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Cardiovascular trials lose more women than men
A new analysis of 11 phase 3/4 cardiovascular clinical trials conducted by the Thrombolysis in Myocardial Infarction (TIMI) group shows that women are more likely than men to discontinue study medications, and to withdraw from trials. The differences could not be explained by different frequencies of reporting adverse events, or by baseline differences.
The findings are significant, since cardiovascular drugs are routinely prescribed to women based on clinical trials that are populated largely by men, according to lead study author Emily Lau, MD, who is an advanced cardiology fellow at Massachusetts General Hospital, Boston. “It highlights an important disparity in clinical research in cardiology, because if women are already not represented well in clinical trials, and if once in clinical trials they don’t complete the study, it’s very hard to extrapolate the clinical trial findings to our female population in an accurate way,” Dr. Lau said in an interview. She also noted that sex-specific and reproductive factors are increasingly recognized as being important in the development and progression of cardiovascular disease.
The study was published in the journal Circulation.
The study refutes previously advanced explanations for higher withdrawal among women, including sex difference and comorbidities, according to an accompanying editorial by Sofia Sederholm Lawesson, MD, PhD, Eva Swahn, MD, PhD, and Joakim Alfredsson, MD, PhD, of Linköping University, Sweden. They also pointed out that the study found a larger between-sex difference in failure to adhere to study drug in North America (odds ratio, 1.35; 95% confidence interval, 1.30-1.41), but a more moderate difference among participants in Europe/Middle East/Africa (OR, 1.13; 95% CI, 1.09-1.17) and Asia/Pacific (OR, 1.13; 95% CI, 1.03-1.23) regions. And there were no sex differences at all among South/Central American populations.
They noted that high rates of nonadherence increase the chances of a false negative finding and overestimation of drug safety. “We know the associations between nonadherence and clinical outcomes. The next step should be to better understand the underlying reasons for, as well as consistent reporting of, nonadherence, and discontinuation in RCTs,” the editorial authors wrote.
Dr. Lau suggested a simple method to better understand reasons for withdrawal: Addition of questions to the case report form that asks about reasons for drug discontinuation or study withdrawal. “Was it an adverse event? Was it because I’m a mother of three and I can’t get to the clinical trial site after work and also pick up my kids? Are there societal barriers for women, or was it the experience of the clinical trial that was maybe less favorable for women compared to men? Or maybe there are medical reasons we simply don’t know. Something as simple as asking those questions can help us better understand the barriers to female retention,” said Dr. Lau.
The analysis included data from 135,879 men (72%) and 51,812 women (28%) enrolled in the trials. After adjustment for baseline differences, women were more likely than were men to permanently discontinue study drug (adjusted odds ratio [aOR], 1.22: P < .001), which did not vary by study duration. The finding was consistent regardless of the type of drug studied, as well as across placebo and active study arms.
Women also were more likely to prematurely discontinue study drug (trial-adjusted OR, 1.18; P < .001). The rate of drug discontinuation due to adverse event was identical in both men and women, at 36%.
Women were more likely to withdraw consent than were men in a meta-analysis and when individual patient-level results were pooled (aOR, 1.26; P < .001 for both).
Dr. Lau received funding from the National Institutes of Health and has no relevant financial disclosures. The editorial authors had various disclosures, including lecture fees from Bayer, Pfizer, and Boehringer Ingelheim, and they served on advisory boards for AstraZeneca and MSD.
A new analysis of 11 phase 3/4 cardiovascular clinical trials conducted by the Thrombolysis in Myocardial Infarction (TIMI) group shows that women are more likely than men to discontinue study medications, and to withdraw from trials. The differences could not be explained by different frequencies of reporting adverse events, or by baseline differences.
The findings are significant, since cardiovascular drugs are routinely prescribed to women based on clinical trials that are populated largely by men, according to lead study author Emily Lau, MD, who is an advanced cardiology fellow at Massachusetts General Hospital, Boston. “It highlights an important disparity in clinical research in cardiology, because if women are already not represented well in clinical trials, and if once in clinical trials they don’t complete the study, it’s very hard to extrapolate the clinical trial findings to our female population in an accurate way,” Dr. Lau said in an interview. She also noted that sex-specific and reproductive factors are increasingly recognized as being important in the development and progression of cardiovascular disease.
The study was published in the journal Circulation.
The study refutes previously advanced explanations for higher withdrawal among women, including sex difference and comorbidities, according to an accompanying editorial by Sofia Sederholm Lawesson, MD, PhD, Eva Swahn, MD, PhD, and Joakim Alfredsson, MD, PhD, of Linköping University, Sweden. They also pointed out that the study found a larger between-sex difference in failure to adhere to study drug in North America (odds ratio, 1.35; 95% confidence interval, 1.30-1.41), but a more moderate difference among participants in Europe/Middle East/Africa (OR, 1.13; 95% CI, 1.09-1.17) and Asia/Pacific (OR, 1.13; 95% CI, 1.03-1.23) regions. And there were no sex differences at all among South/Central American populations.
They noted that high rates of nonadherence increase the chances of a false negative finding and overestimation of drug safety. “We know the associations between nonadherence and clinical outcomes. The next step should be to better understand the underlying reasons for, as well as consistent reporting of, nonadherence, and discontinuation in RCTs,” the editorial authors wrote.
Dr. Lau suggested a simple method to better understand reasons for withdrawal: Addition of questions to the case report form that asks about reasons for drug discontinuation or study withdrawal. “Was it an adverse event? Was it because I’m a mother of three and I can’t get to the clinical trial site after work and also pick up my kids? Are there societal barriers for women, or was it the experience of the clinical trial that was maybe less favorable for women compared to men? Or maybe there are medical reasons we simply don’t know. Something as simple as asking those questions can help us better understand the barriers to female retention,” said Dr. Lau.
The analysis included data from 135,879 men (72%) and 51,812 women (28%) enrolled in the trials. After adjustment for baseline differences, women were more likely than were men to permanently discontinue study drug (adjusted odds ratio [aOR], 1.22: P < .001), which did not vary by study duration. The finding was consistent regardless of the type of drug studied, as well as across placebo and active study arms.
Women also were more likely to prematurely discontinue study drug (trial-adjusted OR, 1.18; P < .001). The rate of drug discontinuation due to adverse event was identical in both men and women, at 36%.
Women were more likely to withdraw consent than were men in a meta-analysis and when individual patient-level results were pooled (aOR, 1.26; P < .001 for both).
Dr. Lau received funding from the National Institutes of Health and has no relevant financial disclosures. The editorial authors had various disclosures, including lecture fees from Bayer, Pfizer, and Boehringer Ingelheim, and they served on advisory boards for AstraZeneca and MSD.
A new analysis of 11 phase 3/4 cardiovascular clinical trials conducted by the Thrombolysis in Myocardial Infarction (TIMI) group shows that women are more likely than men to discontinue study medications, and to withdraw from trials. The differences could not be explained by different frequencies of reporting adverse events, or by baseline differences.
The findings are significant, since cardiovascular drugs are routinely prescribed to women based on clinical trials that are populated largely by men, according to lead study author Emily Lau, MD, who is an advanced cardiology fellow at Massachusetts General Hospital, Boston. “It highlights an important disparity in clinical research in cardiology, because if women are already not represented well in clinical trials, and if once in clinical trials they don’t complete the study, it’s very hard to extrapolate the clinical trial findings to our female population in an accurate way,” Dr. Lau said in an interview. She also noted that sex-specific and reproductive factors are increasingly recognized as being important in the development and progression of cardiovascular disease.
The study was published in the journal Circulation.
The study refutes previously advanced explanations for higher withdrawal among women, including sex difference and comorbidities, according to an accompanying editorial by Sofia Sederholm Lawesson, MD, PhD, Eva Swahn, MD, PhD, and Joakim Alfredsson, MD, PhD, of Linköping University, Sweden. They also pointed out that the study found a larger between-sex difference in failure to adhere to study drug in North America (odds ratio, 1.35; 95% confidence interval, 1.30-1.41), but a more moderate difference among participants in Europe/Middle East/Africa (OR, 1.13; 95% CI, 1.09-1.17) and Asia/Pacific (OR, 1.13; 95% CI, 1.03-1.23) regions. And there were no sex differences at all among South/Central American populations.
