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CABG reduces cardiovascular mortality in ischemic heart failure regardless of age
ROME – Coronary artery bypass surgery reduces cardiovascular mortality in heart failure patients with ischemic cardiomyopathy to a consistent extent regardless of age at the time of surgery, according to a secondary analysis from the landmark STICH trial, Eric J. Velazquez, MD, reported at the annual congress of the European Society of Cardiology.
“Cardiologists and cardiac surgeons can confidently offer patients CABG in addition to optimal medical therapy with the knowledge that cardiovascular mortality is reduced by CABG to a similar extent across all age groups in this trial through 10 years of follow-up,” said Dr. Velazquez, professor of medicine at Duke University in Durham, N.C.
However, that’s only part of the story. Cardiovascular mortality was a secondary endpoint in STICH (Surgical Treatment for Ischemic Heart Failure). The primary endpoint was all-cause mortality. And CABG’s impact on all-cause mortality was diminished in older STICH participants because of their greater comorbidity burden and the competing risk of noncardiovascular death, he added.
The take-home message is that cardiologists and heart surgeons need to carefully assess competing mortality risks before pursuing CABG in older patients, according to Dr. Velazquez.
Session cochair Kim A. Williams, MD, professor and chief of cardiology at Rush University Medical Center in Chicago, posed a direct question: “Is there an age cutoff for your group for bypass surgery?”
No, Dr. Velazquez replied. He pointed out that cardiovascular mortality remained the No. 1 cause of mortality across all age groups.
“If the expectation is that the major cause of fatal events is going to be cardiovascular, and CABG plus medical therapy reduces that risk consistently regardless of age, we think that there really is no particular age cutoff. There is a point at which the noncardiovascular risk predominates, but in the population we studied we did not see that point,” Dr. Velazquez added.
STICH was a 22-nation trial in which 1,212 patients with a left ventricular ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomized to CABG plus optimal medical therapy or optimal medical therapy alone and followed for a median of 9.8 years (JACC Heart Fail. 2013;1[5]:400-8). For purposes of this secondary analysis, participants were divided into quartiles according to baseline age: Quartile 1 patients were up to 54 years old; quartile 2 were ages 55-60; quartile 3 were ages 61-67; and quartile 4 were ages 68 and up.
Older subjects had more comorbidities. All-cause mortality was significantly higher in older than younger patients: for CABG, 68% vs. 48% in quartiles 4 and 1, respectively; for medical therapy, 79% vs. 60% in the same two quartiles. In contrast, cardiovascular mortality did not differ significantly by age: It was 39% in quartile 4 and 35% in quartile 1 in the CABG group, and 53%, compared with 49%, in medically managed patients in quartiles 4 and 1.
For the secondary composite endpoint of all-cause mortality or cardiovascular hospitalization, the benefit of CABG plus medical management over medical management alone was significantly greater in younger than in older patients.
The rate of noncardiovascular mortality was 5.8% in quartiles 1 and 2, then leapt to 14.7% in quartile 3 and 21.1% in quartile 4.
Although the main focus of Dr. Velazquez’s presentation was the impact of CABG with advancing age, he said he found an important lesson in the younger population as well.
“We saw roughly a 40% relative risk reduction in all-cause mortality with CABG in the youngest quartile, compared with the three older groups. My interpretation of that data is that it’s probably not appropriate to avoid CABG in favor of another strategy in a younger patient when you see this kind of mortality benefit,” the cardiologist said.
One limitation of the STICH analysis, said session cochair Stephan Achenbach, MD, is that the study population was relatively young overall. The oldest patients in STICH were roughly the same age as the average patients undergoing CABG for left ventricular systolic dysfunction today at most centers, according to Dr. Achenbach, professor of cardiology at the University of Erlangen-Nuremberg (Germany).
Dr. Velazquez agreed. “I can’t speak as to whether these trial results would apply to the very elderly, patients age 90 and above,” he said.
Simultaneously with the presentation , the new STICH analysis was published online (Circulation. 2016 Aug 29. doi: 10.1161/CIRCULATIONAHA.116.024800).
STICH was funded by the National Institutes of Health. Dr. Velazquez reported having no relevant financial conflicts.
ROME – Coronary artery bypass surgery reduces cardiovascular mortality in heart failure patients with ischemic cardiomyopathy to a consistent extent regardless of age at the time of surgery, according to a secondary analysis from the landmark STICH trial, Eric J. Velazquez, MD, reported at the annual congress of the European Society of Cardiology.
“Cardiologists and cardiac surgeons can confidently offer patients CABG in addition to optimal medical therapy with the knowledge that cardiovascular mortality is reduced by CABG to a similar extent across all age groups in this trial through 10 years of follow-up,” said Dr. Velazquez, professor of medicine at Duke University in Durham, N.C.
However, that’s only part of the story. Cardiovascular mortality was a secondary endpoint in STICH (Surgical Treatment for Ischemic Heart Failure). The primary endpoint was all-cause mortality. And CABG’s impact on all-cause mortality was diminished in older STICH participants because of their greater comorbidity burden and the competing risk of noncardiovascular death, he added.
The take-home message is that cardiologists and heart surgeons need to carefully assess competing mortality risks before pursuing CABG in older patients, according to Dr. Velazquez.
Session cochair Kim A. Williams, MD, professor and chief of cardiology at Rush University Medical Center in Chicago, posed a direct question: “Is there an age cutoff for your group for bypass surgery?”
No, Dr. Velazquez replied. He pointed out that cardiovascular mortality remained the No. 1 cause of mortality across all age groups.
