment algorithm, with repeat natriuretic peptide levels measured again after the protocol.
Natriuretic peptide-guided therapy failed to show any significant benefit in any clinical outcomes, including the primary composite end point of mortality or heart failure readmissions at 180 days (36% vs 38%, HR 0.99, 95% confidence interval 0.72–1.36). Consistent with the review by McQuade et al,57 achieving the 30% reduction in natriuretic peptide at discharge, in either arm, was associated with a better prognosis, with significantly lower mortality and readmission rates at 180 days (HR 0.39 for rehospitalization or death, 95% confidence interval 0.27–0.55).
As in the observational studies, those who achieved the target natriuretic peptide level at the time of discharge had a better prognosis than those who did not, but neither study showed an improvement in clinical outcomes using a natriuretic peptide level-targeting treatment strategy.
No larger randomized controlled trial results are available for guided therapy in ADHF. However, additional insight may be gained from a subsequent trial61 that evaluated biomarker-guided titration of guideline-directed medical therapy in outpatients with chronic HFrEF.
The GUIDE-IT trial
That trial, the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT)61 trial, was a large multicenter attempt to determine whether a natriuretic peptide-guided treatment strategy was more effective than standard care in the management of 894 high-risk outpatients with chronic HFrEF. Earlier, promising results had been obtained in a meta-analysis62 of more than 11 similar trials in 2,000 outpatients, with a decreased mortality rate (HR 0.62) seen in the biomarker-guided arm. However, the results had not been definitive due to being underpowered.62
Unfortunately, the results of GUIDE-IT were disappointing, with no significant difference in either the combined primary end point of mortality or hospitalization for heart failure, or the secondary end points evident at 15 months, prompting early termination for futility.61 Among other factors, the study authors postulated that this may have partly resulted from a patient population with more severe heart failure and resultant azotemia, limiting the ability to titrate neurohormonal medications to the desired dosage.
The question of whether patients who cannot achieve such biomarker targets need more intensive therapy or whether their heart failure is too severe to respond adequately echoes the question often raised in discussions of inpatient biomarker-guided therapy.58 Thus, only limited insight is gained, and it remains unclear whether a natriuretic peptide-guided treatment strategy can improve outpatient or inpatient outcomes. Until this is clarified, clinical judgment and optimization of guideline-directed management and therapy should remain the bedrock of treatment.
SHOULD ALDOSTERONE ANTAGONISTS BE USED IN ACUTE HFpEF?
Given the encouraging results in chronic HFpEF from post hoc analyses of TOPCAT, are there any additional recent data suggesting a role for aldosterone antagonists such as spironolactone in acute HFpEF?
The ATHENA-HF trial
The Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial63 compared treatment with high-dose spironolactone (100 mg) for 96 hours vs usual care in 360 patients with ADHF. The patient population included those with HFrEF and HFpEF, and usual care included low-dose spironolactone (12.5–25 mg) in roughly 15% of patients. High-dose mineralocorticoid receptor antagonists have been shown to overcome diuretic resistance, improve pulmonary vascular congestion, and partially combat the adverse neurohormonal activation seen in ADHF.
Unfortunately, the trial was completely neutral in regard to the primary end point of reduction in natriuretic peptide levels as well as to the secondary end points of 30-day mortality rate, heart failure readmission, clinical congestion scores, urine output, and change in weight. No suggestion of additional benefit was seen in subgroup analysis of patients with acute HFpEF (ejection fraction > 45%), which yielded similar results.63
Given these lackluster findings, routine use of high-dose spironolactone in ADHF is not recommended.64 However, the treatment was well tolerated, without significant adverse effects of hyperkalemia or kidney injury, leaving the door open as to whether it may have utility in selected patients with diuretic resistance.
Should ARNIs and ivabradine be started during ADHF admissions?
The first half of the focused update3 of the 2013 guidelines,2 reviewed by Okwuosa et al,7 provided recommendations for the use of sacubitril-valsartan, an angiotensin-neprilysin inhibitor (ARNI), and ivabradine, a selective sinoatrial node If channel inhibitor, in chronic HFrEF.
Sacubitril-valsartan was given a class I recommendation for use in patients with NYHA class II or III chronic HFrEF who tolerate an ACE inhibitor or an ARB. This recommendation was given largely based on the benefits in mortality and heart failure hospitalizations seen in PARADIGM-HF (the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)65 compared with enalapril (HR 0.80, 95% CI 0.73–0.87, P < .001).
There is currently no recommendation on initiation or use of ARNIs during admissions for ADHF, but a recent trial may lend some insight.66
THE PIONEER-HF trial
The Comparison of Sacubitril/Valsartan vs Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF) trial66 randomized patients admitted for acute HFrEF, once stabilized, to sacubitril-valsartan or enalapril. Encouragingly, the percentage change of natriuretic peptide levels from the time of inpatient initiation to 4 and 8 weeks thereafter, the primary efficacy end point, was 46.7% with sacubitril-valsartan versus 25.3% with enalapril alone (ratio of change 0.71, 95% CI 0.63–0.81, P < .001). Although not powered for such, a prespecified analysis of a composite of clinical outcomes was also favorable for sacubitril-valsartan, largely driven by a 44% decreased rate of rehospitalization. More definitive, and quite reassuring, was that no significant difference was seen in the key safety outcomes of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema. These results were also applicable to the one-third of study participants who had no former diagnosis of heart failure, the one-third identifying as African American, and the one-third who had not been taking an ACE inhibitor or ARB. These results, taken together with the notion that at study completion the patients become similar to those included in PARADIGM-HF, have led some to assert that PIONEER-HF has the potential to change clinical practice.
Ivabradine was given a class IIa recommendation for use in patients with NYHA class II or III chronic HFrEF with a resting heart rate of at least 70 bpm, in sinus rhythm, despite being on optimal medical therapy including a beta-blocker at a maximum tolerated dose.
This recommendation was largely based on SHIFT (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial), which randomized patients to ivabradine or placebo to evaluate the effects of isolated lowering of the heart rate on the composite primary outcome of cardiovascular death or hospitalization. A significant reduction was seen in the ivabradine arm (HR 0.82, 95% CI 0.75–0.90, P < .0001), mainly driven by decreased hospitalizations.67
Subsequently, a small unblinded single-center study was undertaken to evaluate the efficacy and safety of initiating ivabradine during admissions for ADHF.68
THE ETHIC-AHF trial
The Effect of Early Treatment With Ivabradine Combined With Beta-Blockers vs Beta-Blockers Alone in Patients Hospitalized With Heart Failure and Reduced Left Ventricular Ejection Fraction (ETHIC-AHF) trial68 sought to determine the safety and effectiveness of early coadministration of ivabradine with beta-blockers in patients with acute HFrEF.
This single-center, unblinded study randomized 71 patients to ivabradine and beta-blockade or beta-blockade alone upon clinical stabilization (24–48 hours) after admission for acute decompensated HFrEF.
The primary end point was heart rate at 28 days, with the ivabradine group showing a statistically significant decrease (64 vs 70 bpm, P = .01), which persisted at 4 months. There was no significant difference in the secondary end points of adverse drug effects or the composite of clinical event outcomes (all-cause mortality, admission for heart failure or cardiovascular cause), but a number of surrogate end points including left ventricular ejection fraction, BNP level, and NYHA functional class at 4 months showed mild improvement.
Although this study provided evidence that the coadministration of ivabradine and a beta-blocker is safe and was positive in regard to clinical outcomes, the significant limitations due to its size and study design (single-center, unblinded, 4-month follow-up) simply serve to support the pursuit of larger studies with more stringent design and longer follow-up in order to determine the clinical efficacy.
The PRIME-HF trial
The Predischarge Initiation of Ivabradine in the Management of Heart Failure (PRIME-HF) trial69 is a randomized, open-label, multicenter trial comparing standard care vs the initiation of ivabradine before discharge, but after clinical stabilization, during admissions for ADHF in patients with chronic HFrEF (left ventricular ejection fraction ≤ 35%). At subsequent outpatient visits, the dosage can be modified in the ivabradine group, or ivabradine can be initiated at the provider’s discretion in the usual-care group.
PRIME-HF is attempting to determine whether initiating ivabradine before discharge will result in more patients taking ivabradine at 180 days, its primary end point, as well as in changes in secondary end points including heart rate and patient-centered outcomes. The study is active, with reporting expected in 2019.
As these trials all come to completion, it will not be long before we have further guidance regarding the inpatient initiation of these new and exciting therapeutic agents.
SHOULD INTRAVENOUS IRON BE GIVEN DURING ADHF ADMISSIONS?
Given the high prevalence of iron deficiency in symptomatic HFrEF, its independent association with mortality, improvements in quality of life and functional capacity suggested by repleting with intravenous iron (in FAIR-HF and CONFIRM-HF), the seeming inefficacy of oral iron in IRONOUT, and the logistical challenges of intravenous administration during standard clinic visits, could giving intravenous iron soon be incorporated into admissions for ADHF?
Caution has been advised for several reasons. As discussed above, larger randomized controlled trials powered to detect more definitive clinical end points such as death and the rate of hospitalization are still needed before a stronger recommendation can be made for intravenous iron in HFrEF. Also, without such data, it seems unwise to add the considerable economic burden of routinely assessing for iron deficiency and providing intravenous iron during ADHF admissions to the already staggering costs of heart failure.
The effects seen on morbidity and mortality that become evident in these trials over the next 5 years will help determine future guidelines and whether intravenous iron is routinely administered in bridge clinics, during inpatient admissions for ADHF, or not at all in patients with HFrEF and iron deficiency.
INTERNISTS ARE KEY
Heart failure remains one of the most common, morbid, complex, and costly diseases in the United States, and its prevalence is expected only to increase.4,5 The 2017 update1 of the 2013 guideline2 for the management of heart failure provides recommendations aimed not only at management of heart failure, but also at its comorbidities and, for the first time ever, at its prevention.
Internists provide care for the majority of heart failure patients, as well as for their comorbidities, and are most often the first to come into contact with patients at high risk of developing heart failure. Thus, a thorough understanding of these guidelines and how to apply them to the management of acute decompensated heart failure is of critical importance.
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- Stienen S, Salah K, Moons AH, et al. Rationale and design of PRIMA II: a multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a predefined NT-PRoBNP target on the reduction of readmIssion and mortality rates. Am Heart J 2014; 168(1):30–36. doi:10.1016/j.ahj.2014.04.008
- Felker GM, Anstrom KJ, Adams KF, et al. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2017; 318(8):713–720. doi:10.1001/jama.2017.10565
- Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J 2014; 35(23):1559–1567. doi:10.1093/eurheartj/ehu090
- van Vliet AA, Donker AJ, Nauta JJ, Verheugt FW. Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensin-converting enzyme inhibitor. Am J Cardiol 1993; 71(3):21A–28A. pmid:8422000
- Butler J, Anstrom KJ, Felker GM, et al; National Heart Lung and Blood Institute Heart Failure Clinical Research Network. Efficacy and safety of spironolactone in acute heart failure. The ATHENA-HF randomized clinical trial. JAMA Cardiol 2017; 2(9):950–958. doi:10.1001/jamacardio.2017.2198
- McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11):993–1004. doi:10.1056/NEJMoa1409077
- ClinicalTrials.gov. ComParIson Of Sacubitril/valsartaN Versus Enalapril on Effect on NTpRo-BNP in patients stabilized from an acute Heart Failure episode (PIONEER-HF). https://clinicaltrials.gov/ct2/show/NCT02554890. Accessed January 17, 2019.
- Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010; 376(9744):875–885. doi:10.1016/S0140-6736(10)61198-1
- Hidalgo FJ, Anguita M, Castillo JC, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC-AHF): a randomised study. Int J Cardiol 2016; 217:7–11. doi:10.1016/j.ijcard.2016.04.136
- ClinicalTrials.gov. Predischarge Initiation of Ivabradine in the Management of Heart Failure (PRIME-HF). https://clinicaltrials.gov/ct2/show/NCT02827500. Accessed January 17, 2019.
- Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail 2018; 20(1):125–133. doi:10.1002/ejhf.823
- ClinicalTrials.gov. Intravenous Iron in Patients With Systolic Heart Failure and Iron Deficiency to Improve Morbidity and Mortality (FAIR-HF2). https://clinicaltrials.gov/ct2/show/NCT03036462. Accessed January 17, 2019.
- ClinicalTrials.gov. Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency (AFFIRM-AHF). https://clinicaltrials.gov/ct2/show/record/NCT02937454. Accessed January 17, 2019.
- ClinicalTrials.gov. Randomized Placebo-controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency (HEART-FID). https://clinicaltrials.gov/ct2/show/NCT03037931. Accessed January 17, 2019.
- ClinicalTrials.gov. Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency (IRONMAN). https://clinicaltrials.gov/ct2/show/NCT02642562. Accessed January 17, 2019.
In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) jointly released a focused update1 of the 2013 ACC/AHA guideline for managing heart failure.2 This is the second focused update of the 2013 guidelines; the first update,3 in 2016, covered 2 new drugs (sacubitril-valsartan and ivabradine) for chronic stage C heart failure with reduced ejection fraction (HFrEF).
Rather than focus on new medication classes, this second update provides recommendations regarding:
- Preventing the progression to left ventricular dysfunction or heart failure in patients at high risk (stage A) through screening with B-type natriuretic peptide (BNP) and aiming for more aggressive blood pressure control
- Inpatient biomarker use
- Medications in heart failure with preserved ejection fraction (HFpEF, or diastolic heart failure)
- Blood pressure targets in stage C heart failure
- Managing important comorbidities such as iron deficiency and sleep-disordered breathing to decrease morbidity, improve functional capacity, and enhance quality of life.