They noted that high rates of nonadherence increase the chances of a false negative finding and overestimation of drug safety. “We know the associations between nonadherence and clinical outcomes. The next step should be to better understand the underlying reasons for, as well as consistent reporting of, nonadherence, and discontinuation in RCTs,” the editorial authors wrote.
Dr. Lau suggested a simple method to better understand reasons for withdrawal: Addition of questions to the case report form that asks about reasons for drug discontinuation or study withdrawal. “Was it an adverse event? Was it because I’m a mother of three and I can’t get to the clinical trial site after work and also pick up my kids? Are there societal barriers for women, or was it the experience of the clinical trial that was maybe less favorable for women compared to men? Or maybe there are medical reasons we simply don’t know. Something as simple as asking those questions can help us better understand the barriers to female retention,” said Dr. Lau.
The analysis included data from 135,879 men (72%) and 51,812 women (28%) enrolled in the trials. After adjustment for baseline differences, women were more likely than were men to permanently discontinue study drug (adjusted odds ratio [aOR], 1.22: P < .001), which did not vary by study duration. The finding was consistent regardless of the type of drug studied, as well as across placebo and active study arms.
Women also were more likely to prematurely discontinue study drug (trial-adjusted OR, 1.18; P < .001). The rate of drug discontinuation due to adverse event was identical in both men and women, at 36%.
Women were more likely to withdraw consent than were men in a meta-analysis and when individual patient-level results were pooled (aOR, 1.26; P < .001 for both).
Dr. Lau received funding from the National Institutes of Health and has no relevant financial disclosures. The editorial authors had various disclosures, including lecture fees from Bayer, Pfizer, and Boehringer Ingelheim, and they served on advisory boards for AstraZeneca and MSD.
FROM CIRCULATION
FDA expands sacubitril/valsartan indication to embrace some HFpEF
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
More Americans hospitalized, readmitted for heart failure
Overall primary HF hospitalization rates per 1,000 adults declined from 4.4 in 2010 to 4.1 in 2013, and then increased from 4.2 in 2014 to 4.9 in 2017.
Rates of unique patient visits for HF were also on the way down – falling from 3.4 in 2010 to 3.2 in 2013 and 2014 – before climbing to 3.8 in 2017.
Similar trends were observed for rates of postdischarge HF readmissions (from 1.0 in 2010 to 0.9 in 2014 to 1.1 in 2017) and all-cause 30-day readmissions (from 0.8 in 2010 to 0.7 in 2014 to 0.9 in 2017).
“We should be emphasizing the things we know work to reduce heart failure hospitalization, which is, No. 1, prevention,” senior author Boback Ziaeian, MD, PhD, said in an interview.
Comorbidities that can lead to heart failure crept up over the study period, such that by 2017, hypertension was present in 91.4% of patients, diabetes in 48.9%, and lipid disorders in 53.1%, up from 76.5%, 44.9%, and 40.4%, respectively, in 2010. Half of all patients had coronary artery disease at both time points. Renal disease shot up from 45.9% to 60.6% by 2017.
“If we did a better job of controlling our known risk factors, we would really cut down on the incidence of heart failure being developed and then, among those estimated 6.6 million heart failure patients, we need to get them on our cornerstone therapies,” said Dr. Ziaeian, of the Veterans Affairts Greater Los Angeles Healthcare System and the University of California, Los Angeles.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have shown clear efficacy and safety in trials like DAPA-HF and EMPEROR-Reduced, provide a “huge opportunity” to add on to standard therapies, he noted. Competition for VA contracts has brought the price down to about $50 a month for veterans, compared with a cash price of about $500-$600 a month.
Yet in routine practice, only 8% of veterans with HF at his center are on an SGLT2 inhibitor, compared with 80% on ACE inhibitors or beta blockers, observed Dr. Ziaeian. “This medication has been indicated for the last year and a half and we’re only at 8% in a system where we have pretty easy access to medications.”
As reported online Feb. 10 in JAMA Cardiology, notable sex differences were found in hospitalization, with higher rates per 1,000 persons among men.
In contrast, a 2020 report on HF trends in the VA system showed a 2% decrease in unadjusted 30-day readmissions from 2007 to 2017 and a decline in the adjusted 30-day readmission risk.
The present study did not risk-adjust readmission risk and included a population that was 51% male, compared with about 98% male in the VA, the investigators noted.
“The increasing hospitalization rate in our study may represent an actual increase in HF hospitalizations or shifts in administrative coding practices, increased use of HF biomarkers, or lower thresholds for diagnosis of HF with preserved ejection fraction,” they wrote.
The analysis was based on data from the Nationwide Readmission Database, which included 35,197,725 hospitalizations with a primary or secondary diagnosis of HF and 8,273,270 primary HF hospitalizations from January 2010 to December 2017.
A single primary HF admission occurred in 5,092,626 unique patients and 1,269,109 had two or more HF hospitalizations. The mean age was 72.1 years.
The administrative database did not include clinical data, so it wasn’t possible to differentiate between HF with preserved or reduced ejection fraction, the authors noted. Patient race and ethnicity data also were not available.
“Future studies are needed to verify our findings to better develop and improve individualized strategies for HF prevention, management, and surveillance for men and women,” the investigators concluded.
One coauthor reporting receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen Pharmaceuticals, Medtronic, Merck, and Novartis. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
Overall primary HF hospitalization rates per 1,000 adults declined from 4.4 in 2010 to 4.1 in 2013, and then increased from 4.2 in 2014 to 4.9 in 2017.
Rates of unique patient visits for HF were also on the way down – falling from 3.4 in 2010 to 3.2 in 2013 and 2014 – before climbing to 3.8 in 2017.
Similar trends were observed for rates of postdischarge HF readmissions (from 1.0 in 2010 to 0.9 in 2014 to 1.1 in 2017) and all-cause 30-day readmissions (from 0.8 in 2010 to 0.7 in 2014 to 0.9 in 2017).
“We should be emphasizing the things we know work to reduce heart failure hospitalization, which is, No. 1, prevention,” senior author Boback Ziaeian, MD, PhD, said in an interview.
Comorbidities that can lead to heart failure crept up over the study period, such that by 2017, hypertension was present in 91.4% of patients, diabetes in 48.9%, and lipid disorders in 53.1%, up from 76.5%, 44.9%, and 40.4%, respectively, in 2010. Half of all patients had coronary artery disease at both time points. Renal disease shot up from 45.9% to 60.6% by 2017.
“If we did a better job of controlling our known risk factors, we would really cut down on the incidence of heart failure being developed and then, among those estimated 6.6 million heart failure patients, we need to get them on our cornerstone therapies,” said Dr. Ziaeian, of the Veterans Affairts Greater Los Angeles Healthcare System and the University of California, Los Angeles.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have shown clear efficacy and safety in trials like DAPA-HF and EMPEROR-Reduced, provide a “huge opportunity” to add on to standard therapies, he noted. Competition for VA contracts has brought the price down to about $50 a month for veterans, compared with a cash price of about $500-$600 a month.
Yet in routine practice, only 8% of veterans with HF at his center are on an SGLT2 inhibitor, compared with 80% on ACE inhibitors or beta blockers, observed Dr. Ziaeian. “This medication has been indicated for the last year and a half and we’re only at 8% in a system where we have pretty easy access to medications.”
As reported online Feb. 10 in JAMA Cardiology, notable sex differences were found in hospitalization, with higher rates per 1,000 persons among men.
In contrast, a 2020 report on HF trends in the VA system showed a 2% decrease in unadjusted 30-day readmissions from 2007 to 2017 and a decline in the adjusted 30-day readmission risk.
The present study did not risk-adjust readmission risk and included a population that was 51% male, compared with about 98% male in the VA, the investigators noted.
“The increasing hospitalization rate in our study may represent an actual increase in HF hospitalizations or shifts in administrative coding practices, increased use of HF biomarkers, or lower thresholds for diagnosis of HF with preserved ejection fraction,” they wrote.