“If the expectation is that the major cause of fatal events is going to be cardiovascular, and CABG plus medical therapy reduces that risk consistently regardless of age, we think that there really is no particular age cutoff. There is a point at which the noncardiovascular risk predominates, but in the population we studied we did not see that point,” Dr. Velazquez added.
STICH was a 22-nation trial in which 1,212 patients with a left ventricular ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomized to CABG plus optimal medical therapy or optimal medical therapy alone and followed for a median of 9.8 years (JACC Heart Fail. 2013;1[5]:400-8). For purposes of this secondary analysis, participants were divided into quartiles according to baseline age: Quartile 1 patients were up to 54 years old; quartile 2 were ages 55-60; quartile 3 were ages 61-67; and quartile 4 were ages 68 and up.
Older subjects had more comorbidities. All-cause mortality was significantly higher in older than younger patients: for CABG, 68% vs. 48% in quartiles 4 and 1, respectively; for medical therapy, 79% vs. 60% in the same two quartiles. In contrast, cardiovascular mortality did not differ significantly by age: It was 39% in quartile 4 and 35% in quartile 1 in the CABG group, and 53%, compared with 49%, in medically managed patients in quartiles 4 and 1.
For the secondary composite endpoint of all-cause mortality or cardiovascular hospitalization, the benefit of CABG plus medical management over medical management alone was significantly greater in younger than in older patients.
The rate of noncardiovascular mortality was 5.8% in quartiles 1 and 2, then leapt to 14.7% in quartile 3 and 21.1% in quartile 4.
Although the main focus of Dr. Velazquez’s presentation was the impact of CABG with advancing age, he said he found an important lesson in the younger population as well.
“We saw roughly a 40% relative risk reduction in all-cause mortality with CABG in the youngest quartile, compared with the three older groups. My interpretation of that data is that it’s probably not appropriate to avoid CABG in favor of another strategy in a younger patient when you see this kind of mortality benefit,” the cardiologist said.
One limitation of the STICH analysis, said session cochair Stephan Achenbach, MD, is that the study population was relatively young overall. The oldest patients in STICH were roughly the same age as the average patients undergoing CABG for left ventricular systolic dysfunction today at most centers, according to Dr. Achenbach, professor of cardiology at the University of Erlangen-Nuremberg (Germany).
Dr. Velazquez agreed. “I can’t speak as to whether these trial results would apply to the very elderly, patients age 90 and above,” he said.
Simultaneously with the presentation , the new STICH analysis was published online (Circulation. 2016 Aug 29. doi: 10.1161/CIRCULATIONAHA.116.024800).
STICH was funded by the National Institutes of Health. Dr. Velazquez reported having no relevant financial conflicts.
ROME – Coronary artery bypass surgery reduces cardiovascular mortality in heart failure patients with ischemic cardiomyopathy to a consistent extent regardless of age at the time of surgery, according to a secondary analysis from the landmark STICH trial, Eric J. Velazquez, MD, reported at the annual congress of the European Society of Cardiology.
“Cardiologists and cardiac surgeons can confidently offer patients CABG in addition to optimal medical therapy with the knowledge that cardiovascular mortality is reduced by CABG to a similar extent across all age groups in this trial through 10 years of follow-up,” said Dr. Velazquez, professor of medicine at Duke University in Durham, N.C.
However, that’s only part of the story. Cardiovascular mortality was a secondary endpoint in STICH (Surgical Treatment for Ischemic Heart Failure). The primary endpoint was all-cause mortality. And CABG’s impact on all-cause mortality was diminished in older STICH participants because of their greater comorbidity burden and the competing risk of noncardiovascular death, he added.
The take-home message is that cardiologists and heart surgeons need to carefully assess competing mortality risks before pursuing CABG in older patients, according to Dr. Velazquez.
Session cochair Kim A. Williams, MD, professor and chief of cardiology at Rush University Medical Center in Chicago, posed a direct question: “Is there an age cutoff for your group for bypass surgery?”
No, Dr. Velazquez replied. He pointed out that cardiovascular mortality remained the No. 1 cause of mortality across all age groups.
“If the expectation is that the major cause of fatal events is going to be cardiovascular, and CABG plus medical therapy reduces that risk consistently regardless of age, we think that there really is no particular age cutoff. There is a point at which the noncardiovascular risk predominates, but in the population we studied we did not see that point,” Dr. Velazquez added.
STICH was a 22-nation trial in which 1,212 patients with a left ventricular ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomized to CABG plus optimal medical therapy or optimal medical therapy alone and followed for a median of 9.8 years (JACC Heart Fail. 2013;1[5]:400-8). For purposes of this secondary analysis, participants were divided into quartiles according to baseline age: Quartile 1 patients were up to 54 years old; quartile 2 were ages 55-60; quartile 3 were ages 61-67; and quartile 4 were ages 68 and up.
Older subjects had more comorbidities. All-cause mortality was significantly higher in older than younger patients: for CABG, 68% vs. 48% in quartiles 4 and 1, respectively; for medical therapy, 79% vs. 60% in the same two quartiles. In contrast, cardiovascular mortality did not differ significantly by age: It was 39% in quartile 4 and 35% in quartile 1 in the CABG group, and 53%, compared with 49%, in medically managed patients in quartiles 4 and 1.
For the secondary composite endpoint of all-cause mortality or cardiovascular hospitalization, the benefit of CABG plus medical management over medical management alone was significantly greater in younger than in older patients.
The rate of noncardiovascular mortality was 5.8% in quartiles 1 and 2, then leapt to 14.7% in quartile 3 and 21.1% in quartile 4.