These guidelines and the data that underlie them are explored below. We also discuss potential applications to the management of hospitalization for acute decompensated heart failure (ADHF).
COMMON, COSTLY, AND DEBILITATING
Heart failure—defined by the ACC/AHA as the complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood—remains one of the most common, costly, and debilitating diseases in the United States.2 Based on National Health and Nutrition Examination Survey data from 2011 to 2014, an estimated 6.5 million US adults have it, with projections of more than 8 million by 2030.4,5 More than 960,000 new cases are thought to occur annually, with a lifetime risk of developing it of roughly 20% to 45%.6
Despite ever-growing familiarity and some significant strides in management, the death rate in this syndrome is substantial. After admissions for heart failure (which number 1 million per year), the mortality rate is roughly 10% at 1 year and 40% at 5 years.6 Also staggering are the associated costs, with $30.7 billion attributed to heart failure in 2012 and a projected $69.7 billion annually by 2030.5 Thus, we must direct efforts not only to treatment, but also to prevention.
Preventive efforts would target patients with ACC/AHA stage A heart failure—those at high risk for developing but currently without evidence of structural heart disease or heart failure symptoms (Table 1).7 This group may represent up to one-third of the US adult population, or 75 million people, when including the well-recognized risk factors of coronary artery disease, hypertension, diabetes mellitus, and chronic kidney disease in those without left ventricular dysfunction or heart failure.8
BIOMARKERS FOR PREVENTION
Past ACC/AHA heart failure guidelines2 have included recommendations on the use of biomarkers to aid in diagnosis and prognosis and, to a lesser degree, to guide treatment of heart failure. Largely based on 2 trials (see below), the 2017 guidelines go further, issuing a recommendation on the use of natriuretic peptide biomarkers in a screening strategy to prompt early intervention and prevent the progression to clinical heart failure in high-risk patients (stage A heart failure).
The PONTIAC trial
The NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease (PONTIAC) trial9 randomized 300 outpatients with type 2 diabetes mellitus and an elevated N-terminal proBNP (NT-proBNP) level (> 125 pg/mL) to standard medical care vs standard care plus intensive up-titration of renin-angiotensin system antagonists and beta-blockers in a cardiac clinic over 2 years.
Earlier studies10 had shown NT-proBNP levels to have predictive value for cardiac events in diabetic patients, while the neurohormonal treatments were thought to have an established record of preventing primary and secondary cardiovascular events. In PONTIAC, a significant reduction was seen in the primary end point of hospitalization or death due to cardiac disease (hazard ratio [HR] 0.351, P = .044), as well as in the secondary end point of hospitalization due to heart failure (P < .05), in the aggressive-intervention group. These results laid the foundation for the larger St. Vincent’s Screening to Prevent Heart Failure (STOP-HF) trial.11
The STOP-HF trial
The STOP-HF trial randomized 1,235 outpatients who were at high risk but without left ventricular dysfunction or heart failure symptoms (stage A) to annual screening alone vs annual screening plus BNP testing, in which a BNP level higher than 50 pg/mL triggered echocardiography and evaluation by a cardiologist who would then assist with medications.11
Eligible patients were over age 40 and had 1 or more of the following risk factors:
- Diabetes mellitus
- Hypertension
- Hypercholesterolemia
- Obesity (body mass index > 30 kg/m2)
- Vascular disease (coronary, cerebral, or peripheral arterial disease)
- Arrhythmia requiring treatment
- Moderate to severe valvular disease.
After a mean follow-up of 4.3 years, the primary end point, ie, asymptomatic left ventricular dysfunction with or without newly diagnosed heart failure, was found in 9.7% of the control group and in only 5.9% of the intervention group with BNP screening, a 42% relative risk reduction (P = .013).
Similarly, the incidence of secondary end points of emergency hospitalization for a cardiovascular event (arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis or embolization, or heart failure) was also lower at 45.2 vs 24.4 per 1,000 patient-years, a 46% relative risk reduction.
An important difference in medications between the 2 groups was an increase in subsequently prescribed renin-angiotensin-aldosterone system therapy, mainly consisting of angiotensin II receptor blockers (ARBs), in those with elevated BNP in the intervention group. Notably, blood pressure was about the same in the 2 groups.11
Although these findings are encouraging, larger studies are needed, as the lack of blinding, low event rates, and small absolute risk reduction make the results difficult to generalize.
New or modified recommendations for screening
Employing this novel prevention strategy in the extremely large number of patients with stage A heart failure, thought to be up to one-third of the US adult population, may serve as a way to best direct and utilize limited medical resources.8
BIOMARKERS FOR PROGNOSIS OR ADDED RISK STRATIFICATION
The 2013 guidelines2 recognized that a significant body of work had accumulated showing that natriuretic peptide levels can predict outcomes in both chronic and acute heart failure. Thus, in both conditions, the guidelines contained separate class Ia recommendations to obtain a natriuretic peptide level, troponin level, or both to establish prognosis or disease severity.
The 2017 update1 underscores the importance of timing in measuring natriuretic peptide levels during admission for ADHF, with emphasis on obtaining them at admission and at discharge for acute and postdischarge prognosis. The completely new class IIa recommendation to obtain a predischarge natriuretic peptide level for postdischarge prognosis was based on a number of observational studies, some of which we explore below.
The ELAN-HF meta-analysis
The European Collaboration on Acute Decompensated Heart Failure (ELAN-HF)12 performed a meta-analysis to develop a discharge prognostication score for ADHF that included both absolute level and percent change in natriuretic peptide levels at the time of discharge.
Using data from 7 prospective cohorts totaling 1,301 patients, the authors found that incorporation of these values into a subsequently validated risk model led to significant improvements in the ability to predict the end points of all-cause mortality and the combined end point of all-cause mortality or first readmission for a cardiovascular reason within 180 days.
The OPTIMIZE-HF retrospective analysis
Data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) were retrospectively analyzed13 to determine whether postdischarge outcomes were best predicted by natriuretic peptide levels at admission or discharge or by the relative change in natriuretic peptide level. More than 7,000 patients age 65 or older, in 220 hospitals, were included, and Cox prediction models were compared using clinical variables alone or in combination with the natriuretic peptide levels.
The model that included the discharge natriuretic peptide level was found to be the most predictive, with a c-index of 0.693 for predicting mortality and a c-index of 0.606 for mortality or rehospitalization at 1 year.
New or modified recommendations on biomarkers for prognosis
The 2017 update1 modified the earlier recommendation to obtain a natriuretic peptide or troponin level or both at admission for ADHF to establish prognosis. This now has a class Ia recommendation, emphasizing that such levels be obtained on admission. In addition, a new class IIa recommendation is made to obtain a predischarge natriuretic peptide level for postdischarge prognosis. The former class Ia recommendation to obtain a natriuretic peptide level in chronic heart failure to establish prognosis or disease severity remains unchanged.
Also worth noting is what the 2017 update does not recommend in regard to obtaining biomarker levels. It emphasizes that many patients, particularly those with advanced (stage D) heart failure, have a poor prognosis that is well established with or without biomarker levels. Additionally, there are many cardiac and noncardiac causes of natriuretic peptide elevation; thus, clinical judgment remains paramount.
The 2017 update1 also cautions against setting targets of percent change in or absolute levels of natriuretic peptide at discharge despite observational and retrospective studies demonstrating better outcomes when levels are reduced, as treating for any specific target has never been studied in a large prospective study. Thus, doing so may result in unintended harm. Rather, clinical judgment and optimization of guideline-directed management and therapy are encouraged (Table 2).
PHARMACOLOGIC TREATMENT FOR STAGE C HFpEF
Although the 2013 guidelines2 contain many class I recommendations for various medications in chronic HFrEF, not a single such recommendation is found for chronic HFpEF. A review by Okwuosa et al7 covered HFrEF, including the most recent additions on which the 2016 update was based, sacubitril-valsartan and ivabradine. The 2016 update was similarly devoid of recommendations regarding specific medications in HFpEF, leaving only the 2013 class IIb recommendation to consider using an ARB to decrease hospitalizations in HFpEF.
Evidence behind this recommendation came from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity program’s randomized controlled trial in 3,025 patients with New York Heart Association (NYHA) class II to IV heart failure and left ventricular ejection fraction over 40%, who were treated with candesartan or placebo.14 Over a median follow-up of 36.6 months, there was no significant difference in the primary composite outcome of cardiovascular death or admission for heart failure, but significantly fewer patients in the candesartan arm were admitted (230 vs 270, P = .017). Thus the recommendation.
Although this finding was encouraging, it was clear that no blockbuster drug for HFpEF had been identified. Considering that roughly half of all heart failure patients have preserved ejection fraction, the discovery of such a drug for HFpEF would be met with much excitement.15 Subsequently, other medication classes have been evaluated in the hope of benefit, allowing the 2017 update to provide specific recommendations for aldosterone antagonists, nitrates, and phosphodiesterase-5 inhibitors in HFpEF.
ALDOSTERONE ANTAGONISTS FOR HFpEF
Mineralocorticoid receptor antagonists had previously been shown to significantly reduce morbidity and mortality rates in patients with HFrEF.16 In addition to aldosterone’s effects on sodium retention and many other pathophysiologic mechanisms relating to heart failure, this hormone is also known to play a role in promoting myocardial fibrosis.17 Accordingly, some have wondered whether aldosterone antagonists could improve diastolic dysfunction, and perhaps outcomes, in HFpEF.
The Aldo-DHF trial
The Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial investigated whether the aldosterone antagonist spironolactone would improve diastolic function or maximal exercise capacity in chronic HFpEF.18 It randomized 422 ambulatory patients with NYHA stage II or III heart failure, preserved left ventricular ejection fraction (≥ 50%), and echocardiographic evidence of diastolic dysfunction to receive spironolactone 25 mg daily or placebo.
Although no significant difference was seen in maximal exercise capacity, follow-up over 1 year nevertheless showed significant improvement in echocardiographic diastolic dysfunction (E/e') and perhaps reverse remodeling (decreased left ventricular mass index). These improvements spurred larger trials powered to detect whether clinical outcomes could also be improved.
The TOPCAT trial
The Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial19 was a large, multicenter, international, double-blind, placebo-controlled trial that investigated whether spironolactone could improve clinical outcomes in HFpEF. It randomized 3,445 patients with symptomatic heart failure and left ventricular ejection fraction of 45% or more to spironolactone 15 to 45 mg daily or placebo.
The effect on a composite primary outcome of death from cardiovascular cause, aborted cardiac arrest, or hospitalization for heart failure was evaluated over a mean follow-up of 3.3 years, with only a small (HR 0.89), nonclinically significant reduction evident. Those in the spironolactone group did have a significantly lower incidence of hospitalization for heart failure (12.0% vs 14.2%, P = .04).
Although the results were disappointing in this essentially negative trial, significant regional variations evident on post hoc analysis prompted further investigation and much controversy since the trial’s publication in 2014.
Participants came in roughly equal proportions from the Americas (United States, Canada, Brazil, and Argentina—51%) and from Russia and Georgia (49%), but outcomes between the two groups were markedly different. Concern was first raised when immediate review discovered a 4-fold lower rate of the primary outcome in the placebo groups from Russia and Georgia (8.4%), a rate in fact similar to that in patients without heart failure.19 This led to further exploration that identified other red flags that called into question the data integrity from the non-American sites.20
Not only did patients receiving spironolactone in Russia and Georgia not experience the reduction in clinical outcomes seen in their American counterparts, they also did not manifest the expected elevations in potassium and creatinine, and spironolactone metabolites were undetectable in almost one-third of patients.21
These findings prompted a post hoc analysis that included only the 51% (1,767 patients) of the study population coming from the Americas; in this subgroup, treatment with spironolactone was associated with a statistically significant 18% relative risk reduction in the primary composite outcome, a 26% reduction in cardiovascular mortality, and an 18% reduction in hospitalization for heart failure.20
New or modified recommendations on aldosterone receptor antagonists
Nitrates and phosphodiesterase-5 inhibitors
Earlier studies indicated that long-acting nitrates are prescribed in 15% to 50% of patients with HFpEF, perhaps based on extrapolation from studies in HFrEF suggesting that they might improve exercise intolerance.22 Some have speculated that the hemodynamic effects of nitrates, such as decreasing pulmonary congestion, might improve exercise intolerance in those with the stiff ventricles of HFpEF as well, prompting further study.
The NEAT-HFpEF trial
The Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction (NEAT-HFpEF) trial22 investigated whether extended-release isosorbide mononitrate would increase daily activity levels in patients with HFpEF. This double-blind, crossover study randomized 110 patients with HFpEF (ejection fraction ≥ 50%) and persistent dyspnea to escalating doses of isosorbide mononitrate or placebo over 6 weeks, then to the other arm for another 6 weeks. Daily activity levels during the 120-mg phase were measured with a continuously worn accelerometer.
No beneficial effect of nitrates was evident, with a nonsignificant trend towards decreased activity levels, a significant decrease in hours of activity per day (–0.30 hours, P = .02), and no change in the other secondary end points such as quality-of-life score, 6-minute walk distance, or natriuretic peptide level.