The analysis was based on data from the Nationwide Readmission Database, which included 35,197,725 hospitalizations with a primary or secondary diagnosis of HF and 8,273,270 primary HF hospitalizations from January 2010 to December 2017.
A single primary HF admission occurred in 5,092,626 unique patients and 1,269,109 had two or more HF hospitalizations. The mean age was 72.1 years.
The administrative database did not include clinical data, so it wasn’t possible to differentiate between HF with preserved or reduced ejection fraction, the authors noted. Patient race and ethnicity data also were not available.
“Future studies are needed to verify our findings to better develop and improve individualized strategies for HF prevention, management, and surveillance for men and women,” the investigators concluded.
One coauthor reporting receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen Pharmaceuticals, Medtronic, Merck, and Novartis. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
Overall primary HF hospitalization rates per 1,000 adults declined from 4.4 in 2010 to 4.1 in 2013, and then increased from 4.2 in 2014 to 4.9 in 2017.
Rates of unique patient visits for HF were also on the way down – falling from 3.4 in 2010 to 3.2 in 2013 and 2014 – before climbing to 3.8 in 2017.
Similar trends were observed for rates of postdischarge HF readmissions (from 1.0 in 2010 to 0.9 in 2014 to 1.1 in 2017) and all-cause 30-day readmissions (from 0.8 in 2010 to 0.7 in 2014 to 0.9 in 2017).
“We should be emphasizing the things we know work to reduce heart failure hospitalization, which is, No. 1, prevention,” senior author Boback Ziaeian, MD, PhD, said in an interview.
Comorbidities that can lead to heart failure crept up over the study period, such that by 2017, hypertension was present in 91.4% of patients, diabetes in 48.9%, and lipid disorders in 53.1%, up from 76.5%, 44.9%, and 40.4%, respectively, in 2010. Half of all patients had coronary artery disease at both time points. Renal disease shot up from 45.9% to 60.6% by 2017.
“If we did a better job of controlling our known risk factors, we would really cut down on the incidence of heart failure being developed and then, among those estimated 6.6 million heart failure patients, we need to get them on our cornerstone therapies,” said Dr. Ziaeian, of the Veterans Affairts Greater Los Angeles Healthcare System and the University of California, Los Angeles.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have shown clear efficacy and safety in trials like DAPA-HF and EMPEROR-Reduced, provide a “huge opportunity” to add on to standard therapies, he noted. Competition for VA contracts has brought the price down to about $50 a month for veterans, compared with a cash price of about $500-$600 a month.
Yet in routine practice, only 8% of veterans with HF at his center are on an SGLT2 inhibitor, compared with 80% on ACE inhibitors or beta blockers, observed Dr. Ziaeian. “This medication has been indicated for the last year and a half and we’re only at 8% in a system where we have pretty easy access to medications.”
As reported online Feb. 10 in JAMA Cardiology, notable sex differences were found in hospitalization, with higher rates per 1,000 persons among men.
In contrast, a 2020 report on HF trends in the VA system showed a 2% decrease in unadjusted 30-day readmissions from 2007 to 2017 and a decline in the adjusted 30-day readmission risk.
The present study did not risk-adjust readmission risk and included a population that was 51% male, compared with about 98% male in the VA, the investigators noted.
“The increasing hospitalization rate in our study may represent an actual increase in HF hospitalizations or shifts in administrative coding practices, increased use of HF biomarkers, or lower thresholds for diagnosis of HF with preserved ejection fraction,” they wrote.
The analysis was based on data from the Nationwide Readmission Database, which included 35,197,725 hospitalizations with a primary or secondary diagnosis of HF and 8,273,270 primary HF hospitalizations from January 2010 to December 2017.
A single primary HF admission occurred in 5,092,626 unique patients and 1,269,109 had two or more HF hospitalizations. The mean age was 72.1 years.
The administrative database did not include clinical data, so it wasn’t possible to differentiate between HF with preserved or reduced ejection fraction, the authors noted. Patient race and ethnicity data also were not available.
“Future studies are needed to verify our findings to better develop and improve individualized strategies for HF prevention, management, and surveillance for men and women,” the investigators concluded.
One coauthor reporting receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen Pharmaceuticals, Medtronic, Merck, and Novartis. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
Coffee lowers heart failure risk in unique study
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
Higher coffee consumption is associated with a lower risk of heart failure, according to a machine learning–based algorithm that analyzed data from three large observational trials.
“Coffee consumption actually was predictive on top of known risk factors originally identified from those three trials.” The study is significant because it underscores the potential of big data for individualizing patient management, lead investigator David Kao, MD, said in an interview. “We in fact adjusted for the scores that are commonly used to predict heart disease, and coffee consumption remained a predictor even on top of that.”
The study used supervised machine learning to analyze data on diet and other variables from three well-known observational studies: Framingham Heart Study (FHS), Cardiovascular Heart Study (CHS), and ARIC (Atherosclerosis Risk in Communities). The goal of the study, published online on Feb. 9, 2021*, was to identify potential novel risk factors for incident coronary heart disease, stroke, and heart failure.
“The main difference of the relationship between coffee and heart disease, compared with prior analyses, is that we’re able to find it in these well-known and well-accepted studies that have helped us find risk factors before,” Dr. Kao said
The study included 2,732 FHS participants aged 30-62 years, 3,704 CHS patients aged 65 and older, and 14,925 ARIC subjects aged 45-64, all of whom had no history of cardiovascular disease events when they enrolled. Primary outcomes for the machine-learning study were times to incident coronary heart disease, heart failure, and stroke.
Mathematics, not hypotheses
To compensate for variations in methodologies between the three observational trials, the study used 204 data measurements collected at the first FHS exam, including 16 dietary variables and for which similar data were collected for the other two studies.
The machine-learning model used what’s known as a random forest analysis to identify the leading potential risk factors from among the 204 variables. To confirm findings between studies, the authors used a technique called “data harmonization” to smooth variations in the methodologies of the trials, not only with participant age and duration and date of the trials, but also in how data on coffee consumption were gathered. For example, FHS collected that data as cups per day, whereas CHS and ARIC collected that as monthly, weekly, and daily consumption. The study converted the coffee consumption data from CHS and ARIC to cups per day to conform to FHS data.
Random forest analysis is a type of machine learning that randomly creates a cluster of decision trees – the “forest” – to determine which variables, such as dietary factors, are important in predicting a result. The analysis uses mathematics, not hypotheses, to identify important variables.
Heart failure and risk reduced
In this study, the analysis determined that each cup of caffeinated coffee daily was linked with a 5% reduction in the risk of heart failure (hazard ratio, 0.95; P = .02) and 6% reduction in stroke risk (HR, 0.94; P = .02), but had no significant impact on risk for coronary heart disease or cardiovascular disease.
When the data were adjusted for the FHS CVD risk score, increasing coffee consumption remained significantly associated with an identical lower risk of heart failure (P = .03) but not stroke (P = .33).
While the study supports an association between coffee consumption and heart failure risk, it doesn’t establish causation, noted Alice H. Lichtenstein, DSc, director and senior scientist at the Cardiovascular Nutrition Laboratory at Tufts University, Boston. “The authors could not rule out the possibility that caffeinated coffee intake was a proxy for other heart-healthy lifestyle behaviors,” Dr. Lichtenstein said. “Perhaps the best message from the study is that there appears to be no adverse effects of drinking moderate amounts of caffeinated coffee, and there may be benefits.”
She added a note of caution. “This result does not suggest coffee intake should be increased, nor does it give license to increasing coffee drinks with a lot of added cream and sugar.”
Machine learning mines observational trials
Dr. Kao explained the rationale for applying a machine-learning algorithm to the three observational trials. “When these trials were designed in general, they had an idea of what they were looking for in terms of what might be a risk factor,” said Dr. Kao, of the University of Colorado at Denver, Aurora. “What we were interested in doing was to look for risk factors that nobody really thought about ahead of time and let the data show us what might be a predictor without any bias of what we imagined to be true.”
He described the role of machine learning in extracting and “filtering” data from the trials. “Machine learning allows us to look at a very large number of factors or variables and identify the most important ones in predicting a specific outcome,” he said. This study evaluated the 204 variables and focused on dietary factors because they’re modifiable.