Although the main focus of Dr. Velazquez’s presentation was the impact of CABG with advancing age, he said he found an important lesson in the younger population as well.
“We saw roughly a 40% relative risk reduction in all-cause mortality with CABG in the youngest quartile, compared with the three older groups. My interpretation of that data is that it’s probably not appropriate to avoid CABG in favor of another strategy in a younger patient when you see this kind of mortality benefit,” the cardiologist said.
One limitation of the STICH analysis, said session cochair Stephan Achenbach, MD, is that the study population was relatively young overall. The oldest patients in STICH were roughly the same age as the average patients undergoing CABG for left ventricular systolic dysfunction today at most centers, according to Dr. Achenbach, professor of cardiology at the University of Erlangen-Nuremberg (Germany).
Dr. Velazquez agreed. “I can’t speak as to whether these trial results would apply to the very elderly, patients age 90 and above,” he said.
Simultaneously with the presentation , the new STICH analysis was published online (Circulation. 2016 Aug 29. doi: 10.1161/CIRCULATIONAHA.116.024800).
STICH was funded by the National Institutes of Health. Dr. Velazquez reported having no relevant financial conflicts.
AT THE ESC CONGRESS 2016
Key clinical point: There should be no age cutoff in offering CABG to older patients with ischemic heart failure.
Major finding: CABG provided an absolute 14.4% reduction in cardiovascular mortality, compared with medical management, in both the youngest and oldest quartiles of patients with heart failure due to ischemic cardiomyopathy.
Data source: A secondary analysis of the STICH trial, in which 1,212 heart failure patients with ischemic cardiomyopathy were randomized to CABG plus medical therapy or medical therapy alone and followed for nearly 10 years.
Disclosures: The study was funded by the National Institutes of Health. The presenter reported having no relevant financial conflicts.
More TOPCAT flaws back spironolactone’s HFpEF efficacy
ORLANDO – Spironolactone inched a little closer toward becoming the first and only agent with proven efficacy for treating patients with heart failure with preserved ejection fraction based on further evidence for the drug’s efficacy in a subgroup of patients enrolled in the TOPCAT trial.
In 2014, the initial TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) report showed that spironolactone treatment of patients with heart failure with preserved ejection fraction (HFpEF) for 3 years produced a small, 11% relative reduction in the primary risk endpoint, compared with placebo that was not statistically significant (N Engl J Med. 2014 Apr 10;370[15]:1383-92).
But a follow-up post hoc analysis a year later showed evidence that the roughly half of patients in TOPCAT enrolled at centers in Russia and the Republic of Georgia may not have had HFpEF and also may not have received the planned dosage of spironolactone (Circulation. 2015 Jan 6;131[1]:34-42). An analysis that focused only on the 1,767 HFpEF patients (51% of the total TOPCAT cohort) enrolled in the Americas (United States, Canada, Argentina, and Brazil) showed that, compared with placebo, treatment with spironolactone cut the combined rate of cardiovascular death, nonfatal cardiac arrest, and heart failure hospitalization by 4.5 percentage points, an 18% relative risk reduction that was statistically significant. In the Americas, spironolactone also cut cardiovascular death alone by a relative 26%, and reduced heart failure hospitalization by a relative 18%, both statistically significant.
Additional analysis reported at the annual scientific meeting of the Heart Failure Society of America further supported the idea that many TOPCAT patients enrolled in Russia did not receive a physiologically meaningful dosage of spironolactone. Among 66 Russian patients randomized to the spironolactone arm who reported taking their drug as prescribed and who participated in a random draw of blood specimens 1 year into the study, 20 (30%) failed to show detectable blood levels of canrenone, a characteristic spironolactone metabolite, reported Eileen O’Meara, MD, at the meeting. In contrast, 2 (3%) of 76 enrolled U.S. patients failed to show detectable blood levels of the canrenone metabolite, a 10-fold difference said Dr. O’Meara, a cardiologist at the Montreal Heart Institute.The tested U.S. patients also showed a clear dose-response relationship between their reported spironolactone dosage and their canrenone levels, something not seen in the Russian patients. These new findings, plus the evidence cited in the 2015 analysis, create a compelling case that “actual use of spironolactone in Russia was lower than reported” by the trial participants in Russia and probably in Georgia as well, Dr. O’Meara said. The implication is that spironolactone’s real impact on HFpEF patients is best represented in the 51% of TOPCAT patients from the Americas, she added.
“We believe these findings emphasize the reliability of the Americas data,” said Marc A. Pfeffer, MD, a coinvestigator for TOPCAT and lead author of the 2015 post hoc analysis. “Until someone comes up with a better treatment for patients with HFpEF, we should pay attention to this. People need to get this message. And spironolactone costs 7 cents a day,” said Dr. Pfeffer, professor of medicine at Harvard Medical School in Boston.Currently, no agent is considered proven effective for improving outcomes in HFpEF patients. The 2016 guidelinesfor heart failure treatment from the European Society of Cardiology said “no treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF.”
After the TOPCAT results and post hoc analysis came out in 2014 and 2015 and word spread of spironolactone’s apparent efficacy in the American half of the trial, use of spironolactone to treat HFpEF patient has increased, commented Margaret M. Redfield, MD, a heart failure physician and professor at the Mayo Clinic in Rochester, Minn. She said she often prescribes spironolactone patients to HFpEF patients who require potassium supplementation, generally because of their diuretic treatment. These are the “safest” HFpEF patients for spironolactone treatment, she said, because they face the lowest risk for hyperkalemia, the major adverse effect from spironolactone.