Suggested explanations for these negative findings include the possibility of rapid dose escalation leading to increased subtle side effects (headache, dizziness, fatigue) that, in turn, decreased activity. Additionally, given the imprecise diagnostic criteria for HFpEF, difficulties with patient selection may have led to inclusion of a large number of patients without elevated left-sided filling pressures.23
The RELAX trial
The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction (RELAX) trial24 investigated whether the phosphodiesterase-5 inhibitor sildenafil would improve exercise capacity in HFpEF. Improvements in both exercise capacity and clinical outcomes had already been seen in earlier trials in patients with pulmonary hypertension, as well as in those with HFrEF.25 A smaller study in HFpEF patients with pulmonary hypertension was also encouraging.26
Thus, it was disappointing that, after randomizing 216 outpatients with HFpEF to sildenafil or placebo for 24 weeks, no benefit was seen in the primary end point of change in peak oxygen consumption or in secondary end points of change in 6-minute walk distance or composite clinical score. Unlike in NEAT-HFpEF, patients here were required to have elevated natriuretic peptide levels or elevated invasively measured filling pressures.
The study authors speculated that pulmonary arterial hypertension and right ventricular systolic failure might need to be significant for patients with HFpEF to benefit from phosphodiesterase-5 inhibitors, with their known effects of dilation of pulmonary vasculature and increasing contractility of the right ventricle.24
New or modified recommendations on nitrates or phosphodiesterase-5 drugs
Given these disappointing results, the 2017 update provides a class III (no benefit) recommendation against the routine use of nitrates or phosphodiesterase-5 inhibitors to improve exercise tolerance or quality of life in HFpEF, citing them as ineffective (Table 3).1
IRON DEFICIENCY IN HEART FAILURE
Not only is iron deficiency present in roughly 50% of patients with symptomatic heart failure (stage C and D HFrEF),27 it is also associated with increased heart failure symptoms such as fatigue and exercise intolerance,28 reduced functional capacity, decreased quality of life, and increased mortality.
Notably, this association exists regardless of the hemoglobin level.29 In fact, even in those without heart failure or anemia, iron deficiency alone results in worsened aerobic performance, exercise intolerance, and increased fatigue.30 Conversely, improvement in symptoms, exercise tolerance, and cognition have been shown with repletion of iron stores in such patients.31
At the time of the 2013 guidelines, only a single large trial of intravenous iron in HFrEF and iron deficiency had been carried out (see below), and although the results were promising, it was felt that the evidence base on which to make recommendations was inadequate. Thus, recommendations were deferred until more data could be obtained.
Of note, in all the trials discussed below, iron deficiency was diagnosed in the setting of heart failure as ferritin less than 100 mg/mL (absolute iron deficiency) or as ferritin 100 to 300 mg/mL with transferrin saturation less than 20% (relative deficiency).32
The CONFIRM-HF trial
As in the Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial,33 the subsequent Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination With Chronic Heart Failure (CONFIRM-HF) trial34 involved the intravenous infusion of iron (ferric carboxymaltose) in outpatients with symptomatic HFrEF and iron deficiency. It showed that benefits remained evident with a more objective primary end point (change in 6-minute walk test distance at 24 weeks), and that such benefits were sustained, as seen in numerous secondary end points related to functional capacity at 52 weeks. Benefits in CONFIRM-HF were evident independently from anemia, specifically whether hemoglobin was under or over 12 g/dL.
Although these results were promising, it remained unclear whether such improvements could be obtained with a much easier to administer, more readily available, and less expensive oral iron formulation.
The IRONOUT-HF trial
The Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT-HF) trial35 investigated whether oral, rather than intravenous, iron supplementation could improve peak exercise capacity in patients with HFrEF and iron deficiency. This double-blind, placebo-controlled trial randomized 225 patients with NYHA class II to IV HFrEF and iron deficiency to treatment with oral iron polysaccharide (150 mg twice daily) or placebo for 16 weeks.
Contrary to the supportive findings above, no significant change was seen in the primary end point of change in peak oxygen uptake or in any of the secondary end points (change in 6-minute walk, quality of life). Also, despite a 15-fold increase in the amount of iron administered in oral form compared with intravenously, little change was evident in the indices of iron stores over the course of the study, with only a 3% increase in transferrin saturation and an 11 ng/mL increase in ferritin. The intravenous trials resulted in a 4-fold greater increase in transferrin saturation and a 20-fold greater increase in ferritin.36
What keeps heart failure patients from absorbing oral iron? It is unclear why oral iron administration in HFrEF, such as in IRONOUT-HF, seems to be so ineffective, but hepcidin—a protein hormone made by the liver that shuts down intestinal iron absorption and iron release from macrophages—may play a central role.37 When iron stores are adequate, hepcidin is upregulated to prevent iron overload. However, hepcidin is also increased in inflammatory states, and chronic heart failure is often associated with inflammation.
With this in mind, the IRONOUT-HF investigators measured baseline hepcidin levels at the beginning and at the end of the 16 weeks and found that high baseline hepcidin levels predicted poorer response to oral iron. Other inflammatory mediators, such as interleukin 6, may also play a role.38,39 Unlike oral iron formulations such as iron polysaccharide, intravenous iron (ferric carboxymaltose) bypasses these regulatory mechanisms, which may partly explain its much more significant effect on the indices of iron stores and outcomes.
New or modified recommendations on iron
The 2017 update1 makes recommendations regarding iron deficiency and anemia in heart failure for the first time.
A class IIb recommendation states that it might be reasonable to treat NYHA class II and III heart failure patients with iron deficiency with intravenous iron to improve functional status and quality of life. A strong recommendation has been deferred until more is known about morbidity and mortality effects from adequately powered trials, some of which are under way and explored further below.
The 2017 update also withholds any recommendations regarding oral iron supplementation in heart failure, citing an uncertain evidence base. Certainly, the subsequent IRONOUT-HF trial does not lend enthusiasm for this approach.
Lastly, given the lack of benefit coupled with the increased risk of thromboembolic events evident in a trial of darbepoetin alfa vs placebo in non-iron deficiency-related anemia in HFrEF,40,41 the 2017 update provides a class III (no benefit) recommendation against using erythropoietin-stimulating agents in heart failure and anemia.
HYPERTENSION IN HEART FAILURE
The 2013 guidelines for the management of heart failure simply provided a class I recommendation to control hypertension and lipid disorders in accordance with contemporary guidelines to lower the risk of heart failure.1
SPRINT
The Systolic Blood Pressure Intervention Trial (SPRINT)42 sought to determine whether a lower systolic blood pressure target (120 vs 140 mm Hg) would reduce clinical events in patients at high risk for cardiovascular events but without diabetes mellitus. Patients at high risk were defined as over age 75, or with known vascular disease, chronic kidney disease, or a Framingham Risk Score higher than 15%. This multicenter, open-label controlled trial randomized 9,361 patients to intensive treatment (goal systolic blood pressure < 120 mm Hg) or standard treatment (goal systolic blood pressure < 140 mm Hg).
SPRINT was stopped early at a median follow-up of 3.26 years when a 25% relative risk reduction in the primary composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes became evident in the intensive-treatment group (1.65% vs 2.19% per year, HR 0.75, P < .0001).
All-cause mortality was also lower in the intensive-treatment group (HR 0.73, P = .003), while the incidence of serious adverse events (hypotension, syncope, electrolyte abnormalities, acute kidney injury, and noninjurious falls) was only slightly higher (38.3% vs 37.1%, P = .25). Most pertinent, a significant 38% relative risk reduction in heart failure and a 43% relative risk reduction in cardiovascular events were also evident.
Of note, blood pressure measurements were taken as the average of 3 measurements obtained by an automated cuff taken after the patient had been sitting quietly alone in a room for 5 minutes.
New or modified recommendations on hypertension in heart failure
Given the impressive 25% relative risk reduction in myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes in SPRINT,42 the 2017 update1 incorporated the intensive targets of SPRINT into its recommendations. However, to compensate for what are expected to be higher blood pressures obtained in real-world clinical practice as opposed to the near-perfect conditions used in SPRINT, a slightly higher blood pressure goal of less than 130/80 mm Hg was set.
Although not specifically included in SPRINT, given the lack of trial data on specific blood pressure targets in HFrEF and the decreased cardiovascular events noted above, a class I (level of evidence C, expert opinion) recommendation to target a goal systolic blood pressure less than 130 mm Hg in stage C HFrEF with hypertension is also given. Standard guideline-directed medications in the treatment of HFrEF are to be used (Table 4).
Similarly, a new class I (level of evidence C, expert opinion) recommendation is given for hypertension in HFpEF to target a systolic blood pressure of less than 130 mm Hg, with special mention to first manage any element of volume overload with diuretics. Other than avoiding nitrates (unless used for angina) and phosphodiesterase inhibitors, it is noted that few data exist to guide the choice of antihypertensive further, although perhaps renin-angiotensin-aldosterone system inhibition, especially aldosterone antagonists, may be considered. These recommendations are fully in line with the 2017 ACC/AHA high blood pressure clinical practice guidelines,43 ie, that renin-angiotensin-aldosterone system inhibition with an angiotensin-converting enzyme (ACE) inhibitor or ARB and especially mineralocorticoid receptor antagonists would be the preferred choice (Table 4).
SLEEP-DISORDERED BREATHING IN HEART FAILURE
Sleep-disordered breathing, either obstructive sleep apnea (OSA) or central sleep apnea, is quite commonly associated with symptomatic HFrEF.44 Whereas OSA is found in roughly 18% and central sleep apnea in 1% of the general population, sleep-disordered breathing is found in nearly 60% of patients with HFrEF, with some studies showing a nearly equal proportion of OSA and central sleep apnea.45 A similar prevalence is seen in HFpEF, although with a much higher proportion of OSA.46 Central sleep apnea tends to be a marker of more severe heart failure, as it is strongly associated with severe cardiac systolic dysfunction and worse functional capacity.47
Not surprisingly, the underlying mechanism of central sleep apnea is quite different from that of OSA. Whereas OSA predominantly occurs because of repeated obstruction of the pharynx due to nocturnal pharyngeal muscle relaxation, no such airway patency issues or strained breathing patterns exist in central sleep apnea. Central sleep apnea, which can manifest as Cheyne-Stokes respirations, is thought to occur due to an abnormal ventilatory control system with complex pathophysiology such as altered sensitivity of central chemoreceptors to carbon dioxide, interplay of pulmonary congestion, subsequent hyperventilation, and prolonged circulation times due to reduced cardiac output.48
What the two types of sleep-disordered breathing have in common is an association with negative health outcomes. Both appear to induce inflammation and sympathetic nervous system activity via oxidative stress from intermittent nocturnal hypoxemia and hypercapnea.49 OSA was already known to be associated with significant morbidity and mortality rates in the general population,50 and central sleep apnea had been identified as an independent predictor of mortality in HFrEF.51
At the time of the 2013 guidelines, only small or observational studies with limited results had been done evaluating treatment effects of continuous positive airway pressure therapy (CPAP) on OSA and central sleep apnea. Given the relative paucity of data, only a single class IIa recommendation stating that CPAP could be beneficial to increase left ventricular ejection fraction and functional status in concomitant sleep apnea and heart failure was given in 2013. However, many larger trials were under way,52–59 some with surprising results such as a significant increase in cardiovascular and all-cause mortality (Table 5).54
New or modified recommendations on sleep-disordered breathing
Given the common association with heart failure (60%)45 and the marked variation in response to treatment, including potential for harm with adaptive servo-ventilation and central sleep apnea, a class IIa recommendation is made stating that it is reasonable to obtain a formal sleep study in any patient with symptomatic (NYHA class II–IV) heart failure.1
Due to the potential for harm with adaptive servo-ventilation in patients with central sleep apnea and NYHA class II to IV HFrEF, a class III (harm) recommendation is made against its use.
Largely based on the results of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial,56 a class IIb, level of evidence B-R (moderate, based on randomized trials) recommendation is given, stating that the use of CPAP in those with OSA and known cardiovascular disease may be reasonable to improve sleep quality and reduce daytime sleepiness.
POTENTIAL APPLICATIONS IN ACUTE DECOMPENSATED HEART FAILURE
Although the 2017 update1 is directed mostly toward managing chronic heart failure, it is worth considering how it might apply to the management of ADHF.
SHOULD WE USE BIOMARFER TARGETS TO GUIDE THERAPY IN ADHF?
The 2017 update1 does offer direct recommendations regarding the use of biomarker levels during admissions for ADHF. Mainly, they emphasize that the admission biomarker levels provide valuable information regarding acute prognosis and risk stratification (class I recommendation), while natriuretic peptide levels just before discharge provide the same for the postdischarge timeframe (class IIa recommendation).
The update also explicitly cautions against using a natriuretic peptide level-guided treatment strategy, such as setting targets for predischarge absolute level or percent change in level of natriuretic peptides during admissions for ADHF. Although observational and retrospective studies have shown better outcomes when levels are reduced at discharge, treating for any specific inpatient target has never been tested in any large, prospective study; thus, doing so could result in unintended harm.
So what do we know?
McQuade et al systematic review
McQuade et al57 performed a systematic review of more than 40 ADHF trials, which showed that, indeed, patients who achieved a target absolute natriuretic peptide level (BNP ≤ 250 pg/mL) or percent reduction (≥ 30%) at time of discharge had significantly improved outcomes such as reduced postdischarge all-cause mortality and rehospitalization rates. However, these were mostly prospective cohort studies that did not use any type of natriuretic peptide level-guided treatment protocol, leaving it unclear whether such a strategy could positively influence outcomes.