“We looked at them in these different studies where we could, and coffee was the one that was reproducible in all of them,” he said. “Machine learning helped filter down these very large numbers of variables in ways you can’t do with traditional statistics. It’s useful in studies like this because they gather thousands and thousands of variables that generally nobody uses, but these methods allow you to actually do something with them – to determine which ones are most important.”
He added: “These methods I think will take us toward personalized medicine where you’re really individualizing a plan for keeping a patient healthy. We still have a lot of work to do, but there’s a lot of promise for really helping each of us to figure out the ways we can become the healthiest that we can be.”
The study was supported with funding from the National Heart, Lung, and Blood Institute and the American Heart Association. Dr. Kao and coauthors, as well as Dr. Lichtenstein, had no relevant financial relationships to disclose.
*Correction, 2/10/21: An earlier version of this article misstated the study's publication date.
FROM CIRCULATION: HEART FAILURE
Cardiac activity not uncommon after lifesaving measures stop
Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.
Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.
“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.
“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”
About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.
Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.
The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.
As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.
A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.
The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.
Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.
In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.
“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”
In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”
The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.
“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”
He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.
“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”
Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.
“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”
The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.
Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.
“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.
“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”
About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.
Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.
The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.
As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.
A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.
The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.
Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.
In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.
“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”
In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”
The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.
“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”
He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.
“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”
Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.
“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”
The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.
Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.
“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.
“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”
About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.
Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.
The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.
As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.
A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.
The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.
Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.
In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.
“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”
In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”
The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.
“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”
He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.
“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”
Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.
“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”
The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Study flags cardiovascular disease in men with breast cancer
.
Among 24 male breast cancer patients evaluated over a decade in the Washington area, 88% were obese or overweight, 58% had hypertension, and 54% had hyperlipidemia.
Tachyarrhythmia existed in 8% of the men before cancer treatment and developed in 13% during treatment.
Two patients had preexisting heart failure, two patients developed the disease after treatment, and another two patients experienced a decline in left ventricular ejection fraction during the course of their cancer treatment.
“Our hope is that treating male breast cancer patients becomes a multidisciplinary approach where oncologists recruit their cardio-oncologist counterparts to mitigate cardiovascular risk factors, so patients live a long and healthy life after cancer treatment,” said Michael Ibrahim, one of the study authors and a 4th-year medical student at Georgetown University in Washington.
The data were presented Jan. 25 as part of the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient virtual course, which is hosting live sessions Feb. 5-6.
Although the association between cardiovascular disease and breast cancer is well documented in female breast cancer patients, there is little evidence in their male counterparts, especially African Americans, Mr. Ibrahim noted.
To provide some context, Mr. Ibrahim highlighted a 2018 report in nearly 3,500 female breast cancer patients, ages 40-79, in whom 52% were obese/overweight, 35% had hypertension, and 28% had hyperlipidemia.
Diabetes was present in 7.5% of the women, which was roughly equivalent to the 8% found among the men, Mr. Ibrahim said. The men were of similar age (38-79 years), with 42% being African American, 29% White, 4% Hispanic, and 25% another ethnicity.
Importantly, half of the men had a family history of breast cancer, and two were positive for a mutation in the BRCA gene.
A 2017 in-depth review of male breast cancer cites advancing age, hormonal imbalance, radiation exposure, and family history of breast cancer as key risk factors for the development of the disease, but the “most relevant risk factor” is a mutation in the BRCA2 gene.
Male breast cancer accounts for less than 1% of all breast cancers, but the incidence is rising and, in some patient groups, reaching 15% over their lifetimes, the paper notes. Additionally, these patients are at special risk for developing a second cancer.
Remarkably, 25% of men in the D.C. cohort were diagnosed with a second primary malignancy, 13% a third primary cancer, and 4% a fourth primary cancer, Mr. Ibrahim reported. “This goes to show that male breast cancer patients should routinely undergo cancer screening,” he said.
The initial diagnosis was invasive ductal carcinoma in 79% of the men, with the remaining ductal carcinoma in situ. All patients underwent mastectomy, 17% had anthracycline chemotherapy, 8% received HER2-targeted therapy, 16% had radiation, and 71% received hormone therapy.
In terms of cardiovascular management, statins were the most prescribed medication (46%), followed by antiplatelet therapy (42%) and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (38%).
An implantable cardioverter defibrillator/pacemaker was the most common intervention (16%), followed by bypass surgery in 8% and coronary angioplasty in 4%.
Mr. Ibrahim noted that the study was limited by the small sample size and that further research is needed to understand the risk of preexisting cardiovascular disease on long-term outcomes as well as the cardiotoxic effects of chemoradiation in male breast cancer patients.
In a statement, Mr. Ibrahim reiterated the need for a multidisciplinary cancer care team to evaluate patients’ cardiovascular risk prior to and through cancer treatment.
“On a more personal level, cancer patients are already surprised by their cancer diagnosis,” he added. “Similar to the pretreatment consultation with radiation oncology, breast surgery, and medical oncology, an upfront cardiovascular risk assessment provides greater comfort and further minimizes psychological surprise with cardiovascular complications going into cancer treatment.”
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
Among 24 male breast cancer patients evaluated over a decade in the Washington area, 88% were obese or overweight, 58% had hypertension, and 54% had hyperlipidemia.
Tachyarrhythmia existed in 8% of the men before cancer treatment and developed in 13% during treatment.
Two patients had preexisting heart failure, two patients developed the disease after treatment, and another two patients experienced a decline in left ventricular ejection fraction during the course of their cancer treatment.
“Our hope is that treating male breast cancer patients becomes a multidisciplinary approach where oncologists recruit their cardio-oncologist counterparts to mitigate cardiovascular risk factors, so patients live a long and healthy life after cancer treatment,” said Michael Ibrahim, one of the study authors and a 4th-year medical student at Georgetown University in Washington.
The data were presented Jan. 25 as part of the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient virtual course, which is hosting live sessions Feb. 5-6.
Although the association between cardiovascular disease and breast cancer is well documented in female breast cancer patients, there is little evidence in their male counterparts, especially African Americans, Mr. Ibrahim noted.
To provide some context, Mr. Ibrahim highlighted a 2018 report in nearly 3,500 female breast cancer patients, ages 40-79, in whom 52% were obese/overweight, 35% had hypertension, and 28% had hyperlipidemia.
Diabetes was present in 7.5% of the women, which was roughly equivalent to the 8% found among the men, Mr. Ibrahim said. The men were of similar age (38-79 years), with 42% being African American, 29% White, 4% Hispanic, and 25% another ethnicity.
Importantly, half of the men had a family history of breast cancer, and two were positive for a mutation in the BRCA gene.
A 2017 in-depth review of male breast cancer cites advancing age, hormonal imbalance, radiation exposure, and family history of breast cancer as key risk factors for the development of the disease, but the “most relevant risk factor” is a mutation in the BRCA2 gene.
Male breast cancer accounts for less than 1% of all breast cancers, but the incidence is rising and, in some patient groups, reaching 15% over their lifetimes, the paper notes. Additionally, these patients are at special risk for developing a second cancer.
Remarkably, 25% of men in the D.C. cohort were diagnosed with a second primary malignancy, 13% a third primary cancer, and 4% a fourth primary cancer, Mr. Ibrahim reported. “This goes to show that male breast cancer patients should routinely undergo cancer screening,” he said.
The initial diagnosis was invasive ductal carcinoma in 79% of the men, with the remaining ductal carcinoma in situ. All patients underwent mastectomy, 17% had anthracycline chemotherapy, 8% received HER2-targeted therapy, 16% had radiation, and 71% received hormone therapy.
In terms of cardiovascular management, statins were the most prescribed medication (46%), followed by antiplatelet therapy (42%) and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (38%).
An implantable cardioverter defibrillator/pacemaker was the most common intervention (16%), followed by bypass surgery in 8% and coronary angioplasty in 4%.
Mr. Ibrahim noted that the study was limited by the small sample size and that further research is needed to understand the risk of preexisting cardiovascular disease on long-term outcomes as well as the cardiotoxic effects of chemoradiation in male breast cancer patients.