On Twitter @mitchelzoler
This is extraordinarily important information from an extraordinarily important study. I’m strongly persuaded that the data from the Americas in TOPCAT show that spironolactone worked. The new data presented on canrenone levels make me even more ready to exclude from consideration the TOPCAT data from Russia and Georgia.
 |
| Mitchel L. Zoler/Frontline Medical News Dr. Barry H. Greenberg |
The heart failure community is left to decide what conclusions to draw from TOPCAT. I think guideline committees will struggle over what to make of the TOPCAT evidence. Any recommendation in favor of spironolactone needs to be somewhat guarded, but if a group made recommendations in support of spironolactone it would add an impetus for using it.
There has been long-standing interest in treating patients with heart failure with preserved ejection fraction with spironolactone. Currently, about a quarter of these patients take spironolactone. I’m not sure this level of use will increase dramatically because of what we now know about TOPCAT.
Dr. Barry H. Greenberg is professor of medicine and director of the advanced heart failure treatment program at the University of California, San Diego. He had no relevant disclosures. He made these comments in an interview.
This is extraordinarily important information from an extraordinarily important study. I’m strongly persuaded that the data from the Americas in TOPCAT show that spironolactone worked. The new data presented on canrenone levels make me even more ready to exclude from consideration the TOPCAT data from Russia and Georgia.
|
| Mitchel L. Zoler/Frontline Medical News Dr. Barry H. Greenberg |
The heart failure community is left to decide what conclusions to draw from TOPCAT. I think guideline committees will struggle over what to make of the TOPCAT evidence. Any recommendation in favor of spironolactone needs to be somewhat guarded, but if a group made recommendations in support of spironolactone it would add an impetus for using it.
There has been long-standing interest in treating patients with heart failure with preserved ejection fraction with spironolactone. Currently, about a quarter of these patients take spironolactone. I’m not sure this level of use will increase dramatically because of what we now know about TOPCAT.
Dr. Barry H. Greenberg is professor of medicine and director of the advanced heart failure treatment program at the University of California, San Diego. He had no relevant disclosures. He made these comments in an interview.
This is extraordinarily important information from an extraordinarily important study. I’m strongly persuaded that the data from the Americas in TOPCAT show that spironolactone worked. The new data presented on canrenone levels make me even more ready to exclude from consideration the TOPCAT data from Russia and Georgia.
|
| Mitchel L. Zoler/Frontline Medical News Dr. Barry H. Greenberg |
The heart failure community is left to decide what conclusions to draw from TOPCAT. I think guideline committees will struggle over what to make of the TOPCAT evidence. Any recommendation in favor of spironolactone needs to be somewhat guarded, but if a group made recommendations in support of spironolactone it would add an impetus for using it.
There has been long-standing interest in treating patients with heart failure with preserved ejection fraction with spironolactone. Currently, about a quarter of these patients take spironolactone. I’m not sure this level of use will increase dramatically because of what we now know about TOPCAT.
Dr. Barry H. Greenberg is professor of medicine and director of the advanced heart failure treatment program at the University of California, San Diego. He had no relevant disclosures. He made these comments in an interview.
ORLANDO – Spironolactone inched a little closer toward becoming the first and only agent with proven efficacy for treating patients with heart failure with preserved ejection fraction based on further evidence for the drug’s efficacy in a subgroup of patients enrolled in the TOPCAT trial.
In 2014, the initial TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) report showed that spironolactone treatment of patients with heart failure with preserved ejection fraction (HFpEF) for 3 years produced a small, 11% relative reduction in the primary risk endpoint, compared with placebo that was not statistically significant (N Engl J Med. 2014 Apr 10;370[15]:1383-92).
But a follow-up post hoc analysis a year later showed evidence that the roughly half of patients in TOPCAT enrolled at centers in Russia and the Republic of Georgia may not have had HFpEF and also may not have received the planned dosage of spironolactone (Circulation. 2015 Jan 6;131[1]:34-42). An analysis that focused only on the 1,767 HFpEF patients (51% of the total TOPCAT cohort) enrolled in the Americas (United States, Canada, Argentina, and Brazil) showed that, compared with placebo, treatment with spironolactone cut the combined rate of cardiovascular death, nonfatal cardiac arrest, and heart failure hospitalization by 4.5 percentage points, an 18% relative risk reduction that was statistically significant. In the Americas, spironolactone also cut cardiovascular death alone by a relative 26%, and reduced heart failure hospitalization by a relative 18%, both statistically significant.
Additional analysis reported at the annual scientific meeting of the Heart Failure Society of America further supported the idea that many TOPCAT patients enrolled in Russia did not receive a physiologically meaningful dosage of spironolactone. Among 66 Russian patients randomized to the spironolactone arm who reported taking their drug as prescribed and who participated in a random draw of blood specimens 1 year into the study, 20 (30%) failed to show detectable blood levels of canrenone, a characteristic spironolactone metabolite, reported Eileen O’Meara, MD, at the meeting. In contrast, 2 (3%) of 76 enrolled U.S. patients failed to show detectable blood levels of the canrenone metabolite, a 10-fold difference said Dr. O’Meara, a cardiologist at the Montreal Heart Institute.The tested U.S. patients also showed a clear dose-response relationship between their reported spironolactone dosage and their canrenone levels, something not seen in the Russian patients. These new findings, plus the evidence cited in the 2015 analysis, create a compelling case that “actual use of spironolactone in Russia was lower than reported” by the trial participants in Russia and probably in Georgia as well, Dr. O’Meara said. The implication is that spironolactone’s real impact on HFpEF patients is best represented in the 51% of TOPCAT patients from the Americas, she added.