For this reason, both McQuade et al57 and, in an accompanying editorial, Felker et al58 called for properly designed, randomized controlled trials to investigate such a strategy. Felker noted that only 2 such phase II trials in ADHF have been completed,59,60 with unconvincing results.
PRIMA II
The Multicenter, Randomized Clinical Trial to Study the Impact of In-hospital Guidance for Acute Decompensated Heart Failure Treatment by a Predefined NT-ProBNP Target on the Reduction of Readmission and Mortality Rates (PRIMA II)60 randomized patients to natriuretic peptide level-guided treatment or standard care during admission for ADHF.
Many participants (60%) reached the predetermined target of 30% reduction in natriuretic peptide levels at the time of clinical stabilization and randomization; 405 patients were randomized. Patients in the natriuretic peptide level-guided treatment group underwent a prespecified treatment algorithm, with repeat natriuretic peptide levels measured again after the protocol.
Natriuretic peptide-guided therapy failed to show any significant benefit in any clinical outcomes, including the primary composite end point of mortality or heart failure readmissions at 180 days (36% vs 38%, HR 0.99, 95% confidence interval 0.72–1.36). Consistent with the review by McQuade et al,57 achieving the 30% reduction in natriuretic peptide at discharge, in either arm, was associated with a better prognosis, with significantly lower mortality and readmission rates at 180 days (HR 0.39 for rehospitalization or death, 95% confidence interval 0.27–0.55).
As in the observational studies, those who achieved the target natriuretic peptide level at the time of discharge had a better prognosis than those who did not, but neither study showed an improvement in clinical outcomes using a natriuretic peptide level-targeting treatment strategy.
No larger randomized controlled trial results are available for guided therapy in ADHF. However, additional insight may be gained from a subsequent trial61 that evaluated biomarker-guided titration of guideline-directed medical therapy in outpatients with chronic HFrEF.
The GUIDE-IT trial
That trial, the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT)61 trial, was a large multicenter attempt to determine whether a natriuretic peptide-guided treatment strategy was more effective than standard care in the management of 894 high-risk outpatients with chronic HFrEF. Earlier, promising results had been obtained in a meta-analysis62 of more than 11 similar trials in 2,000 outpatients, with a decreased mortality rate (HR 0.62) seen in the biomarker-guided arm. However, the results had not been definitive due to being underpowered.62
Unfortunately, the results of GUIDE-IT were disappointing, with no significant difference in either the combined primary end point of mortality or hospitalization for heart failure, or the secondary end points evident at 15 months, prompting early termination for futility.61 Among other factors, the study authors postulated that this may have partly resulted from a patient population with more severe heart failure and resultant azotemia, limiting the ability to titrate neurohormonal medications to the desired dosage.
The question of whether patients who cannot achieve such biomarker targets need more intensive therapy or whether their heart failure is too severe to respond adequately echoes the question often raised in discussions of inpatient biomarker-guided therapy.58 Thus, only limited insight is gained, and it remains unclear whether a natriuretic peptide-guided treatment strategy can improve outpatient or inpatient outcomes. Until this is clarified, clinical judgment and optimization of guideline-directed management and therapy should remain the bedrock of treatment.
SHOULD ALDOSTERONE ANTAGONISTS BE USED IN ACUTE HFpEF?
Given the encouraging results in chronic HFpEF from post hoc analyses of TOPCAT, are there any additional recent data suggesting a role for aldosterone antagonists such as spironolactone in acute HFpEF?
The ATHENA-HF trial
The Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial63 compared treatment with high-dose spironolactone (100 mg) for 96 hours vs usual care in 360 patients with ADHF. The patient population included those with HFrEF and HFpEF, and usual care included low-dose spironolactone (12.5–25 mg) in roughly 15% of patients. High-dose mineralocorticoid receptor antagonists have been shown to overcome diuretic resistance, improve pulmonary vascular congestion, and partially combat the adverse neurohormonal activation seen in ADHF.
Unfortunately, the trial was completely neutral in regard to the primary end point of reduction in natriuretic peptide levels as well as to the secondary end points of 30-day mortality rate, heart failure readmission, clinical congestion scores, urine output, and change in weight. No suggestion of additional benefit was seen in subgroup analysis of patients with acute HFpEF (ejection fraction > 45%), which yielded similar results.63
Given these lackluster findings, routine use of high-dose spironolactone in ADHF is not recommended.64 However, the treatment was well tolerated, without significant adverse effects of hyperkalemia or kidney injury, leaving the door open as to whether it may have utility in selected patients with diuretic resistance.
Should ARNIs and ivabradine be started during ADHF admissions?
The first half of the focused update3 of the 2013 guidelines,2 reviewed by Okwuosa et al,7 provided recommendations for the use of sacubitril-valsartan, an angiotensin-neprilysin inhibitor (ARNI), and ivabradine, a selective sinoatrial node If channel inhibitor, in chronic HFrEF.
Sacubitril-valsartan was given a class I recommendation for use in patients with NYHA class II or III chronic HFrEF who tolerate an ACE inhibitor or an ARB. This recommendation was given largely based on the benefits in mortality and heart failure hospitalizations seen in PARADIGM-HF (the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)65 compared with enalapril (HR 0.80, 95% CI 0.73–0.87, P < .001).
There is currently no recommendation on initiation or use of ARNIs during admissions for ADHF, but a recent trial may lend some insight.66
THE PIONEER-HF trial
The Comparison of Sacubitril/Valsartan vs Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF) trial66 randomized patients admitted for acute HFrEF, once stabilized, to sacubitril-valsartan or enalapril. Encouragingly, the percentage change of natriuretic peptide levels from the time of inpatient initiation to 4 and 8 weeks thereafter, the primary efficacy end point, was 46.7% with sacubitril-valsartan versus 25.3% with enalapril alone (ratio of change 0.71, 95% CI 0.63–0.81, P < .001). Although not powered for such, a prespecified analysis of a composite of clinical outcomes was also favorable for sacubitril-valsartan, largely driven by a 44% decreased rate of rehospitalization. More definitive, and quite reassuring, was that no significant difference was seen in the key safety outcomes of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema. These results were also applicable to the one-third of study participants who had no former diagnosis of heart failure, the one-third identifying as African American, and the one-third who had not been taking an ACE inhibitor or ARB. These results, taken together with the notion that at study completion the patients become similar to those included in PARADIGM-HF, have led some to assert that PIONEER-HF has the potential to change clinical practice.
Ivabradine was given a class IIa recommendation for use in patients with NYHA class II or III chronic HFrEF with a resting heart rate of at least 70 bpm, in sinus rhythm, despite being on optimal medical therapy including a beta-blocker at a maximum tolerated dose.
This recommendation was largely based on SHIFT (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial), which randomized patients to ivabradine or placebo to evaluate the effects of isolated lowering of the heart rate on the composite primary outcome of cardiovascular death or hospitalization. A significant reduction was seen in the ivabradine arm (HR 0.82, 95% CI 0.75–0.90, P < .0001), mainly driven by decreased hospitalizations.67
Subsequently, a small unblinded single-center study was undertaken to evaluate the efficacy and safety of initiating ivabradine during admissions for ADHF.68
THE ETHIC-AHF trial
The Effect of Early Treatment With Ivabradine Combined With Beta-Blockers vs Beta-Blockers Alone in Patients Hospitalized With Heart Failure and Reduced Left Ventricular Ejection Fraction (ETHIC-AHF) trial68 sought to determine the safety and effectiveness of early coadministration of ivabradine with beta-blockers in patients with acute HFrEF.
This single-center, unblinded study randomized 71 patients to ivabradine and beta-blockade or beta-blockade alone upon clinical stabilization (24–48 hours) after admission for acute decompensated HFrEF.
The primary end point was heart rate at 28 days, with the ivabradine group showing a statistically significant decrease (64 vs 70 bpm, P = .01), which persisted at 4 months. There was no significant difference in the secondary end points of adverse drug effects or the composite of clinical event outcomes (all-cause mortality, admission for heart failure or cardiovascular cause), but a number of surrogate end points including left ventricular ejection fraction, BNP level, and NYHA functional class at 4 months showed mild improvement.
Although this study provided evidence that the coadministration of ivabradine and a beta-blocker is safe and was positive in regard to clinical outcomes, the significant limitations due to its size and study design (single-center, unblinded, 4-month follow-up) simply serve to support the pursuit of larger studies with more stringent design and longer follow-up in order to determine the clinical efficacy.
The PRIME-HF trial
The Predischarge Initiation of Ivabradine in the Management of Heart Failure (PRIME-HF) trial69 is a randomized, open-label, multicenter trial comparing standard care vs the initiation of ivabradine before discharge, but after clinical stabilization, during admissions for ADHF in patients with chronic HFrEF (left ventricular ejection fraction ≤ 35%). At subsequent outpatient visits, the dosage can be modified in the ivabradine group, or ivabradine can be initiated at the provider’s discretion in the usual-care group.
PRIME-HF is attempting to determine whether initiating ivabradine before discharge will result in more patients taking ivabradine at 180 days, its primary end point, as well as in changes in secondary end points including heart rate and patient-centered outcomes. The study is active, with reporting expected in 2019.
As these trials all come to completion, it will not be long before we have further guidance regarding the inpatient initiation of these new and exciting therapeutic agents.
SHOULD INTRAVENOUS IRON BE GIVEN DURING ADHF ADMISSIONS?
Given the high prevalence of iron deficiency in symptomatic HFrEF, its independent association with mortality, improvements in quality of life and functional capacity suggested by repleting with intravenous iron (in FAIR-HF and CONFIRM-HF), the seeming inefficacy of oral iron in IRONOUT, and the logistical challenges of intravenous administration during standard clinic visits, could giving intravenous iron soon be incorporated into admissions for ADHF?
Caution has been advised for several reasons. As discussed above, larger randomized controlled trials powered to detect more definitive clinical end points such as death and the rate of hospitalization are still needed before a stronger recommendation can be made for intravenous iron in HFrEF. Also, without such data, it seems unwise to add the considerable economic burden of routinely assessing for iron deficiency and providing intravenous iron during ADHF admissions to the already staggering costs of heart failure.
The effects seen on morbidity and mortality that become evident in these trials over the next 5 years will help determine future guidelines and whether intravenous iron is routinely administered in bridge clinics, during inpatient admissions for ADHF, or not at all in patients with HFrEF and iron deficiency.
INTERNISTS ARE KEY
Heart failure remains one of the most common, morbid, complex, and costly diseases in the United States, and its prevalence is expected only to increase.4,5 The 2017 update1 of the 2013 guideline2 for the management of heart failure provides recommendations aimed not only at management of heart failure, but also at its comorbidities and, for the first time ever, at its prevention.
Internists provide care for the majority of heart failure patients, as well as for their comorbidities, and are most often the first to come into contact with patients at high risk of developing heart failure. Thus, a thorough understanding of these guidelines and how to apply them to the management of acute decompensated heart failure is of critical importance.
In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) jointly released a focused update1 of the 2013 ACC/AHA guideline for managing heart failure.2 This is the second focused update of the 2013 guidelines; the first update,3 in 2016, covered 2 new drugs (sacubitril-valsartan and ivabradine) for chronic stage C heart failure with reduced ejection fraction (HFrEF).
Rather than focus on new medication classes, this second update provides recommendations regarding:
- Preventing the progression to left ventricular dysfunction or heart failure in patients at high risk (stage A) through screening with B-type natriuretic peptide (BNP) and aiming for more aggressive blood pressure control
- Inpatient biomarker use
- Medications in heart failure with preserved ejection fraction (HFpEF, or diastolic heart failure)
- Blood pressure targets in stage C heart failure
- Managing important comorbidities such as iron deficiency and sleep-disordered breathing to decrease morbidity, improve functional capacity, and enhance quality of life.
These guidelines and the data that underlie them are explored below. We also discuss potential applications to the management of hospitalization for acute decompensated heart failure (ADHF).
COMMON, COSTLY, AND DEBILITATING
Heart failure—defined by the ACC/AHA as the complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood—remains one of the most common, costly, and debilitating diseases in the United States.2 Based on National Health and Nutrition Examination Survey data from 2011 to 2014, an estimated 6.5 million US adults have it, with projections of more than 8 million by 2030.4,5 More than 960,000 new cases are thought to occur annually, with a lifetime risk of developing it of roughly 20% to 45%.6
Despite ever-growing familiarity and some significant strides in management, the death rate in this syndrome is substantial. After admissions for heart failure (which number 1 million per year), the mortality rate is roughly 10% at 1 year and 40% at 5 years.6 Also staggering are the associated costs, with $30.7 billion attributed to heart failure in 2012 and a projected $69.7 billion annually by 2030.5 Thus, we must direct efforts not only to treatment, but also to prevention.
Preventive efforts would target patients with ACC/AHA stage A heart failure—those at high risk for developing but currently without evidence of structural heart disease or heart failure symptoms (Table 1).7 This group may represent up to one-third of the US adult population, or 75 million people, when including the well-recognized risk factors of coronary artery disease, hypertension, diabetes mellitus, and chronic kidney disease in those without left ventricular dysfunction or heart failure.8
BIOMARKERS FOR PREVENTION
Past ACC/AHA heart failure guidelines2 have included recommendations on the use of biomarkers to aid in diagnosis and prognosis and, to a lesser degree, to guide treatment of heart failure. Largely based on 2 trials (see below), the 2017 guidelines go further, issuing a recommendation on the use of natriuretic peptide biomarkers in a screening strategy to prompt early intervention and prevent the progression to clinical heart failure in high-risk patients (stage A heart failure).