In a statement, Mr. Ibrahim reiterated the need for a multidisciplinary cancer care team to evaluate patients’ cardiovascular risk prior to and through cancer treatment.
“On a more personal level, cancer patients are already surprised by their cancer diagnosis,” he added. “Similar to the pretreatment consultation with radiation oncology, breast surgery, and medical oncology, an upfront cardiovascular risk assessment provides greater comfort and further minimizes psychological surprise with cardiovascular complications going into cancer treatment.”
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
Among 24 male breast cancer patients evaluated over a decade in the Washington area, 88% were obese or overweight, 58% had hypertension, and 54% had hyperlipidemia.
Tachyarrhythmia existed in 8% of the men before cancer treatment and developed in 13% during treatment.
Two patients had preexisting heart failure, two patients developed the disease after treatment, and another two patients experienced a decline in left ventricular ejection fraction during the course of their cancer treatment.
“Our hope is that treating male breast cancer patients becomes a multidisciplinary approach where oncologists recruit their cardio-oncologist counterparts to mitigate cardiovascular risk factors, so patients live a long and healthy life after cancer treatment,” said Michael Ibrahim, one of the study authors and a 4th-year medical student at Georgetown University in Washington.
The data were presented Jan. 25 as part of the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient virtual course, which is hosting live sessions Feb. 5-6.
Although the association between cardiovascular disease and breast cancer is well documented in female breast cancer patients, there is little evidence in their male counterparts, especially African Americans, Mr. Ibrahim noted.
To provide some context, Mr. Ibrahim highlighted a 2018 report in nearly 3,500 female breast cancer patients, ages 40-79, in whom 52% were obese/overweight, 35% had hypertension, and 28% had hyperlipidemia.
Diabetes was present in 7.5% of the women, which was roughly equivalent to the 8% found among the men, Mr. Ibrahim said. The men were of similar age (38-79 years), with 42% being African American, 29% White, 4% Hispanic, and 25% another ethnicity.
Importantly, half of the men had a family history of breast cancer, and two were positive for a mutation in the BRCA gene.
A 2017 in-depth review of male breast cancer cites advancing age, hormonal imbalance, radiation exposure, and family history of breast cancer as key risk factors for the development of the disease, but the “most relevant risk factor” is a mutation in the BRCA2 gene.
Male breast cancer accounts for less than 1% of all breast cancers, but the incidence is rising and, in some patient groups, reaching 15% over their lifetimes, the paper notes. Additionally, these patients are at special risk for developing a second cancer.
Remarkably, 25% of men in the D.C. cohort were diagnosed with a second primary malignancy, 13% a third primary cancer, and 4% a fourth primary cancer, Mr. Ibrahim reported. “This goes to show that male breast cancer patients should routinely undergo cancer screening,” he said.
The initial diagnosis was invasive ductal carcinoma in 79% of the men, with the remaining ductal carcinoma in situ. All patients underwent mastectomy, 17% had anthracycline chemotherapy, 8% received HER2-targeted therapy, 16% had radiation, and 71% received hormone therapy.
In terms of cardiovascular management, statins were the most prescribed medication (46%), followed by antiplatelet therapy (42%) and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (38%).
An implantable cardioverter defibrillator/pacemaker was the most common intervention (16%), followed by bypass surgery in 8% and coronary angioplasty in 4%.
Mr. Ibrahim noted that the study was limited by the small sample size and that further research is needed to understand the risk of preexisting cardiovascular disease on long-term outcomes as well as the cardiotoxic effects of chemoradiation in male breast cancer patients.
In a statement, Mr. Ibrahim reiterated the need for a multidisciplinary cancer care team to evaluate patients’ cardiovascular risk prior to and through cancer treatment.
“On a more personal level, cancer patients are already surprised by their cancer diagnosis,” he added. “Similar to the pretreatment consultation with radiation oncology, breast surgery, and medical oncology, an upfront cardiovascular risk assessment provides greater comfort and further minimizes psychological surprise with cardiovascular complications going into cancer treatment.”
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Newer iPhones disable implanted defibrillators
Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.
“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.
The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.
The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.
The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.
Tests were performed on a patient wearing a Medtronic ICD.
“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.
Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.
With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.
More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.
This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.
On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.
Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”
Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.
“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”
The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.
However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”
Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.
Dr. Greenberg reported no potential conflicts of interest.
Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.
“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.
The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.
The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.
The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.
Tests were performed on a patient wearing a Medtronic ICD.
“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.
Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.
With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.
More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.
This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.
On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.
Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”
Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.
“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”
The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.
However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”
Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.
Dr. Greenberg reported no potential conflicts of interest.
Patients with an implantable cardioverter defibrillator (ICD) should be warned that some newer models of smartphones equipped with magnets, such as the iPhone 12, can disable their device, inhibiting its lifesaving functions, according to investigators who tested and confirmed this effect.
“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted which persisted for the duration of the test,” reported the investigating team led by Joshua C. Greenberg, MD, who is an electrophysiology fellow at Henry Ford Hospital, Detroit. The results were published in Heart Rhythm.
The American Heart Association has already cautioned that magnetic fields can inhibit the pulse generators for ICDs and pacemakers. On the AHA website, there is a list of devices and their potential for functional interference, but cell phones and other common devices are identified as posing a low risk.
The most recent iPhone and perhaps other advanced smartphones appear to be different. According to the authors of a study that tested the iPhone 12, this model has a circular array of magnets around a central charging coil. This array interacts with Apple’s proprietary MagSafe technology, which accelerates charging. The magnets also serve to orient the phone on the charger and enable other MagSafe accessories.
The authors of the new study were concerned that this array of magnets might be sufficiently strong to interfere with ICDs or other devices at risk. In a previously published study, the strength of a magnetic field sufficient to interfere with implantable cardiac devices was estimated to be at least 10 gauss.
Tests were performed on a patient wearing a Medtronic ICD.
“Once the iPhone was brought close to the ICD over the left chest area, immediate suspension of ICD therapies was noted,” according to the authors of the study. The functional loss of the ICS persisted for the duration of proximity. It was reproduced multiple times and with multiple phone positions.
Previous studies have provided evidence that earlier models do not share this risk. In a study testing the iPhone 6 and an Apple Watch in 148 patients with various types of implantable electronic devices, including pacemakers, cardioverter defibrillators, resynchronization defibrillators, and resynchronization pacemakers, only one instance of interference was observed in 1,352 tests.
With wand telemetry, iPhone-induced interferences could be detected with the iPhone 6 in 14% of the patients, but these did not appear to be clinically meaningful, and this type of interference could not be detected with the Apple Watch, according to the report. The single observed interaction, which was between an iPhone 6 and a dual-chamber pacemaker, suggested device-device interactions are uncommon.
More recently, a woman with a single-chamber Medtronic ICD who went to sleep wearing an Apple Watch was awoken by warning beeps from her cardiac device, according to a case report published online. The Apple watch became the prime suspect in causing the ICD warning when proximity of the watch reproduced the warning during clinical examination. However, the magnetic interference was ultimately found to be emanating from the wristband, not the watch.
This case prompted additional studies with Fitbit and other Apple Watch wristbands. Both wristbands contain magnets used to track heart rate. Both were found capable of deactivating ICDs at distances of approximately 2 cm. On the basis of these results, the authors concluded that patients should be counseled about the risk posed by wristbands used in fitness tracking, concluding that they should be kept at least 6 inches away from ICDs and not worn while sleeping.
On their website, Apple maintains a page that specifically warns about the potential for interactions between iPhone 12s and medical devices . Although there is an acknowledgment that the iPhone12 contains more magnets than prior iPhone models, it is stated that iPhone 12 models are “not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” Nevertheless, the Apple instructions advise keeping the iPhone and MagSafe accessories more than 6 inches away from medical devices.
Dr. Greenberg and coinvestigators concluded that the iPhone 12 does pose a greater risk to the dysfunction of ICDs and other medical devices because of the more powerful magnets. As a result, the study brings forward “an important public health issue concerning the newer generation iPhone 12.”