“We believe these findings emphasize the reliability of the Americas data,” said Marc A. Pfeffer, MD, a coinvestigator for TOPCAT and lead author of the 2015 post hoc analysis. “Until someone comes up with a better treatment for patients with HFpEF, we should pay attention to this. People need to get this message. And spironolactone costs 7 cents a day,” said Dr. Pfeffer, professor of medicine at Harvard Medical School in Boston.Currently, no agent is considered proven effective for improving outcomes in HFpEF patients. The 2016 guidelinesfor heart failure treatment from the European Society of Cardiology said “no treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF.”
After the TOPCAT results and post hoc analysis came out in 2014 and 2015 and word spread of spironolactone’s apparent efficacy in the American half of the trial, use of spironolactone to treat HFpEF patient has increased, commented Margaret M. Redfield, MD, a heart failure physician and professor at the Mayo Clinic in Rochester, Minn. She said she often prescribes spironolactone patients to HFpEF patients who require potassium supplementation, generally because of their diuretic treatment. These are the “safest” HFpEF patients for spironolactone treatment, she said, because they face the lowest risk for hyperkalemia, the major adverse effect from spironolactone.
On Twitter @mitchelzoler
ORLANDO – Spironolactone inched a little closer toward becoming the first and only agent with proven efficacy for treating patients with heart failure with preserved ejection fraction based on further evidence for the drug’s efficacy in a subgroup of patients enrolled in the TOPCAT trial.
In 2014, the initial TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) report showed that spironolactone treatment of patients with heart failure with preserved ejection fraction (HFpEF) for 3 years produced a small, 11% relative reduction in the primary risk endpoint, compared with placebo that was not statistically significant (N Engl J Med. 2014 Apr 10;370[15]:1383-92).
But a follow-up post hoc analysis a year later showed evidence that the roughly half of patients in TOPCAT enrolled at centers in Russia and the Republic of Georgia may not have had HFpEF and also may not have received the planned dosage of spironolactone (Circulation. 2015 Jan 6;131[1]:34-42). An analysis that focused only on the 1,767 HFpEF patients (51% of the total TOPCAT cohort) enrolled in the Americas (United States, Canada, Argentina, and Brazil) showed that, compared with placebo, treatment with spironolactone cut the combined rate of cardiovascular death, nonfatal cardiac arrest, and heart failure hospitalization by 4.5 percentage points, an 18% relative risk reduction that was statistically significant. In the Americas, spironolactone also cut cardiovascular death alone by a relative 26%, and reduced heart failure hospitalization by a relative 18%, both statistically significant.
Additional analysis reported at the annual scientific meeting of the Heart Failure Society of America further supported the idea that many TOPCAT patients enrolled in Russia did not receive a physiologically meaningful dosage of spironolactone. Among 66 Russian patients randomized to the spironolactone arm who reported taking their drug as prescribed and who participated in a random draw of blood specimens 1 year into the study, 20 (30%) failed to show detectable blood levels of canrenone, a characteristic spironolactone metabolite, reported Eileen O’Meara, MD, at the meeting. In contrast, 2 (3%) of 76 enrolled U.S. patients failed to show detectable blood levels of the canrenone metabolite, a 10-fold difference said Dr. O’Meara, a cardiologist at the Montreal Heart Institute.The tested U.S. patients also showed a clear dose-response relationship between their reported spironolactone dosage and their canrenone levels, something not seen in the Russian patients. These new findings, plus the evidence cited in the 2015 analysis, create a compelling case that “actual use of spironolactone in Russia was lower than reported” by the trial participants in Russia and probably in Georgia as well, Dr. O’Meara said. The implication is that spironolactone’s real impact on HFpEF patients is best represented in the 51% of TOPCAT patients from the Americas, she added.
“We believe these findings emphasize the reliability of the Americas data,” said Marc A. Pfeffer, MD, a coinvestigator for TOPCAT and lead author of the 2015 post hoc analysis. “Until someone comes up with a better treatment for patients with HFpEF, we should pay attention to this. People need to get this message. And spironolactone costs 7 cents a day,” said Dr. Pfeffer, professor of medicine at Harvard Medical School in Boston.Currently, no agent is considered proven effective for improving outcomes in HFpEF patients. The 2016 guidelinesfor heart failure treatment from the European Society of Cardiology said “no treatment has yet been shown, convincingly, to reduce morbidity or mortality in patients with HFpEF.”
After the TOPCAT results and post hoc analysis came out in 2014 and 2015 and word spread of spironolactone’s apparent efficacy in the American half of the trial, use of spironolactone to treat HFpEF patient has increased, commented Margaret M. Redfield, MD, a heart failure physician and professor at the Mayo Clinic in Rochester, Minn. She said she often prescribes spironolactone patients to HFpEF patients who require potassium supplementation, generally because of their diuretic treatment. These are the “safest” HFpEF patients for spironolactone treatment, she said, because they face the lowest risk for hyperkalemia, the major adverse effect from spironolactone.
On Twitter @mitchelzoler
AT THE HFSA ANNUAL SCIENTIFIC MEETING
Key clinical point: A post hoc analysis of spironolactone use among TOPCAT participants further fueled the idea that spironolactone provides real benefit to patients with HFpEF.
Major finding: Among patients reportedly taking spironolactone, 30% of tested Russians and 3% of tested Americans did not have detectable canrenone levels.
Data source: TOPCAT, a multicenter, randomized trial with 3,445 HFpEF patients.