The PONTIAC trial
The NT-proBNP Selected Prevention of Cardiac Events in a Population of Diabetic Patients Without a History of Cardiac Disease (PONTIAC) trial9 randomized 300 outpatients with type 2 diabetes mellitus and an elevated N-terminal proBNP (NT-proBNP) level (> 125 pg/mL) to standard medical care vs standard care plus intensive up-titration of renin-angiotensin system antagonists and beta-blockers in a cardiac clinic over 2 years.
Earlier studies10 had shown NT-proBNP levels to have predictive value for cardiac events in diabetic patients, while the neurohormonal treatments were thought to have an established record of preventing primary and secondary cardiovascular events. In PONTIAC, a significant reduction was seen in the primary end point of hospitalization or death due to cardiac disease (hazard ratio [HR] 0.351, P = .044), as well as in the secondary end point of hospitalization due to heart failure (P < .05), in the aggressive-intervention group. These results laid the foundation for the larger St. Vincent’s Screening to Prevent Heart Failure (STOP-HF) trial.11
The STOP-HF trial
The STOP-HF trial randomized 1,235 outpatients who were at high risk but without left ventricular dysfunction or heart failure symptoms (stage A) to annual screening alone vs annual screening plus BNP testing, in which a BNP level higher than 50 pg/mL triggered echocardiography and evaluation by a cardiologist who would then assist with medications.11
Eligible patients were over age 40 and had 1 or more of the following risk factors:
- Diabetes mellitus
- Hypertension
- Hypercholesterolemia
- Obesity (body mass index > 30 kg/m2)
- Vascular disease (coronary, cerebral, or peripheral arterial disease)
- Arrhythmia requiring treatment
- Moderate to severe valvular disease.
After a mean follow-up of 4.3 years, the primary end point, ie, asymptomatic left ventricular dysfunction with or without newly diagnosed heart failure, was found in 9.7% of the control group and in only 5.9% of the intervention group with BNP screening, a 42% relative risk reduction (P = .013).
Similarly, the incidence of secondary end points of emergency hospitalization for a cardiovascular event (arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis or embolization, or heart failure) was also lower at 45.2 vs 24.4 per 1,000 patient-years, a 46% relative risk reduction.
An important difference in medications between the 2 groups was an increase in subsequently prescribed renin-angiotensin-aldosterone system therapy, mainly consisting of angiotensin II receptor blockers (ARBs), in those with elevated BNP in the intervention group. Notably, blood pressure was about the same in the 2 groups.11
Although these findings are encouraging, larger studies are needed, as the lack of blinding, low event rates, and small absolute risk reduction make the results difficult to generalize.
New or modified recommendations for screening
Employing this novel prevention strategy in the extremely large number of patients with stage A heart failure, thought to be up to one-third of the US adult population, may serve as a way to best direct and utilize limited medical resources.8
BIOMARKERS FOR PROGNOSIS OR ADDED RISK STRATIFICATION
The 2013 guidelines2 recognized that a significant body of work had accumulated showing that natriuretic peptide levels can predict outcomes in both chronic and acute heart failure. Thus, in both conditions, the guidelines contained separate class Ia recommendations to obtain a natriuretic peptide level, troponin level, or both to establish prognosis or disease severity.
The 2017 update1 underscores the importance of timing in measuring natriuretic peptide levels during admission for ADHF, with emphasis on obtaining them at admission and at discharge for acute and postdischarge prognosis. The completely new class IIa recommendation to obtain a predischarge natriuretic peptide level for postdischarge prognosis was based on a number of observational studies, some of which we explore below.
The ELAN-HF meta-analysis
The European Collaboration on Acute Decompensated Heart Failure (ELAN-HF)12 performed a meta-analysis to develop a discharge prognostication score for ADHF that included both absolute level and percent change in natriuretic peptide levels at the time of discharge.
Using data from 7 prospective cohorts totaling 1,301 patients, the authors found that incorporation of these values into a subsequently validated risk model led to significant improvements in the ability to predict the end points of all-cause mortality and the combined end point of all-cause mortality or first readmission for a cardiovascular reason within 180 days.
The OPTIMIZE-HF retrospective analysis
Data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) were retrospectively analyzed13 to determine whether postdischarge outcomes were best predicted by natriuretic peptide levels at admission or discharge or by the relative change in natriuretic peptide level. More than 7,000 patients age 65 or older, in 220 hospitals, were included, and Cox prediction models were compared using clinical variables alone or in combination with the natriuretic peptide levels.
The model that included the discharge natriuretic peptide level was found to be the most predictive, with a c-index of 0.693 for predicting mortality and a c-index of 0.606 for mortality or rehospitalization at 1 year.
New or modified recommendations on biomarkers for prognosis
The 2017 update1 modified the earlier recommendation to obtain a natriuretic peptide or troponin level or both at admission for ADHF to establish prognosis. This now has a class Ia recommendation, emphasizing that such levels be obtained on admission. In addition, a new class IIa recommendation is made to obtain a predischarge natriuretic peptide level for postdischarge prognosis. The former class Ia recommendation to obtain a natriuretic peptide level in chronic heart failure to establish prognosis or disease severity remains unchanged.
Also worth noting is what the 2017 update does not recommend in regard to obtaining biomarker levels. It emphasizes that many patients, particularly those with advanced (stage D) heart failure, have a poor prognosis that is well established with or without biomarker levels. Additionally, there are many cardiac and noncardiac causes of natriuretic peptide elevation; thus, clinical judgment remains paramount.
The 2017 update1 also cautions against setting targets of percent change in or absolute levels of natriuretic peptide at discharge despite observational and retrospective studies demonstrating better outcomes when levels are reduced, as treating for any specific target has never been studied in a large prospective study. Thus, doing so may result in unintended harm. Rather, clinical judgment and optimization of guideline-directed management and therapy are encouraged (Table 2).
PHARMACOLOGIC TREATMENT FOR STAGE C HFpEF
Although the 2013 guidelines2 contain many class I recommendations for various medications in chronic HFrEF, not a single such recommendation is found for chronic HFpEF. A review by Okwuosa et al7 covered HFrEF, including the most recent additions on which the 2016 update was based, sacubitril-valsartan and ivabradine. The 2016 update was similarly devoid of recommendations regarding specific medications in HFpEF, leaving only the 2013 class IIb recommendation to consider using an ARB to decrease hospitalizations in HFpEF.
Evidence behind this recommendation came from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity program’s randomized controlled trial in 3,025 patients with New York Heart Association (NYHA) class II to IV heart failure and left ventricular ejection fraction over 40%, who were treated with candesartan or placebo.14 Over a median follow-up of 36.6 months, there was no significant difference in the primary composite outcome of cardiovascular death or admission for heart failure, but significantly fewer patients in the candesartan arm were admitted (230 vs 270, P = .017). Thus the recommendation.
Although this finding was encouraging, it was clear that no blockbuster drug for HFpEF had been identified. Considering that roughly half of all heart failure patients have preserved ejection fraction, the discovery of such a drug for HFpEF would be met with much excitement.15 Subsequently, other medication classes have been evaluated in the hope of benefit, allowing the 2017 update to provide specific recommendations for aldosterone antagonists, nitrates, and phosphodiesterase-5 inhibitors in HFpEF.
ALDOSTERONE ANTAGONISTS FOR HFpEF
Mineralocorticoid receptor antagonists had previously been shown to significantly reduce morbidity and mortality rates in patients with HFrEF.16 In addition to aldosterone’s effects on sodium retention and many other pathophysiologic mechanisms relating to heart failure, this hormone is also known to play a role in promoting myocardial fibrosis.17 Accordingly, some have wondered whether aldosterone antagonists could improve diastolic dysfunction, and perhaps outcomes, in HFpEF.
The Aldo-DHF trial
The Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial investigated whether the aldosterone antagonist spironolactone would improve diastolic function or maximal exercise capacity in chronic HFpEF.18 It randomized 422 ambulatory patients with NYHA stage II or III heart failure, preserved left ventricular ejection fraction (≥ 50%), and echocardiographic evidence of diastolic dysfunction to receive spironolactone 25 mg daily or placebo.
Although no significant difference was seen in maximal exercise capacity, follow-up over 1 year nevertheless showed significant improvement in echocardiographic diastolic dysfunction (E/e') and perhaps reverse remodeling (decreased left ventricular mass index). These improvements spurred larger trials powered to detect whether clinical outcomes could also be improved.
The TOPCAT trial
The Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial19 was a large, multicenter, international, double-blind, placebo-controlled trial that investigated whether spironolactone could improve clinical outcomes in HFpEF. It randomized 3,445 patients with symptomatic heart failure and left ventricular ejection fraction of 45% or more to spironolactone 15 to 45 mg daily or placebo.
The effect on a composite primary outcome of death from cardiovascular cause, aborted cardiac arrest, or hospitalization for heart failure was evaluated over a mean follow-up of 3.3 years, with only a small (HR 0.89), nonclinically significant reduction evident. Those in the spironolactone group did have a significantly lower incidence of hospitalization for heart failure (12.0% vs 14.2%, P = .04).
Although the results were disappointing in this essentially negative trial, significant regional variations evident on post hoc analysis prompted further investigation and much controversy since the trial’s publication in 2014.
Participants came in roughly equal proportions from the Americas (United States, Canada, Brazil, and Argentina—51%) and from Russia and Georgia (49%), but outcomes between the two groups were markedly different. Concern was first raised when immediate review discovered a 4-fold lower rate of the primary outcome in the placebo groups from Russia and Georgia (8.4%), a rate in fact similar to that in patients without heart failure.19 This led to further exploration that identified other red flags that called into question the data integrity from the non-American sites.20
Not only did patients receiving spironolactone in Russia and Georgia not experience the reduction in clinical outcomes seen in their American counterparts, they also did not manifest the expected elevations in potassium and creatinine, and spironolactone metabolites were undetectable in almost one-third of patients.21
These findings prompted a post hoc analysis that included only the 51% (1,767 patients) of the study population coming from the Americas; in this subgroup, treatment with spironolactone was associated with a statistically significant 18% relative risk reduction in the primary composite outcome, a 26% reduction in cardiovascular mortality, and an 18% reduction in hospitalization for heart failure.20
New or modified recommendations on aldosterone receptor antagonists
Nitrates and phosphodiesterase-5 inhibitors
Earlier studies indicated that long-acting nitrates are prescribed in 15% to 50% of patients with HFpEF, perhaps based on extrapolation from studies in HFrEF suggesting that they might improve exercise intolerance.22 Some have speculated that the hemodynamic effects of nitrates, such as decreasing pulmonary congestion, might improve exercise intolerance in those with the stiff ventricles of HFpEF as well, prompting further study.
The NEAT-HFpEF trial
The Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction (NEAT-HFpEF) trial22 investigated whether extended-release isosorbide mononitrate would increase daily activity levels in patients with HFpEF. This double-blind, crossover study randomized 110 patients with HFpEF (ejection fraction ≥ 50%) and persistent dyspnea to escalating doses of isosorbide mononitrate or placebo over 6 weeks, then to the other arm for another 6 weeks. Daily activity levels during the 120-mg phase were measured with a continuously worn accelerometer.
No beneficial effect of nitrates was evident, with a nonsignificant trend towards decreased activity levels, a significant decrease in hours of activity per day (–0.30 hours, P = .02), and no change in the other secondary end points such as quality-of-life score, 6-minute walk distance, or natriuretic peptide level.
Suggested explanations for these negative findings include the possibility of rapid dose escalation leading to increased subtle side effects (headache, dizziness, fatigue) that, in turn, decreased activity. Additionally, given the imprecise diagnostic criteria for HFpEF, difficulties with patient selection may have led to inclusion of a large number of patients without elevated left-sided filling pressures.23
The RELAX trial
The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction (RELAX) trial24 investigated whether the phosphodiesterase-5 inhibitor sildenafil would improve exercise capacity in HFpEF. Improvements in both exercise capacity and clinical outcomes had already been seen in earlier trials in patients with pulmonary hypertension, as well as in those with HFrEF.25 A smaller study in HFpEF patients with pulmonary hypertension was also encouraging.26
Thus, it was disappointing that, after randomizing 216 outpatients with HFpEF to sildenafil or placebo for 24 weeks, no benefit was seen in the primary end point of change in peak oxygen consumption or in secondary end points of change in 6-minute walk distance or composite clinical score. Unlike in NEAT-HFpEF, patients here were required to have elevated natriuretic peptide levels or elevated invasively measured filling pressures.
The study authors speculated that pulmonary arterial hypertension and right ventricular systolic failure might need to be significant for patients with HFpEF to benefit from phosphodiesterase-5 inhibitors, with their known effects of dilation of pulmonary vasculature and increasing contractility of the right ventricle.24
New or modified recommendations on nitrates or phosphodiesterase-5 drugs
Given these disappointing results, the 2017 update provides a class III (no benefit) recommendation against the routine use of nitrates or phosphodiesterase-5 inhibitors to improve exercise tolerance or quality of life in HFpEF, citing them as ineffective (Table 3).1
IRON DEFICIENCY IN HEART FAILURE
Not only is iron deficiency present in roughly 50% of patients with symptomatic heart failure (stage C and D HFrEF),27 it is also associated with increased heart failure symptoms such as fatigue and exercise intolerance,28 reduced functional capacity, decreased quality of life, and increased mortality.