Well aware of this issue and this study, Bruce L. Wilkoff, MD, director of cardiac pacing and tachyarrhythmia devices, Cleveland Clinic, agreed. He said the focus should not be restricted to the iPhone 12 series but other wearable devices as alluded to in the study.
“Pacemakers and implantable defibrillators are designed to respond to magnets for important reasons, but magnets have many common uses,” he said. These can change the function of the implantable cardiac devise, but “it is temporary and only when placed in close proximity.”
The solution is simple. “Patients should be careful to avoid locating these objects near these devices,” Dr. Wilkoff said.
However, the first step is awareness. According to the study authors, devices with magnets powerful enough to impair function of implantable devices, such as the iPhone 12 “can potentially inhibit lifesaving therapy.”
Patients should be counseled and provided with practical steps, according to the authors. This includes keeping these devices out of pockets near implantable devices. They called for more noise from makers of smartphones and other devices with strong enough magnets to alter pacemaker and ICD function, and they advised physicians to draw awareness to this issue.
Dr. Greenberg reported no potential conflicts of interest.
FROM HEART RHYTHM
Five reasons sacubitril/valsartan should not be approved for HFpEF
In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.
This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.
The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.
Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
PARAGON-HF
PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.
Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.
The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).
A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.
Now to the five reasons not to approve the drug for this indication.
1. Uncertainty of benefit in HFpEF
A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.
By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.
The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
2. Modest effect size in PARAGON-HF
Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?
For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.
In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.
Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.
What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
3. Subgroups not compelling
Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.
In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.
The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.
FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”
By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.
Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.
Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
4. Approval would stop research
If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.
It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.
It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
5. Opportunity costs
The category of HFpEF is vast.
FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.
Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
Conclusion
Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.
If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?
Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.
Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.
A version of this article first appeared on Medscape.com.
In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.
This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.
The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.
Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
PARAGON-HF
PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.
Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.
The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).
A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.
Now to the five reasons not to approve the drug for this indication.
1. Uncertainty of benefit in HFpEF
A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.
By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.
The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
2. Modest effect size in PARAGON-HF
Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?
For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.
In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.
Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.
What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
3. Subgroups not compelling
Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.
In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.
The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.
FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”
By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.
Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.
Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
4. Approval would stop research
If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.
It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.
It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
5. Opportunity costs
The category of HFpEF is vast.
FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.
Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
Conclusion
Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.
If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?
Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.
Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.
A version of this article first appeared on Medscape.com.
In an ideal world, people could afford sacubitril/valsartan (Entresto), and clinicians would be allowed to prescribe it using clinical judgment as their guide. The imprimatur of an “[Food and Drug Administration]–labeled indication” would be unnecessary.
This is not our world. Guideline writers, third-party payers, and FDA regulators now play major roles in clinical decisions.
The angiotensin receptor neprilysin inhibitor is approved for use in patients with heart failure with reduced ejection fraction (HFrEF). In December 2020, an FDA advisory committee voted 12-1 in support of a vaguely worded question: Does PARAGON-HF provide sufficient evidence to support any indication for the drug in patients with heart failure with preserved ejection fraction (HFpEF)? The committee did not reach a consensus on what that indication should be.
Before I list five reasons why I hope the FDA does not approve the drug for any indication in patients with HFpEF, let’s review the seminal trial.
PARAGON-HF
PARAGON-HF randomly assigned slightly more than 4,800 patients with symptomatic HFpEF (left ventricular ejection fraction [LVEF] ≥45%) to sacubitril/valsartan or valsartan alone. The primary endpoint was total hospitalizations for heart failure (HHF) and death because of cardiovascular (CV) events.
Sacubitril/valsartan reduced the rate of the primary endpoint by 13% (rate ratio, 0.87; 95% confidence interval, 0.75-1.01; P = .06). There were 894 primary endpoint events in the sacubitril/valsartan arm, compared with 1,009 events in the valsartan arm.
The lower rate of events in the sacubitril/valsartan arm was driven by fewer hospitalizations for heart failure. CV death was essentially the same in both arms (204 deaths in the sacubitril/valsartan group versus 212 deaths in the valsartan group).
A note on the patients: the investigators screened more than 10,000 patients and enrolled less than half of them. The mean age was 73 years; 52% of patients were women, but only 2% were Black. The mean LVEF was 57%; 95% of patients had hypertension and were receiving diuretics at baseline.
Now to the five reasons not to approve the drug for this indication.
1. Uncertainty of benefit in HFpEF
A P value for the primary endpoint greater than the threshold of .05 suggests some degree of uncertainty. A nice way of describing this uncertainty is with a Bayesian analysis. Whereas a P value tells you the chance of seeing these results if the drug has no benefit, the Bayesian approach tells you the chance of drug benefit given the trial results.
By email, James Brophy, MD, a senior scientist in the Centre for Outcomes Research and Evaluation at McGill University, Montreal, showed me a Bayesian calculation of PARAGON-HF. He estimated a 38% chance that sacubitril/valsartan had a clinically meaningful 15% reduction in the primary endpoint, a 3% chance that it worsens outcomes, and a 58% chance that it is essentially no better than valsartan.
The take-home is that, in PARAGON-HF, a best-case scenario involving select high-risk patients with run-in periods and trial-level follow-up, there is substantial uncertainty as to whether the drug is any better than a generic standard.
2. Modest effect size in PARAGON-HF
Let’s assume the benefit seen in PARAGON-HF is not caused by chance. Was the effect clinically significant?
For context, consider the large effect size that sacubitril/valsartan had versus enalapril for patients with HFrEF.
In PARADIGM-HF, sacubitril/valsartan led to a 20% reduction in the composite primary endpoint. Importantly, this included equal reductions in both HHF and CV death. All-cause death was also significantly reduced in the active arm.
Because patients with HFpEF have a similarly poor prognosis as those with HFrEF, a truly beneficial drug should reduce not only HHF but also CV death and overall death. The lack of effect on these “harder” endpoints in PARAGON-HF points to a far more modest effect size for sacubitril/valsartan in HFpEF.
What’s more, even the signal of reduced HHF in PARAGON-HF is tenuous. The PARAGON-HF authors chose total HHF, whereas previous trials in patients with HFpEF used first HHF as their primary endpoint. Had PARAGON-HF followed the methods of prior trials, first HHF would not have made statistical significance (hazard ratio, 0.90; 95% CI, 0.79-1.04)
3. Subgroups not compelling
Proponents highlight the possibility that sacubitril/valsartan exerted a heterogenous effect in two subgroups.
In women, sacubitril/valsartan resulted in a 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.59-0.90), whereas men showed no significant difference (HR, 1.03; 95% CI, 0.85-1.25). And the drug seemed to have little benefit over valsartan in patients with a median LVEF greater than 57%.
The problem with subgroups is that, if you look at enough of them, some can be positive on the basis of chance alone. For instance, patients enrolled in western Europe had an outsized benefit from sacubitril/valsartan, compared with patients from other areas.
FDA reviewers noted: “It is possible that the heterogeneity of treatment effect observed in the subgroups by gender and LVEF in PARAGON-HF is a chance finding.”
By email, clinical trial expert Sanjay Kaul, MD, from Cedars-Sinai Medical Center in Los Angeles, expressed serious concern with the subgroup analyses in PARAGON-HF because the sex interaction was confined to HHF alone. There was no interaction for other outcomes, such as CV death, all-cause mortality, renal endpoints, blood pressure, or lowering of N-terminal of the prohormone brain natriuretic peptide.
Similarly, the interaction with ejection fraction was confined to total HHF; it was not seen with New York Heart Association class improvement, all-cause mortality, quality of life, renal endpoints, or time to first event.
Dr. Kaul also emphasized something cardiologists know well, “that ejection fraction is not a static variable and is expected to change during the course of the trial.” This point makes it hard to believe that a partially subjective measurement, such as LVEF, could be a precise modifier of benefit.
4. Approval would stop research
If the FDA approves sacubitril/valsartan for patients with HFpEF, there is a near-zero chance we will learn whether there are subsets of patients who benefit more or less from the drug.
It will be the defibrillator problem all over again. Namely, while the average effect of a defibrillator is to reduce mortality in patients with HFrEF, in approximately 9 of 10 patients the implanted device is never used. Efforts to find subgroups that are most likely to need (or not need) an implantable defibrillator have been impossible because industry has no incentive to fund trials that may narrow the number of patients who qualify for their product.