Disclosures: TOPCAT received no commercial funding. Dr. O’Meara, Dr. Pfeffer, and Dr. Redfield had no relevant disclosures.
Smoking thickens LV wall, worsens function
Current smoking, as well as higher levels of cumulative cigarette exposure from past smoking, were both associated with higher left ventricular mass, a higher LV mass-to-volume ratio, and worse diastolic function in an elderly community-based population with no overt indications of coronary artery disease or heart failure, according to a report published online Sept. 13 in Circulation: Cardiovascular Imaging.
“These findings suggest that smoking is associated with subtle alterations in LV structure and function, which might help explain the higher risk of heart failure [HF] reported for smokers, independent of coronary artery disease [CAD],” said Wilson Nadruz Jr., MD, of the cardiovascular division, Brigham and Women’s Hospital, Boston, and his associates.
They analyzed links between smoking and echocardiographic features using data from the Atherosclerosis Risk in Communities (ARIC) study, an ongoing prospective observational study involving community-dwelling adults who were aged 45-64 years at baseline in 1987-1989. For their study, Dr. Nadruz and his colleagues assessed echocardiographic images taken for 4,580 ARIC participants at follow-up roughly 25 years later. None of these adults had any indication of CAD or HF; 287 (6.3%) were current smokers, 2,316 (50.5%) were former smokers, and 1,977 (43.2%) never smoked.
Compared with never smokers, current smokers showed a greater LV mass index (80.4 vs. 76.7), a greater LV mass-to-volume ratio (1.93 vs. 1.83), and a higher prevalence of LV hypertrophy (15% vs. 9%), as well as a higher prevalence of concentric LV hypertrophy and worse LV diastolic function. The same association was found between never smokers and former smokers who had higher levels of cumulative cigarette exposure, the investigators said (Circ Cardiovasc Imag. 2016 Sep 13. doi: 10.1161/circimaging.116.004950).
This association between smoking and altered LV structure and function remained robust after the data were adjusted to account for numerous cardiac risk factors such as older age, higher BMI, diabetes, hypertension, greater alcohol consumption, and higher heart rate. It also didn’t vary by patient sex, race, or income level. In contrast, there was no association between smoking and right ventricular structure or function.
“These data suggest that smoking can independently lead to thickening of the heart and worsening of heart function, which may lead to a higher risk for heart failure, even in people who don’t have heart attacks,” Dr. Nadruz said in a statement.
Looking at the results in a more positive light, senior author Scott D. Solomon, MD, professor of medicine at Harvard University, Boston, said “The good news is that former smokers had similar heart structure and function, compared with never smokers,” suggesting that “the potential effects of tobacco on the myocardium might be reversible after smoking cessation.”
Current smoking, as well as higher levels of cumulative cigarette exposure from past smoking, were both associated with higher left ventricular mass, a higher LV mass-to-volume ratio, and worse diastolic function in an elderly community-based population with no overt indications of coronary artery disease or heart failure, according to a report published online Sept. 13 in Circulation: Cardiovascular Imaging.
“These findings suggest that smoking is associated with subtle alterations in LV structure and function, which might help explain the higher risk of heart failure [HF] reported for smokers, independent of coronary artery disease [CAD],” said Wilson Nadruz Jr., MD, of the cardiovascular division, Brigham and Women’s Hospital, Boston, and his associates.
They analyzed links between smoking and echocardiographic features using data from the Atherosclerosis Risk in Communities (ARIC) study, an ongoing prospective observational study involving community-dwelling adults who were aged 45-64 years at baseline in 1987-1989. For their study, Dr. Nadruz and his colleagues assessed echocardiographic images taken for 4,580 ARIC participants at follow-up roughly 25 years later. None of these adults had any indication of CAD or HF; 287 (6.3%) were current smokers, 2,316 (50.5%) were former smokers, and 1,977 (43.2%) never smoked.
Compared with never smokers, current smokers showed a greater LV mass index (80.4 vs. 76.7), a greater LV mass-to-volume ratio (1.93 vs. 1.83), and a higher prevalence of LV hypertrophy (15% vs. 9%), as well as a higher prevalence of concentric LV hypertrophy and worse LV diastolic function. The same association was found between never smokers and former smokers who had higher levels of cumulative cigarette exposure, the investigators said (Circ Cardiovasc Imag. 2016 Sep 13. doi: 10.1161/circimaging.116.004950).
This association between smoking and altered LV structure and function remained robust after the data were adjusted to account for numerous cardiac risk factors such as older age, higher BMI, diabetes, hypertension, greater alcohol consumption, and higher heart rate. It also didn’t vary by patient sex, race, or income level. In contrast, there was no association between smoking and right ventricular structure or function.
“These data suggest that smoking can independently lead to thickening of the heart and worsening of heart function, which may lead to a higher risk for heart failure, even in people who don’t have heart attacks,” Dr. Nadruz said in a statement.
Looking at the results in a more positive light, senior author Scott D. Solomon, MD, professor of medicine at Harvard University, Boston, said “The good news is that former smokers had similar heart structure and function, compared with never smokers,” suggesting that “the potential effects of tobacco on the myocardium might be reversible after smoking cessation.”
Current smoking, as well as higher levels of cumulative cigarette exposure from past smoking, were both associated with higher left ventricular mass, a higher LV mass-to-volume ratio, and worse diastolic function in an elderly community-based population with no overt indications of coronary artery disease or heart failure, according to a report published online Sept. 13 in Circulation: Cardiovascular Imaging.