Notably, this association exists regardless of the hemoglobin level.29 In fact, even in those without heart failure or anemia, iron deficiency alone results in worsened aerobic performance, exercise intolerance, and increased fatigue.30 Conversely, improvement in symptoms, exercise tolerance, and cognition have been shown with repletion of iron stores in such patients.31
At the time of the 2013 guidelines, only a single large trial of intravenous iron in HFrEF and iron deficiency had been carried out (see below), and although the results were promising, it was felt that the evidence base on which to make recommendations was inadequate. Thus, recommendations were deferred until more data could be obtained.
Of note, in all the trials discussed below, iron deficiency was diagnosed in the setting of heart failure as ferritin less than 100 mg/mL (absolute iron deficiency) or as ferritin 100 to 300 mg/mL with transferrin saturation less than 20% (relative deficiency).32
The CONFIRM-HF trial
As in the Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial,33 the subsequent Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination With Chronic Heart Failure (CONFIRM-HF) trial34 involved the intravenous infusion of iron (ferric carboxymaltose) in outpatients with symptomatic HFrEF and iron deficiency. It showed that benefits remained evident with a more objective primary end point (change in 6-minute walk test distance at 24 weeks), and that such benefits were sustained, as seen in numerous secondary end points related to functional capacity at 52 weeks. Benefits in CONFIRM-HF were evident independently from anemia, specifically whether hemoglobin was under or over 12 g/dL.
Although these results were promising, it remained unclear whether such improvements could be obtained with a much easier to administer, more readily available, and less expensive oral iron formulation.
The IRONOUT-HF trial
The Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT-HF) trial35 investigated whether oral, rather than intravenous, iron supplementation could improve peak exercise capacity in patients with HFrEF and iron deficiency. This double-blind, placebo-controlled trial randomized 225 patients with NYHA class II to IV HFrEF and iron deficiency to treatment with oral iron polysaccharide (150 mg twice daily) or placebo for 16 weeks.
Contrary to the supportive findings above, no significant change was seen in the primary end point of change in peak oxygen uptake or in any of the secondary end points (change in 6-minute walk, quality of life). Also, despite a 15-fold increase in the amount of iron administered in oral form compared with intravenously, little change was evident in the indices of iron stores over the course of the study, with only a 3% increase in transferrin saturation and an 11 ng/mL increase in ferritin. The intravenous trials resulted in a 4-fold greater increase in transferrin saturation and a 20-fold greater increase in ferritin.36
What keeps heart failure patients from absorbing oral iron? It is unclear why oral iron administration in HFrEF, such as in IRONOUT-HF, seems to be so ineffective, but hepcidin—a protein hormone made by the liver that shuts down intestinal iron absorption and iron release from macrophages—may play a central role.37 When iron stores are adequate, hepcidin is upregulated to prevent iron overload. However, hepcidin is also increased in inflammatory states, and chronic heart failure is often associated with inflammation.
With this in mind, the IRONOUT-HF investigators measured baseline hepcidin levels at the beginning and at the end of the 16 weeks and found that high baseline hepcidin levels predicted poorer response to oral iron. Other inflammatory mediators, such as interleukin 6, may also play a role.38,39 Unlike oral iron formulations such as iron polysaccharide, intravenous iron (ferric carboxymaltose) bypasses these regulatory mechanisms, which may partly explain its much more significant effect on the indices of iron stores and outcomes.
New or modified recommendations on iron
The 2017 update1 makes recommendations regarding iron deficiency and anemia in heart failure for the first time.
A class IIb recommendation states that it might be reasonable to treat NYHA class II and III heart failure patients with iron deficiency with intravenous iron to improve functional status and quality of life. A strong recommendation has been deferred until more is known about morbidity and mortality effects from adequately powered trials, some of which are under way and explored further below.
The 2017 update also withholds any recommendations regarding oral iron supplementation in heart failure, citing an uncertain evidence base. Certainly, the subsequent IRONOUT-HF trial does not lend enthusiasm for this approach.
Lastly, given the lack of benefit coupled with the increased risk of thromboembolic events evident in a trial of darbepoetin alfa vs placebo in non-iron deficiency-related anemia in HFrEF,40,41 the 2017 update provides a class III (no benefit) recommendation against using erythropoietin-stimulating agents in heart failure and anemia.
HYPERTENSION IN HEART FAILURE
The 2013 guidelines for the management of heart failure simply provided a class I recommendation to control hypertension and lipid disorders in accordance with contemporary guidelines to lower the risk of heart failure.1
SPRINT
The Systolic Blood Pressure Intervention Trial (SPRINT)42 sought to determine whether a lower systolic blood pressure target (120 vs 140 mm Hg) would reduce clinical events in patients at high risk for cardiovascular events but without diabetes mellitus. Patients at high risk were defined as over age 75, or with known vascular disease, chronic kidney disease, or a Framingham Risk Score higher than 15%. This multicenter, open-label controlled trial randomized 9,361 patients to intensive treatment (goal systolic blood pressure < 120 mm Hg) or standard treatment (goal systolic blood pressure < 140 mm Hg).
SPRINT was stopped early at a median follow-up of 3.26 years when a 25% relative risk reduction in the primary composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes became evident in the intensive-treatment group (1.65% vs 2.19% per year, HR 0.75, P < .0001).
All-cause mortality was also lower in the intensive-treatment group (HR 0.73, P = .003), while the incidence of serious adverse events (hypotension, syncope, electrolyte abnormalities, acute kidney injury, and noninjurious falls) was only slightly higher (38.3% vs 37.1%, P = .25). Most pertinent, a significant 38% relative risk reduction in heart failure and a 43% relative risk reduction in cardiovascular events were also evident.
Of note, blood pressure measurements were taken as the average of 3 measurements obtained by an automated cuff taken after the patient had been sitting quietly alone in a room for 5 minutes.
New or modified recommendations on hypertension in heart failure
Given the impressive 25% relative risk reduction in myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes in SPRINT,42 the 2017 update1 incorporated the intensive targets of SPRINT into its recommendations. However, to compensate for what are expected to be higher blood pressures obtained in real-world clinical practice as opposed to the near-perfect conditions used in SPRINT, a slightly higher blood pressure goal of less than 130/80 mm Hg was set.
Although not specifically included in SPRINT, given the lack of trial data on specific blood pressure targets in HFrEF and the decreased cardiovascular events noted above, a class I (level of evidence C, expert opinion) recommendation to target a goal systolic blood pressure less than 130 mm Hg in stage C HFrEF with hypertension is also given. Standard guideline-directed medications in the treatment of HFrEF are to be used (Table 4).
Similarly, a new class I (level of evidence C, expert opinion) recommendation is given for hypertension in HFpEF to target a systolic blood pressure of less than 130 mm Hg, with special mention to first manage any element of volume overload with diuretics. Other than avoiding nitrates (unless used for angina) and phosphodiesterase inhibitors, it is noted that few data exist to guide the choice of antihypertensive further, although perhaps renin-angiotensin-aldosterone system inhibition, especially aldosterone antagonists, may be considered. These recommendations are fully in line with the 2017 ACC/AHA high blood pressure clinical practice guidelines,43 ie, that renin-angiotensin-aldosterone system inhibition with an angiotensin-converting enzyme (ACE) inhibitor or ARB and especially mineralocorticoid receptor antagonists would be the preferred choice (Table 4).
SLEEP-DISORDERED BREATHING IN HEART FAILURE
Sleep-disordered breathing, either obstructive sleep apnea (OSA) or central sleep apnea, is quite commonly associated with symptomatic HFrEF.44 Whereas OSA is found in roughly 18% and central sleep apnea in 1% of the general population, sleep-disordered breathing is found in nearly 60% of patients with HFrEF, with some studies showing a nearly equal proportion of OSA and central sleep apnea.45 A similar prevalence is seen in HFpEF, although with a much higher proportion of OSA.46 Central sleep apnea tends to be a marker of more severe heart failure, as it is strongly associated with severe cardiac systolic dysfunction and worse functional capacity.47
Not surprisingly, the underlying mechanism of central sleep apnea is quite different from that of OSA. Whereas OSA predominantly occurs because of repeated obstruction of the pharynx due to nocturnal pharyngeal muscle relaxation, no such airway patency issues or strained breathing patterns exist in central sleep apnea. Central sleep apnea, which can manifest as Cheyne-Stokes respirations, is thought to occur due to an abnormal ventilatory control system with complex pathophysiology such as altered sensitivity of central chemoreceptors to carbon dioxide, interplay of pulmonary congestion, subsequent hyperventilation, and prolonged circulation times due to reduced cardiac output.48
What the two types of sleep-disordered breathing have in common is an association with negative health outcomes. Both appear to induce inflammation and sympathetic nervous system activity via oxidative stress from intermittent nocturnal hypoxemia and hypercapnea.49 OSA was already known to be associated with significant morbidity and mortality rates in the general population,50 and central sleep apnea had been identified as an independent predictor of mortality in HFrEF.51
At the time of the 2013 guidelines, only small or observational studies with limited results had been done evaluating treatment effects of continuous positive airway pressure therapy (CPAP) on OSA and central sleep apnea. Given the relative paucity of data, only a single class IIa recommendation stating that CPAP could be beneficial to increase left ventricular ejection fraction and functional status in concomitant sleep apnea and heart failure was given in 2013. However, many larger trials were under way,52–59 some with surprising results such as a significant increase in cardiovascular and all-cause mortality (Table 5).54
New or modified recommendations on sleep-disordered breathing
Given the common association with heart failure (60%)45 and the marked variation in response to treatment, including potential for harm with adaptive servo-ventilation and central sleep apnea, a class IIa recommendation is made stating that it is reasonable to obtain a formal sleep study in any patient with symptomatic (NYHA class II–IV) heart failure.1
Due to the potential for harm with adaptive servo-ventilation in patients with central sleep apnea and NYHA class II to IV HFrEF, a class III (harm) recommendation is made against its use.
Largely based on the results of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial,56 a class IIb, level of evidence B-R (moderate, based on randomized trials) recommendation is given, stating that the use of CPAP in those with OSA and known cardiovascular disease may be reasonable to improve sleep quality and reduce daytime sleepiness.
POTENTIAL APPLICATIONS IN ACUTE DECOMPENSATED HEART FAILURE
Although the 2017 update1 is directed mostly toward managing chronic heart failure, it is worth considering how it might apply to the management of ADHF.
SHOULD WE USE BIOMARFER TARGETS TO GUIDE THERAPY IN ADHF?
The 2017 update1 does offer direct recommendations regarding the use of biomarker levels during admissions for ADHF. Mainly, they emphasize that the admission biomarker levels provide valuable information regarding acute prognosis and risk stratification (class I recommendation), while natriuretic peptide levels just before discharge provide the same for the postdischarge timeframe (class IIa recommendation).
The update also explicitly cautions against using a natriuretic peptide level-guided treatment strategy, such as setting targets for predischarge absolute level or percent change in level of natriuretic peptides during admissions for ADHF. Although observational and retrospective studies have shown better outcomes when levels are reduced at discharge, treating for any specific inpatient target has never been tested in any large, prospective study; thus, doing so could result in unintended harm.
So what do we know?
McQuade et al systematic review
McQuade et al57 performed a systematic review of more than 40 ADHF trials, which showed that, indeed, patients who achieved a target absolute natriuretic peptide level (BNP ≤ 250 pg/mL) or percent reduction (≥ 30%) at time of discharge had significantly improved outcomes such as reduced postdischarge all-cause mortality and rehospitalization rates. However, these were mostly prospective cohort studies that did not use any type of natriuretic peptide level-guided treatment protocol, leaving it unclear whether such a strategy could positively influence outcomes.
For this reason, both McQuade et al57 and, in an accompanying editorial, Felker et al58 called for properly designed, randomized controlled trials to investigate such a strategy. Felker noted that only 2 such phase II trials in ADHF have been completed,59,60 with unconvincing results.
PRIMA II
The Multicenter, Randomized Clinical Trial to Study the Impact of In-hospital Guidance for Acute Decompensated Heart Failure Treatment by a Predefined NT-ProBNP Target on the Reduction of Readmission and Mortality Rates (PRIMA II)60 randomized patients to natriuretic peptide level-guided treatment or standard care during admission for ADHF.
Many participants (60%) reached the predetermined target of 30% reduction in natriuretic peptide levels at the time of clinical stabilization and randomization; 405 patients were randomized. Patients in the natriuretic peptide level-guided treatment group underwent a prespecified treatment algorithm, with repeat natriuretic peptide levels measured again after the protocol.
Natriuretic peptide-guided therapy failed to show any significant benefit in any clinical outcomes, including the primary composite end point of mortality or heart failure readmissions at 180 days (36% vs 38%, HR 0.99, 95% confidence interval 0.72–1.36). Consistent with the review by McQuade et al,57 achieving the 30% reduction in natriuretic peptide at discharge, in either arm, was associated with a better prognosis, with significantly lower mortality and readmission rates at 180 days (HR 0.39 for rehospitalization or death, 95% confidence interval 0.27–0.55).
As in the observational studies, those who achieved the target natriuretic peptide level at the time of discharge had a better prognosis than those who did not, but neither study showed an improvement in clinical outcomes using a natriuretic peptide level-targeting treatment strategy.
No larger randomized controlled trial results are available for guided therapy in ADHF. However, additional insight may be gained from a subsequent trial61 that evaluated biomarker-guided titration of guideline-directed medical therapy in outpatients with chronic HFrEF.