It will be the same with sacubitril/valsartan. This is not nefarious; it is merely a limitation of industry funding of trials.
5. Opportunity costs
The category of HFpEF is vast.
FDA approval – even for a subset of these patients – would have huge cost implications. I understand cost issues are considered outside the purview of the FDA, but health care spending isn’t infinite. Money spent covering this costly drug is money not available for other things.
Despite this nation’s wealth, we struggle to provide even basic care to large numbers of people. Approval of an expensive drug with no or modest benefit will only exacerbate these stark disparities.
Conclusion
Given our current system of health care delivery, my pragmatic answer is for the FDA to say no to sacubitril/valsartan for HFpEF.
If you believe the drug has outsized benefits in women or those with mild impairment of systolic function, the way to answer these questions is not with subgroup analyses from a trial that did not reach statistical significance in its primary endpoint, but with more randomized trials. Isn’t that what “exploratory” subgroups are for?
Holding off on an indication for HFpEF will force proponents to define a subset of patients who garner a clear and substantial benefit from sacubitril/valsartan.
Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. MDedge is part of the Medscape Professional Network.
A version of this article first appeared on Medscape.com.
Neprilysin, corin singled out for potential to guide heart failure therapy
Although not correlated with each other, increased levels of circulating according to prospective analysis involving 1,009 HF patients.
This implies that these enzymes might have value for individualizing care, including treatment of patients in heart failure with preserved ejection fraction (HFpEF), reported a team of investigators led by D.H. Frank Gommans, MD, PhD, department of cardiology, Radboud University Medical Center, Nijmegen, the Netherlands.
When followed for up to 7 years and after adjustment for differences in sex and age, the highest risk for the primary composite endpoint of cardiovascular (CV) death and heart failure hospitalization was observed in those with both high soluble neprilysin (sNEP) and high soluble corin (sCOR). The lowest risk was observed in the group with low levels of both enzymes.
The data suggest that monitoring these enzymes might provide “a step toward individualized CHF patient management,” Dr. Gommans reported in JACC Heart Failure, the adjusted hazard ratio for elevated sNEP and sCOR translated into a greater than 50% increase in the composite primary endpoint relative to low levels of both (HR, 1.56; P = .003). After a “comprehensive multivariable analysis,” the increased risk remained substantial and significant (HR, 1.41; P = .03).
In the natriuretic peptide pathway, which has long been recognized as a mediator of vasodilation, venous compliance, diuresis, and other processes dysregulated in heart failure, NEP and COR are “key mediators,” according to the investigators, who cited previously published studies. More attention has turned to these enzymes as potential biomarkers in the context of the PARADIGM trial, which associated an angiotensin-receptor neprilysin inhibitor (ARNI) with a survival benefit in CHF.
The observational study consisted of CHF patients attending a heart failure clinic and who were ARNI naive at inclusion. On the basis of circulating enzyme measurements undertaken from blood samples employing standard techniques, they were stratified into four groups. Those with low levels of both enzymes served as the reference. They were compared with those with low sNEP and high sCOR, those with high sNEP and low sCOR, and those with high levels of both enzymes.
Over the course of a median 4.5 years of follow-up, there were 511 deaths, of which 54% were from a CV cause. There were also 331 heart failure hospitalizations. In all, 449 patients reached the primary composite endpoint.
When compared with the group with low sNEP and low sCOR, an elevation in either enzyme was associated with a numerically but not significantly greater hazard ratio for the primary composite endpoint. The lack of correlation in the elevation of these two enzymes suggests each provides different prognostic information, although it appears that both must be considered together to predict outcomes.
Clinically, stratification of these enzymes might be most useful in HFpEF patients. Relative to the separation of event curves in the CHF patients with reduced ejection fraction (HFrEF), the divergence in the event curves for HFpEF were greater. In addition, event curves separated from the reference in HFpEF patients but not the HFrEF patients if either enzyme was elevated.
Asked if these data hold particular promise for monitoring and individualizing therapy in HFpEF patients, Dr. Gommans said yes. Although he cautioned that this was an observational study and that the differences between the HFpEF and HFrEF should be considered exploratory, he agreed that components of the natriuretic peptide pathway have particular potential to provide new prognostic information and individualize care in HFpEF, where therapeutic options remain limited.
Stratification of natriuretic peptide enzymes in this group might “present as an interesting alternative to ejection fraction” for prognosis and the consideration of treatment choices, he suggested.
Although further validation of the prognostic importance of sNEP and sCOR is needed, according to Dr. Gommans, he foresees the potential of therapeutic trials based on elevated levels of these enzymes. For example, he speculated that these levels might distinguish HFpEF patients who could benefit from a first-line ARNI.
In an accompanying editorial, significant doubts were expressed about simple measurements of sNEP and sCOR concentrations to predict clinical course or guide treatment decisions. The authors of the editorial agreed this is an important area of study but warned of its complexity.
“Concentrations of circulating neprilysin have been shown to correlate poorly with neprilysin activity. Thus the rate of natriuretic peptide degradation by neprilysin cannot be determined solely by measuring circulating levels,” cautioned Peder L. Myhre, MD, PhD, who is a cardiology fellow at Akershus University Hospital in Nordbyhagen, Norway, and postdoc researcher at the University of Oslo.
“Accordingly, concentrations of neprilysin and corin cannot alone be used to predict response to therapies interacting with these peptides,” he added. He agreed that neprilysin and corin might be appropriate biomarkers in CHF, but he thinks the focus must be on their enzymatic activity, not their circulating levels.
“Measuring the enzymatic activity may be a feasible strategy, but this remains to be seen,” he said.
Dr. Gommans reported a financial relationship with Novartis. Dr. Myhre reported financial relationships with Amgen, Novartis, and Novo Nordisk.
Although not correlated with each other, increased levels of circulating according to prospective analysis involving 1,009 HF patients.
This implies that these enzymes might have value for individualizing care, including treatment of patients in heart failure with preserved ejection fraction (HFpEF), reported a team of investigators led by D.H. Frank Gommans, MD, PhD, department of cardiology, Radboud University Medical Center, Nijmegen, the Netherlands.
When followed for up to 7 years and after adjustment for differences in sex and age, the highest risk for the primary composite endpoint of cardiovascular (CV) death and heart failure hospitalization was observed in those with both high soluble neprilysin (sNEP) and high soluble corin (sCOR). The lowest risk was observed in the group with low levels of both enzymes.
The data suggest that monitoring these enzymes might provide “a step toward individualized CHF patient management,” Dr. Gommans reported in JACC Heart Failure, the adjusted hazard ratio for elevated sNEP and sCOR translated into a greater than 50% increase in the composite primary endpoint relative to low levels of both (HR, 1.56; P = .003). After a “comprehensive multivariable analysis,” the increased risk remained substantial and significant (HR, 1.41; P = .03).
In the natriuretic peptide pathway, which has long been recognized as a mediator of vasodilation, venous compliance, diuresis, and other processes dysregulated in heart failure, NEP and COR are “key mediators,” according to the investigators, who cited previously published studies. More attention has turned to these enzymes as potential biomarkers in the context of the PARADIGM trial, which associated an angiotensin-receptor neprilysin inhibitor (ARNI) with a survival benefit in CHF.
The observational study consisted of CHF patients attending a heart failure clinic and who were ARNI naive at inclusion. On the basis of circulating enzyme measurements undertaken from blood samples employing standard techniques, they were stratified into four groups. Those with low levels of both enzymes served as the reference. They were compared with those with low sNEP and high sCOR, those with high sNEP and low sCOR, and those with high levels of both enzymes.
Over the course of a median 4.5 years of follow-up, there were 511 deaths, of which 54% were from a CV cause. There were also 331 heart failure hospitalizations. In all, 449 patients reached the primary composite endpoint.
When compared with the group with low sNEP and low sCOR, an elevation in either enzyme was associated with a numerically but not significantly greater hazard ratio for the primary composite endpoint. The lack of correlation in the elevation of these two enzymes suggests each provides different prognostic information, although it appears that both must be considered together to predict outcomes.