“These findings suggest that smoking is associated with subtle alterations in LV structure and function, which might help explain the higher risk of heart failure [HF] reported for smokers, independent of coronary artery disease [CAD],” said Wilson Nadruz Jr., MD, of the cardiovascular division, Brigham and Women’s Hospital, Boston, and his associates.
They analyzed links between smoking and echocardiographic features using data from the Atherosclerosis Risk in Communities (ARIC) study, an ongoing prospective observational study involving community-dwelling adults who were aged 45-64 years at baseline in 1987-1989. For their study, Dr. Nadruz and his colleagues assessed echocardiographic images taken for 4,580 ARIC participants at follow-up roughly 25 years later. None of these adults had any indication of CAD or HF; 287 (6.3%) were current smokers, 2,316 (50.5%) were former smokers, and 1,977 (43.2%) never smoked.
Compared with never smokers, current smokers showed a greater LV mass index (80.4 vs. 76.7), a greater LV mass-to-volume ratio (1.93 vs. 1.83), and a higher prevalence of LV hypertrophy (15% vs. 9%), as well as a higher prevalence of concentric LV hypertrophy and worse LV diastolic function. The same association was found between never smokers and former smokers who had higher levels of cumulative cigarette exposure, the investigators said (Circ Cardiovasc Imag. 2016 Sep 13. doi: 10.1161/circimaging.116.004950).
This association between smoking and altered LV structure and function remained robust after the data were adjusted to account for numerous cardiac risk factors such as older age, higher BMI, diabetes, hypertension, greater alcohol consumption, and higher heart rate. It also didn’t vary by patient sex, race, or income level. In contrast, there was no association between smoking and right ventricular structure or function.
“These data suggest that smoking can independently lead to thickening of the heart and worsening of heart function, which may lead to a higher risk for heart failure, even in people who don’t have heart attacks,” Dr. Nadruz said in a statement.
Looking at the results in a more positive light, senior author Scott D. Solomon, MD, professor of medicine at Harvard University, Boston, said “The good news is that former smokers had similar heart structure and function, compared with never smokers,” suggesting that “the potential effects of tobacco on the myocardium might be reversible after smoking cessation.”
FROM CIRCULATION: CARDIOVASCULAR IMAGING
Key clinical point: Current smoking was associated with higher left ventricular mass, a higher LV mass-to-volume ratio, and worse diastolic function.
Major finding: Compared with never smokers, current smokers showed a greater LV mass index (80.4 vs. 76.7), a greater LV mass-to-volume ratio (1.93 vs. 1.83), and a higher prevalence of LV hypertrophy (15% vs. 9%).
Data source: A secondary analysis of data for 4,580 elderly participants in ARIC, a large community-based cohort.
Disclosures: This study was supported by Brigham and Women’s Hospital, Boston. Dr. Nadruz and his associates reported having no relevant financial disclosures.
Trials offer lessons despite negative primary endpoints
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
The new heart failure: A call for new research initiatives
Walking around the Cardiac Intensive Care Unit (CICU) with one of my heart failure colleagues, I was struck by the relative absence of patients with acute myocardial infarctions. Over the past 50 years, they have been replaced by patients with advanced heart failure, many of whom had been implanted with left ventricular assist devices or connected to a variety of extracorporeal support devices.
Although some of the patients were new New York Heart Association class IV patients, many had been treated for years with beta-blockers and renal ACE inhibitors or aldosterone antagonists. Their disease had now recurred and progressed despite what I had presumed to be curative drug therapy. They were experiencing the relentless progression of heart failure despite treatment that was developed almost 20 years ago and which has not advanced much since then. Many cardiologists of my generation presumed that heart failure was no longer a problem even though we knew that annual mortality rates of heart failure remained in the 10% range and that its incidence was increasing.
It has become clear to many of us that there has been little advance in the treatment of heart failure since the introduction of those 20th century drugs, notwithstanding the importance of the development of end stage cardiac support devices.
It seems our success in treating patients with ischemic heart disease had only delayed the expression and progression of cardiac dysfunction. Even with our success in treating patients with nonischemic heart failure, whatever that is, after reaching a brief plateau with drug therapy, they often experienced recurrence. It is true that many patients had improved as a result of drug therapy and that progression had been arrested and in some patients heart failure had actually been reversed. But many, like the patients I saw in our CICU, had progressed to advanced heart failure with little to be offered other than end-stage device therapy or heart transplantation. Both of these outcomes, although lifesaving, represent therapeutic failures.
It is time that we refocus our efforts on the treatment and eradication of heart failure. Although a number of contemporary treatment strategies have been developed, for the most part they have only resulted in modest additive benefit. We need to reconsider the protection of the heart during and after an ischemic event and prevent the insidious progression of ischemia in those patients with chronic coronary heart disease. In addition we need to direct our research to understand the pathophysiology of the “heart” in heart failure and to unlock the mysticism associated with the many etiologies of idiopathic nonischemic heart failure. Our knowledge in this disease or diseases is embarrassingly poor.
It is time to move on from the 20th century drug foundation of therapy based on neurohumoral control, to a 21st century understanding of the cellular and molecular targets affecting cardiac function. Recent investigations of collagen synthesis and degradation, cardiac energetics, and mitochondrial function have provided provocative information but represent only forays into the vast unknown mechanism of heart failure. The solution to worldwide heart failure is not in device therapy for everyone but in a deeper understanding of the mechanisms of heart failure and its application to therapy.
Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.
Walking around the Cardiac Intensive Care Unit (CICU) with one of my heart failure colleagues, I was struck by the relative absence of patients with acute myocardial infarctions. Over the past 50 years, they have been replaced by patients with advanced heart failure, many of whom had been implanted with left ventricular assist devices or connected to a variety of extracorporeal support devices.