The GUIDE-IT trial
That trial, the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT)61 trial, was a large multicenter attempt to determine whether a natriuretic peptide-guided treatment strategy was more effective than standard care in the management of 894 high-risk outpatients with chronic HFrEF. Earlier, promising results had been obtained in a meta-analysis62 of more than 11 similar trials in 2,000 outpatients, with a decreased mortality rate (HR 0.62) seen in the biomarker-guided arm. However, the results had not been definitive due to being underpowered.62
Unfortunately, the results of GUIDE-IT were disappointing, with no significant difference in either the combined primary end point of mortality or hospitalization for heart failure, or the secondary end points evident at 15 months, prompting early termination for futility.61 Among other factors, the study authors postulated that this may have partly resulted from a patient population with more severe heart failure and resultant azotemia, limiting the ability to titrate neurohormonal medications to the desired dosage.
The question of whether patients who cannot achieve such biomarker targets need more intensive therapy or whether their heart failure is too severe to respond adequately echoes the question often raised in discussions of inpatient biomarker-guided therapy.58 Thus, only limited insight is gained, and it remains unclear whether a natriuretic peptide-guided treatment strategy can improve outpatient or inpatient outcomes. Until this is clarified, clinical judgment and optimization of guideline-directed management and therapy should remain the bedrock of treatment.
SHOULD ALDOSTERONE ANTAGONISTS BE USED IN ACUTE HFpEF?
Given the encouraging results in chronic HFpEF from post hoc analyses of TOPCAT, are there any additional recent data suggesting a role for aldosterone antagonists such as spironolactone in acute HFpEF?
The ATHENA-HF trial
The Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) trial63 compared treatment with high-dose spironolactone (100 mg) for 96 hours vs usual care in 360 patients with ADHF. The patient population included those with HFrEF and HFpEF, and usual care included low-dose spironolactone (12.5–25 mg) in roughly 15% of patients. High-dose mineralocorticoid receptor antagonists have been shown to overcome diuretic resistance, improve pulmonary vascular congestion, and partially combat the adverse neurohormonal activation seen in ADHF.
Unfortunately, the trial was completely neutral in regard to the primary end point of reduction in natriuretic peptide levels as well as to the secondary end points of 30-day mortality rate, heart failure readmission, clinical congestion scores, urine output, and change in weight. No suggestion of additional benefit was seen in subgroup analysis of patients with acute HFpEF (ejection fraction > 45%), which yielded similar results.63
Given these lackluster findings, routine use of high-dose spironolactone in ADHF is not recommended.64 However, the treatment was well tolerated, without significant adverse effects of hyperkalemia or kidney injury, leaving the door open as to whether it may have utility in selected patients with diuretic resistance.
Should ARNIs and ivabradine be started during ADHF admissions?
The first half of the focused update3 of the 2013 guidelines,2 reviewed by Okwuosa et al,7 provided recommendations for the use of sacubitril-valsartan, an angiotensin-neprilysin inhibitor (ARNI), and ivabradine, a selective sinoatrial node If channel inhibitor, in chronic HFrEF.
Sacubitril-valsartan was given a class I recommendation for use in patients with NYHA class II or III chronic HFrEF who tolerate an ACE inhibitor or an ARB. This recommendation was given largely based on the benefits in mortality and heart failure hospitalizations seen in PARADIGM-HF (the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)65 compared with enalapril (HR 0.80, 95% CI 0.73–0.87, P < .001).
There is currently no recommendation on initiation or use of ARNIs during admissions for ADHF, but a recent trial may lend some insight.66
THE PIONEER-HF trial
The Comparison of Sacubitril/Valsartan vs Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF) trial66 randomized patients admitted for acute HFrEF, once stabilized, to sacubitril-valsartan or enalapril. Encouragingly, the percentage change of natriuretic peptide levels from the time of inpatient initiation to 4 and 8 weeks thereafter, the primary efficacy end point, was 46.7% with sacubitril-valsartan versus 25.3% with enalapril alone (ratio of change 0.71, 95% CI 0.63–0.81, P < .001). Although not powered for such, a prespecified analysis of a composite of clinical outcomes was also favorable for sacubitril-valsartan, largely driven by a 44% decreased rate of rehospitalization. More definitive, and quite reassuring, was that no significant difference was seen in the key safety outcomes of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema. These results were also applicable to the one-third of study participants who had no former diagnosis of heart failure, the one-third identifying as African American, and the one-third who had not been taking an ACE inhibitor or ARB. These results, taken together with the notion that at study completion the patients become similar to those included in PARADIGM-HF, have led some to assert that PIONEER-HF has the potential to change clinical practice.
Ivabradine was given a class IIa recommendation for use in patients with NYHA class II or III chronic HFrEF with a resting heart rate of at least 70 bpm, in sinus rhythm, despite being on optimal medical therapy including a beta-blocker at a maximum tolerated dose.
This recommendation was largely based on SHIFT (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial), which randomized patients to ivabradine or placebo to evaluate the effects of isolated lowering of the heart rate on the composite primary outcome of cardiovascular death or hospitalization. A significant reduction was seen in the ivabradine arm (HR 0.82, 95% CI 0.75–0.90, P < .0001), mainly driven by decreased hospitalizations.67
Subsequently, a small unblinded single-center study was undertaken to evaluate the efficacy and safety of initiating ivabradine during admissions for ADHF.68
THE ETHIC-AHF trial
The Effect of Early Treatment With Ivabradine Combined With Beta-Blockers vs Beta-Blockers Alone in Patients Hospitalized With Heart Failure and Reduced Left Ventricular Ejection Fraction (ETHIC-AHF) trial68 sought to determine the safety and effectiveness of early coadministration of ivabradine with beta-blockers in patients with acute HFrEF.
This single-center, unblinded study randomized 71 patients to ivabradine and beta-blockade or beta-blockade alone upon clinical stabilization (24–48 hours) after admission for acute decompensated HFrEF.
The primary end point was heart rate at 28 days, with the ivabradine group showing a statistically significant decrease (64 vs 70 bpm, P = .01), which persisted at 4 months. There was no significant difference in the secondary end points of adverse drug effects or the composite of clinical event outcomes (all-cause mortality, admission for heart failure or cardiovascular cause), but a number of surrogate end points including left ventricular ejection fraction, BNP level, and NYHA functional class at 4 months showed mild improvement.
Although this study provided evidence that the coadministration of ivabradine and a beta-blocker is safe and was positive in regard to clinical outcomes, the significant limitations due to its size and study design (single-center, unblinded, 4-month follow-up) simply serve to support the pursuit of larger studies with more stringent design and longer follow-up in order to determine the clinical efficacy.
The PRIME-HF trial
The Predischarge Initiation of Ivabradine in the Management of Heart Failure (PRIME-HF) trial69 is a randomized, open-label, multicenter trial comparing standard care vs the initiation of ivabradine before discharge, but after clinical stabilization, during admissions for ADHF in patients with chronic HFrEF (left ventricular ejection fraction ≤ 35%). At subsequent outpatient visits, the dosage can be modified in the ivabradine group, or ivabradine can be initiated at the provider’s discretion in the usual-care group.
PRIME-HF is attempting to determine whether initiating ivabradine before discharge will result in more patients taking ivabradine at 180 days, its primary end point, as well as in changes in secondary end points including heart rate and patient-centered outcomes. The study is active, with reporting expected in 2019.
As these trials all come to completion, it will not be long before we have further guidance regarding the inpatient initiation of these new and exciting therapeutic agents.
SHOULD INTRAVENOUS IRON BE GIVEN DURING ADHF ADMISSIONS?
Given the high prevalence of iron deficiency in symptomatic HFrEF, its independent association with mortality, improvements in quality of life and functional capacity suggested by repleting with intravenous iron (in FAIR-HF and CONFIRM-HF), the seeming inefficacy of oral iron in IRONOUT, and the logistical challenges of intravenous administration during standard clinic visits, could giving intravenous iron soon be incorporated into admissions for ADHF?
Caution has been advised for several reasons. As discussed above, larger randomized controlled trials powered to detect more definitive clinical end points such as death and the rate of hospitalization are still needed before a stronger recommendation can be made for intravenous iron in HFrEF. Also, without such data, it seems unwise to add the considerable economic burden of routinely assessing for iron deficiency and providing intravenous iron during ADHF admissions to the already staggering costs of heart failure.
The effects seen on morbidity and mortality that become evident in these trials over the next 5 years will help determine future guidelines and whether intravenous iron is routinely administered in bridge clinics, during inpatient admissions for ADHF, or not at all in patients with HFrEF and iron deficiency.
INTERNISTS ARE KEY
Heart failure remains one of the most common, morbid, complex, and costly diseases in the United States, and its prevalence is expected only to increase.4,5 The 2017 update1 of the 2013 guideline2 for the management of heart failure provides recommendations aimed not only at management of heart failure, but also at its comorbidities and, for the first time ever, at its prevention.
Internists provide care for the majority of heart failure patients, as well as for their comorbidities, and are most often the first to come into contact with patients at high risk of developing heart failure. Thus, a thorough understanding of these guidelines and how to apply them to the management of acute decompensated heart failure is of critical importance.
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- Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med 2013; 368(13):1210–1219. doi:10.1056/NEJMoa1214865
- Ghali JK, Anand IS, Abraham WT, et al; Study of Anemia in Heart Failure Trial (STAMINA-HeFT) Group. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation 2008; 117(4):526–535. doi:10.1161/CIRCULATIONAHA.107.698514
- SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood pressure control. N Engl J Med 2015; 373(22):2103–2116. doi:10.1056/NEJMoa1511939
- Whelton PK, Carey RM, Arnow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71(19):e127–e248. doi:10.1016/j.jacc.2017.11.006
- Young T, Shahar E, Nieto FJ, et al; Sleep Heart Health Study Research Group. Predictors of sleep-disordered breathing in community dwelling adults: the Sleep Heart Health Study. Arch Intern Med 2002; 162(8):893–900. pmid:11966340
- MacDonald M, Fang J, Pittman SD, White DP, Malhotra A.The current prevalence of sleep disordered breathing in congestive heart failure patients treated with beta-blockers. J Clin Sleep Med 2008; 4(1):38-42. pmid:18350960
- Bitter T, Faber L, Hering D, Langer C, Horstkotte D, Oldenburg O. Sleep-disordered breathing in heart failure with normal left ventricular ejection fraction. Eur J Heart Fail 2009; 11(6):602–608. doi:10.1093/eurjhf/hfp057
- Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999; 160(4):1101–1106. doi:10.1164/ajrccm.160.4.9903020
- Ng AC, Freedman SB. Sleep disordered breathing in chronic heart failure. Heart Fail Rev 2009; 14(2):89–99. doi:10.1007/s10741-008-9096-8
- Kasai T, Bradley TD. Obstructive sleep apnea and heart failure: pathophysiologic and therapeutic implications. J Am Coll Cardiol 2011; 57(2):119–127. doi:10.1016/j.jacc.2010.08.627
- Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365(9464):1046–1053. doi:10.1016/S0140-6736(05)71141-7
- Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007; 49(20):2028–2034. doi:10.1016/j.jacc.2007.01.084
- Bradley TD, Logan AG, Kimoff RJ, et al; CANPAP Investigators. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005; 353(19):2025–2033. doi:10.1056/NEJMoa051001
- Arzt M, Floras JS, Logan AG, et al; CANPAP Investigators. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007; 115(25):3173–3180. doi:10.1161/CIRCULATIONAHA.106.683482
- Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med 2015; 373(12):1095–1105. doi:10.1056/NEJMoa1506459
- O’Connor CM, Whellan DJ, Fiuzat M, et al. Cardiovascular outcomes with minute ventilation-targeted adaptive servo-ventilation therapy in heart failure: the CAT-HF Trial. J Am Coll Cardiol 2017; 69(12):1577–1587. doi:10.1016/j.jacc.2017.01.041
- McEvoy RD, Antic NA, Heeley E, et al; SAVE Investigators and Coordinators. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med 2016; 375(10):919–931. doi:10.1056/NEJMoa1606599
- McQuade CN, Mizus M, Wald JW, Goldberg L, Jessup M, Umscheid CA. Brain-type natriuretic peptide and amino-terminal pro-brain-type natriuretic peptide discharge thresholds for acute decompensated heart failure: a systematic review. Ann Intern Med 2017; 166(3):180–190. doi:10.7326/M16-1468
- Felker GM, Whellan DJ. Inpatient management of heart failure: are we shooting at the right target? Ann Intern Med 2017; 166(3):223–224. doi:10.7326/M16-2667
- Carubelli V, Lombardi C, Lazzarini V, et al. N-terminal pro-B-type natriuretic peptide-guided therapy in patients hospitalized for acute heart failure. J Cardiovasc Med (Hagerstown) 2016; 17(11):828–839. doi:10.2459/JCM.0000000000000419
- Stienen S, Salah K, Moons AH, et al. Rationale and design of PRIMA II: a multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a predefined NT-PRoBNP target on the reduction of readmIssion and mortality rates. Am Heart J 2014; 168(1):30–36. doi:10.1016/j.ahj.2014.04.008
- Felker GM, Anstrom KJ, Adams KF, et al. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2017; 318(8):713–720. doi:10.1001/jama.2017.10565
- Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J 2014; 35(23):1559–1567. doi:10.1093/eurheartj/ehu090
- van Vliet AA, Donker AJ, Nauta JJ, Verheugt FW. Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensin-converting enzyme inhibitor. Am J Cardiol 1993; 71(3):21A–28A. pmid:8422000
- Butler J, Anstrom KJ, Felker GM, et al; National Heart Lung and Blood Institute Heart Failure Clinical Research Network. Efficacy and safety of spironolactone in acute heart failure. The ATHENA-HF randomized clinical trial. JAMA Cardiol 2017; 2(9):950–958. doi:10.1001/jamacardio.2017.2198
- McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11):993–1004. doi:10.1056/NEJMoa1409077
- ClinicalTrials.gov. ComParIson Of Sacubitril/valsartaN Versus Enalapril on Effect on NTpRo-BNP in patients stabilized from an acute Heart Failure episode (PIONEER-HF). https://clinicaltrials.gov/ct2/show/NCT02554890. Accessed January 17, 2019.
- Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010; 376(9744):875–885. doi:10.1016/S0140-6736(10)61198-1
- Hidalgo FJ, Anguita M, Castillo JC, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC-AHF): a randomised study. Int J Cardiol 2016; 217:7–11. doi:10.1016/j.ijcard.2016.04.136
- ClinicalTrials.gov. Predischarge Initiation of Ivabradine in the Management of Heart Failure (PRIME-HF). https://clinicaltrials.gov/ct2/show/NCT02827500. Accessed January 17, 2019.
- Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail 2018; 20(1):125–133. doi:10.1002/ejhf.823
- ClinicalTrials.gov. Intravenous Iron in Patients With Systolic Heart Failure and Iron Deficiency to Improve Morbidity and Mortality (FAIR-HF2). https://clinicaltrials.gov/ct2/show/NCT03036462. Accessed January 17, 2019.
- ClinicalTrials.gov. Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency (AFFIRM-AHF). https://clinicaltrials.gov/ct2/show/record/NCT02937454. Accessed January 17, 2019.
- ClinicalTrials.gov. Randomized Placebo-controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency (HEART-FID). https://clinicaltrials.gov/ct2/show/NCT03037931. Accessed January 17, 2019.
- ClinicalTrials.gov. Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency (IRONMAN). https://clinicaltrials.gov/ct2/show/NCT02642562. Accessed January 17, 2019.
KEY POINTS
- Despite advances in treatment, heart failure remains highly morbid, common, and costly. Prevention is key.
- Strategies to prevent progression to clinical heart failure in high-risk patients include new blood pressure targets (< 130/80 mm Hg) and B-type natriuretic peptide screening to prompt referral to a cardiovascular specialist.
- An aldosterone receptor antagonist might be considered to decrease hospitalizations in appropriately selected stage C HFpEF patients. Routine use of nitrates or phosphodiesterase-5 inhibitors in such patients is not recommended.
- Outpatient intravenous iron infusions are reasonable in persistently symptomatic New York Heart Association stage II to III heart failure with reduced ejection fraction (HFrEF) to improve functional capacity and quality of life.
- The new systolic blood pressure target is less than 130 mm Hg for stage A heart failure, stage C HFrEF, and stage C HFpEF.
There is more to the TSH than a number
At a quick read, the messages from these articles may seem contradictory. But the biology is more complex in the setting of endogenous production of T4 by the thyroid gland, which is regulated by TSH, which in turn is regulated in a feedback loop by the thyroid-produced T4. In the setting of a fixed replacement dose of exogenous levothyroxine, the provided hormone affects the pituitary production of TSH, which likely will have no significant subsequent effect on the T4 level. Thus, the feedback control loop is far simpler.
There has not been a definitive study demonstrating that thyroxine supplementation in patients with subclinical hypothyroidism results in a superior clinical outcome. There are hints that this may be the case, and Azim and Nasr cite some of these studies. Recognizing a few markedly different physiologic reasons why the TSH can be slightly elevated and the T4 normal helps explain the lack of uniform clinical success with supplementation therapy and provides rationales for some management strategies.
Any biological variability in the responsiveness of the thyroid gland to TSH may affect the relationship between the levels of TSH and thyroid gland-released T4. In theory, if the thyroid receptor has decreased affinity for TSH, a higher TSH concentration will be needed to get the thyroid gland to secrete the level of T4 that the pituitary sensing mechanism deems normal for that individual. If the receptor affinity was decreased due to a gene polymorphism, this relationship between TSH and T4 may be stable, and providing exogenous T4 will result in a lower, “normalized” TSH level but may disrupt the thyroid-pituitary crosstalk and may even produce clinical hyperthyroidism.
A similar scenario exists in the setting of early thyroid gland failure, such as in Hashimoto thyroiditis. But in the latter scenario, the TSH-to-T4 production relationship may be unstable over time, for as additional thyroid gland is destroyed, T4 production will continue to decrease, the TSH will increase, and the thyroid gland may ultimately fail and hypothyroidism will occur. Hence the recommendation that in the setting of subclinical hypothyroidism and antiperoxidase antibodies, T4 and TSH levels should be monitored regularly in order to detect early true thyroid gland failure when the T4 level can no longer be maintained despite the increased stimulation of the gland by the elevated TSH. Analogous to this may be subclinical hypothyroidism in the elderly, in whom thyroid gland failure may develop, despite an increased TSH, from senescence rather than autoimmunity. What I am suggesting is that the natural history of all patients with subclinical hypothyroidism is not alike, and it thus should not be surprising that there does not seem to be a one-size-fits-all approach to management.
Symptoms in patients with subclinical hypothyroidism have not uniformly improved with T4 treatment compared with placebo. Notably, most patients with subclinical hypothyroidism experience no symptoms. But consider the extremely common symptom of fatigue, which can be present for a myriad of defined and undefined reasons. This symptom may often lead physicians to check the TSH and, if that is even slightly elevated, to also check the T4. It may also lead some physicians to routinely check the T4. Subclinical hypothyroidism is also quite common; thus, by chance alone or because of the circadian timing of checking the TSH, a slightly elevated TSH and fatigue may coexist and yet be unrelated.
Additionally, a positive biochemical response to thyroxine supplementation, such as a lowering of cholesterol, does not prove that the patient was clinically hypothyroid prior to supplementation, any more than lowering a patient’s blood glucose with insulin proves that the patient was diabetic. The management of subclinical hypothyroidism should be nuanced and based on both clinical and laboratory parameters.
- Nasr C. Is a serum TSH measurement sufficient to monitor the treatment of primary hypothyroidism? Cleve Clin J Med 2016; 83(8):571–573. doi:10.3949/ccjm.83a.15165
- Mandell BF. Trust the thyroid thermostat. Cleve Clin J Med 2016; 83(8):552–553. doi:10.3949/ccjm.83b.08016
At a quick read, the messages from these articles may seem contradictory. But the biology is more complex in the setting of endogenous production of T4 by the thyroid gland, which is regulated by TSH, which in turn is regulated in a feedback loop by the thyroid-produced T4. In the setting of a fixed replacement dose of exogenous levothyroxine, the provided hormone affects the pituitary production of TSH, which likely will have no significant subsequent effect on the T4 level. Thus, the feedback control loop is far simpler.
There has not been a definitive study demonstrating that thyroxine supplementation in patients with subclinical hypothyroidism results in a superior clinical outcome. There are hints that this may be the case, and Azim and Nasr cite some of these studies. Recognizing a few markedly different physiologic reasons why the TSH can be slightly elevated and the T4 normal helps explain the lack of uniform clinical success with supplementation therapy and provides rationales for some management strategies.
Any biological variability in the responsiveness of the thyroid gland to TSH may affect the relationship between the levels of TSH and thyroid gland-released T4. In theory, if the thyroid receptor has decreased affinity for TSH, a higher TSH concentration will be needed to get the thyroid gland to secrete the level of T4 that the pituitary sensing mechanism deems normal for that individual. If the receptor affinity was decreased due to a gene polymorphism, this relationship between TSH and T4 may be stable, and providing exogenous T4 will result in a lower, “normalized” TSH level but may disrupt the thyroid-pituitary crosstalk and may even produce clinical hyperthyroidism.
A similar scenario exists in the setting of early thyroid gland failure, such as in Hashimoto thyroiditis. But in the latter scenario, the TSH-to-T4 production relationship may be unstable over time, for as additional thyroid gland is destroyed, T4 production will continue to decrease, the TSH will increase, and the thyroid gland may ultimately fail and hypothyroidism will occur. Hence the recommendation that in the setting of subclinical hypothyroidism and antiperoxidase antibodies, T4 and TSH levels should be monitored regularly in order to detect early true thyroid gland failure when the T4 level can no longer be maintained despite the increased stimulation of the gland by the elevated TSH. Analogous to this may be subclinical hypothyroidism in the elderly, in whom thyroid gland failure may develop, despite an increased TSH, from senescence rather than autoimmunity. What I am suggesting is that the natural history of all patients with subclinical hypothyroidism is not alike, and it thus should not be surprising that there does not seem to be a one-size-fits-all approach to management.
Symptoms in patients with subclinical hypothyroidism have not uniformly improved with T4 treatment compared with placebo. Notably, most patients with subclinical hypothyroidism experience no symptoms. But consider the extremely common symptom of fatigue, which can be present for a myriad of defined and undefined reasons. This symptom may often lead physicians to check the TSH and, if that is even slightly elevated, to also check the T4. It may also lead some physicians to routinely check the T4. Subclinical hypothyroidism is also quite common; thus, by chance alone or because of the circadian timing of checking the TSH, a slightly elevated TSH and fatigue may coexist and yet be unrelated.
Additionally, a positive biochemical response to thyroxine supplementation, such as a lowering of cholesterol, does not prove that the patient was clinically hypothyroid prior to supplementation, any more than lowering a patient’s blood glucose with insulin proves that the patient was diabetic. The management of subclinical hypothyroidism should be nuanced and based on both clinical and laboratory parameters.
At a quick read, the messages from these articles may seem contradictory. But the biology is more complex in the setting of endogenous production of T4 by the thyroid gland, which is regulated by TSH, which in turn is regulated in a feedback loop by the thyroid-produced T4. In the setting of a fixed replacement dose of exogenous levothyroxine, the provided hormone affects the pituitary production of TSH, which likely will have no significant subsequent effect on the T4 level. Thus, the feedback control loop is far simpler.
There has not been a definitive study demonstrating that thyroxine supplementation in patients with subclinical hypothyroidism results in a superior clinical outcome. There are hints that this may be the case, and Azim and Nasr cite some of these studies. Recognizing a few markedly different physiologic reasons why the TSH can be slightly elevated and the T4 normal helps explain the lack of uniform clinical success with supplementation therapy and provides rationales for some management strategies.
Any biological variability in the responsiveness of the thyroid gland to TSH may affect the relationship between the levels of TSH and thyroid gland-released T4. In theory, if the thyroid receptor has decreased affinity for TSH, a higher TSH concentration will be needed to get the thyroid gland to secrete the level of T4 that the pituitary sensing mechanism deems normal for that individual. If the receptor affinity was decreased due to a gene polymorphism, this relationship between TSH and T4 may be stable, and providing exogenous T4 will result in a lower, “normalized” TSH level but may disrupt the thyroid-pituitary crosstalk and may even produce clinical hyperthyroidism.
A similar scenario exists in the setting of early thyroid gland failure, such as in Hashimoto thyroiditis. But in the latter scenario, the TSH-to-T4 production relationship may be unstable over time, for as additional thyroid gland is destroyed, T4 production will continue to decrease, the TSH will increase, and the thyroid gland may ultimately fail and hypothyroidism will occur. Hence the recommendation that in the setting of subclinical hypothyroidism and antiperoxidase antibodies, T4 and TSH levels should be monitored regularly in order to detect early true thyroid gland failure when the T4 level can no longer be maintained despite the increased stimulation of the gland by the elevated TSH. Analogous to this may be subclinical hypothyroidism in the elderly, in whom thyroid gland failure may develop, despite an increased TSH, from senescence rather than autoimmunity. What I am suggesting is that the natural history of all patients with subclinical hypothyroidism is not alike, and it thus should not be surprising that there does not seem to be a one-size-fits-all approach to management.
Symptoms in patients with subclinical hypothyroidism have not uniformly improved with T4 treatment compared with placebo. Notably, most patients with subclinical hypothyroidism experience no symptoms. But consider the extremely common symptom of fatigue, which can be present for a myriad of defined and undefined reasons. This symptom may often lead physicians to check the TSH and, if that is even slightly elevated, to also check the T4. It may also lead some physicians to routinely check the T4. Subclinical hypothyroidism is also quite common; thus, by chance alone or because of the circadian timing of checking the TSH, a slightly elevated TSH and fatigue may coexist and yet be unrelated.
Additionally, a positive biochemical response to thyroxine supplementation, such as a lowering of cholesterol, does not prove that the patient was clinically hypothyroid prior to supplementation, any more than lowering a patient’s blood glucose with insulin proves that the patient was diabetic. The management of subclinical hypothyroidism should be nuanced and based on both clinical and laboratory parameters.
- Nasr C. Is a serum TSH measurement sufficient to monitor the treatment of primary hypothyroidism? Cleve Clin J Med 2016; 83(8):571–573. doi:10.3949/ccjm.83a.15165
- Mandell BF. Trust the thyroid thermostat. Cleve Clin J Med 2016; 83(8):552–553. doi:10.3949/ccjm.83b.08016
- Nasr C. Is a serum TSH measurement sufficient to monitor the treatment of primary hypothyroidism? Cleve Clin J Med 2016; 83(8):571–573. doi:10.3949/ccjm.83a.15165
- Mandell BF. Trust the thyroid thermostat. Cleve Clin J Med 2016; 83(8):552–553. doi:10.3949/ccjm.83b.08016