Clinically, stratification of these enzymes might be most useful in HFpEF patients. Relative to the separation of event curves in the CHF patients with reduced ejection fraction (HFrEF), the divergence in the event curves for HFpEF were greater. In addition, event curves separated from the reference in HFpEF patients but not the HFrEF patients if either enzyme was elevated.
Asked if these data hold particular promise for monitoring and individualizing therapy in HFpEF patients, Dr. Gommans said yes. Although he cautioned that this was an observational study and that the differences between the HFpEF and HFrEF should be considered exploratory, he agreed that components of the natriuretic peptide pathway have particular potential to provide new prognostic information and individualize care in HFpEF, where therapeutic options remain limited.
Stratification of natriuretic peptide enzymes in this group might “present as an interesting alternative to ejection fraction” for prognosis and the consideration of treatment choices, he suggested.
Although further validation of the prognostic importance of sNEP and sCOR is needed, according to Dr. Gommans, he foresees the potential of therapeutic trials based on elevated levels of these enzymes. For example, he speculated that these levels might distinguish HFpEF patients who could benefit from a first-line ARNI.
In an accompanying editorial, significant doubts were expressed about simple measurements of sNEP and sCOR concentrations to predict clinical course or guide treatment decisions. The authors of the editorial agreed this is an important area of study but warned of its complexity.
“Concentrations of circulating neprilysin have been shown to correlate poorly with neprilysin activity. Thus the rate of natriuretic peptide degradation by neprilysin cannot be determined solely by measuring circulating levels,” cautioned Peder L. Myhre, MD, PhD, who is a cardiology fellow at Akershus University Hospital in Nordbyhagen, Norway, and postdoc researcher at the University of Oslo.
“Accordingly, concentrations of neprilysin and corin cannot alone be used to predict response to therapies interacting with these peptides,” he added. He agreed that neprilysin and corin might be appropriate biomarkers in CHF, but he thinks the focus must be on their enzymatic activity, not their circulating levels.
“Measuring the enzymatic activity may be a feasible strategy, but this remains to be seen,” he said.
Dr. Gommans reported a financial relationship with Novartis. Dr. Myhre reported financial relationships with Amgen, Novartis, and Novo Nordisk.
Although not correlated with each other, increased levels of circulating according to prospective analysis involving 1,009 HF patients.
This implies that these enzymes might have value for individualizing care, including treatment of patients in heart failure with preserved ejection fraction (HFpEF), reported a team of investigators led by D.H. Frank Gommans, MD, PhD, department of cardiology, Radboud University Medical Center, Nijmegen, the Netherlands.
When followed for up to 7 years and after adjustment for differences in sex and age, the highest risk for the primary composite endpoint of cardiovascular (CV) death and heart failure hospitalization was observed in those with both high soluble neprilysin (sNEP) and high soluble corin (sCOR). The lowest risk was observed in the group with low levels of both enzymes.
The data suggest that monitoring these enzymes might provide “a step toward individualized CHF patient management,” Dr. Gommans reported in JACC Heart Failure, the adjusted hazard ratio for elevated sNEP and sCOR translated into a greater than 50% increase in the composite primary endpoint relative to low levels of both (HR, 1.56; P = .003). After a “comprehensive multivariable analysis,” the increased risk remained substantial and significant (HR, 1.41; P = .03).
In the natriuretic peptide pathway, which has long been recognized as a mediator of vasodilation, venous compliance, diuresis, and other processes dysregulated in heart failure, NEP and COR are “key mediators,” according to the investigators, who cited previously published studies. More attention has turned to these enzymes as potential biomarkers in the context of the PARADIGM trial, which associated an angiotensin-receptor neprilysin inhibitor (ARNI) with a survival benefit in CHF.
The observational study consisted of CHF patients attending a heart failure clinic and who were ARNI naive at inclusion. On the basis of circulating enzyme measurements undertaken from blood samples employing standard techniques, they were stratified into four groups. Those with low levels of both enzymes served as the reference. They were compared with those with low sNEP and high sCOR, those with high sNEP and low sCOR, and those with high levels of both enzymes.
Over the course of a median 4.5 years of follow-up, there were 511 deaths, of which 54% were from a CV cause. There were also 331 heart failure hospitalizations. In all, 449 patients reached the primary composite endpoint.
When compared with the group with low sNEP and low sCOR, an elevation in either enzyme was associated with a numerically but not significantly greater hazard ratio for the primary composite endpoint. The lack of correlation in the elevation of these two enzymes suggests each provides different prognostic information, although it appears that both must be considered together to predict outcomes.
Clinically, stratification of these enzymes might be most useful in HFpEF patients. Relative to the separation of event curves in the CHF patients with reduced ejection fraction (HFrEF), the divergence in the event curves for HFpEF were greater. In addition, event curves separated from the reference in HFpEF patients but not the HFrEF patients if either enzyme was elevated.
Asked if these data hold particular promise for monitoring and individualizing therapy in HFpEF patients, Dr. Gommans said yes. Although he cautioned that this was an observational study and that the differences between the HFpEF and HFrEF should be considered exploratory, he agreed that components of the natriuretic peptide pathway have particular potential to provide new prognostic information and individualize care in HFpEF, where therapeutic options remain limited.
Stratification of natriuretic peptide enzymes in this group might “present as an interesting alternative to ejection fraction” for prognosis and the consideration of treatment choices, he suggested.
Although further validation of the prognostic importance of sNEP and sCOR is needed, according to Dr. Gommans, he foresees the potential of therapeutic trials based on elevated levels of these enzymes. For example, he speculated that these levels might distinguish HFpEF patients who could benefit from a first-line ARNI.
In an accompanying editorial, significant doubts were expressed about simple measurements of sNEP and sCOR concentrations to predict clinical course or guide treatment decisions. The authors of the editorial agreed this is an important area of study but warned of its complexity.
“Concentrations of circulating neprilysin have been shown to correlate poorly with neprilysin activity. Thus the rate of natriuretic peptide degradation by neprilysin cannot be determined solely by measuring circulating levels,” cautioned Peder L. Myhre, MD, PhD, who is a cardiology fellow at Akershus University Hospital in Nordbyhagen, Norway, and postdoc researcher at the University of Oslo.
“Accordingly, concentrations of neprilysin and corin cannot alone be used to predict response to therapies interacting with these peptides,” he added. He agreed that neprilysin and corin might be appropriate biomarkers in CHF, but he thinks the focus must be on their enzymatic activity, not their circulating levels.
“Measuring the enzymatic activity may be a feasible strategy, but this remains to be seen,” he said.
Dr. Gommans reported a financial relationship with Novartis. Dr. Myhre reported financial relationships with Amgen, Novartis, and Novo Nordisk.
FROM JACC HEART FAILURE
Myocarditis by CMR may be rare after COVID-19 in elite athletes
Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.
Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).
That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.
The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.
The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.
One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.
“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.
Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”
The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”
The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.
Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
Reassurance and concern
“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”
The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).
As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.
The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”
Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.
“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”
Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”
It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.
“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.
Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.
Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.
There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”
The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”
The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
Routine CMR for positive cases
The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.
The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.
All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.
Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.
The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.
They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.
The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.
The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.
At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.
“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”
Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.
A version of this article first appeared on Medscape.com.
Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.
Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).
That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.
The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.
The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.
One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.
“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.
Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”
The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”
The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.
Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
Reassurance and concern
“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”
The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).
As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.
The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”
Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.
“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”
Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”
It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.
“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.
Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.
Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.
There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”
The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”
The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
Routine CMR for positive cases
The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.
The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.
All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.
Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.
The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.
They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.
The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.
The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.
At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.
“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”
Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.
A version of this article first appeared on Medscape.com.
Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.
Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).
That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.
The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.
The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.
One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.
“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.
Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”
The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”
The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.
Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
Reassurance and concern
“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”
The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).
As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.
The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”
Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.
“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”
Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”
It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.
“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.
Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.
Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.
There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”
The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”
The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
Routine CMR for positive cases
The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.
The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.
All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.
Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.
The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.
They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.
The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.
The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.
At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.
“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”
Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.
A version of this article first appeared on Medscape.com.