Although some of the patients were new New York Heart Association class IV patients, many had been treated for years with beta-blockers and renal ACE inhibitors or aldosterone antagonists. Their disease had now recurred and progressed despite what I had presumed to be curative drug therapy. They were experiencing the relentless progression of heart failure despite treatment that was developed almost 20 years ago and which has not advanced much since then. Many cardiologists of my generation presumed that heart failure was no longer a problem even though we knew that annual mortality rates of heart failure remained in the 10% range and that its incidence was increasing.
It has become clear to many of us that there has been little advance in the treatment of heart failure since the introduction of those 20th century drugs, notwithstanding the importance of the development of end stage cardiac support devices.
It seems our success in treating patients with ischemic heart disease had only delayed the expression and progression of cardiac dysfunction. Even with our success in treating patients with nonischemic heart failure, whatever that is, after reaching a brief plateau with drug therapy, they often experienced recurrence. It is true that many patients had improved as a result of drug therapy and that progression had been arrested and in some patients heart failure had actually been reversed. But many, like the patients I saw in our CICU, had progressed to advanced heart failure with little to be offered other than end-stage device therapy or heart transplantation. Both of these outcomes, although lifesaving, represent therapeutic failures.
It is time that we refocus our efforts on the treatment and eradication of heart failure. Although a number of contemporary treatment strategies have been developed, for the most part they have only resulted in modest additive benefit. We need to reconsider the protection of the heart during and after an ischemic event and prevent the insidious progression of ischemia in those patients with chronic coronary heart disease. In addition we need to direct our research to understand the pathophysiology of the “heart” in heart failure and to unlock the mysticism associated with the many etiologies of idiopathic nonischemic heart failure. Our knowledge in this disease or diseases is embarrassingly poor.
It is time to move on from the 20th century drug foundation of therapy based on neurohumoral control, to a 21st century understanding of the cellular and molecular targets affecting cardiac function. Recent investigations of collagen synthesis and degradation, cardiac energetics, and mitochondrial function have provided provocative information but represent only forays into the vast unknown mechanism of heart failure. The solution to worldwide heart failure is not in device therapy for everyone but in a deeper understanding of the mechanisms of heart failure and its application to therapy.
Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.
Walking around the Cardiac Intensive Care Unit (CICU) with one of my heart failure colleagues, I was struck by the relative absence of patients with acute myocardial infarctions. Over the past 50 years, they have been replaced by patients with advanced heart failure, many of whom had been implanted with left ventricular assist devices or connected to a variety of extracorporeal support devices.
Although some of the patients were new New York Heart Association class IV patients, many had been treated for years with beta-blockers and renal ACE inhibitors or aldosterone antagonists. Their disease had now recurred and progressed despite what I had presumed to be curative drug therapy. They were experiencing the relentless progression of heart failure despite treatment that was developed almost 20 years ago and which has not advanced much since then. Many cardiologists of my generation presumed that heart failure was no longer a problem even though we knew that annual mortality rates of heart failure remained in the 10% range and that its incidence was increasing.
It has become clear to many of us that there has been little advance in the treatment of heart failure since the introduction of those 20th century drugs, notwithstanding the importance of the development of end stage cardiac support devices.
It seems our success in treating patients with ischemic heart disease had only delayed the expression and progression of cardiac dysfunction. Even with our success in treating patients with nonischemic heart failure, whatever that is, after reaching a brief plateau with drug therapy, they often experienced recurrence. It is true that many patients had improved as a result of drug therapy and that progression had been arrested and in some patients heart failure had actually been reversed. But many, like the patients I saw in our CICU, had progressed to advanced heart failure with little to be offered other than end-stage device therapy or heart transplantation. Both of these outcomes, although lifesaving, represent therapeutic failures.
It is time that we refocus our efforts on the treatment and eradication of heart failure. Although a number of contemporary treatment strategies have been developed, for the most part they have only resulted in modest additive benefit. We need to reconsider the protection of the heart during and after an ischemic event and prevent the insidious progression of ischemia in those patients with chronic coronary heart disease. In addition we need to direct our research to understand the pathophysiology of the “heart” in heart failure and to unlock the mysticism associated with the many etiologies of idiopathic nonischemic heart failure. Our knowledge in this disease or diseases is embarrassingly poor.
It is time to move on from the 20th century drug foundation of therapy based on neurohumoral control, to a 21st century understanding of the cellular and molecular targets affecting cardiac function. Recent investigations of collagen synthesis and degradation, cardiac energetics, and mitochondrial function have provided provocative information but represent only forays into the vast unknown mechanism of heart failure. The solution to worldwide heart failure is not in device therapy for everyone but in a deeper understanding of the mechanisms of heart failure and its application to therapy.
Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.
VIDEO: ICDs cut mortality in younger, healthier heart failure patients
ROME – Implantable cardioverter-defibrillators failed to significantly cut total mortality in patients with nonischemic systolic heart failure in the first large, randomized trial designed specifically to test the treatment in this setting. But the devices did show significant efficacy for doing what thy are specifically designed to do: prevent sudden cardiac death.
Results from the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) also highlighted the importance of targeting implantable cardioverter-defibrillator (ICD) treatment to the patients with nonischemic systolic heart failure who are most likely to benefit from it, younger patients who can be expected to live substantially longer than 1 year after they receive the device.
As a consequence, although the DANISH outcome was neutral for the study’s primary endpoint of decreased all-cause mortality several experts who commented on the findings as well as its lead investigator saw the overall results as providing important new evidence that ICDs are beneficial as long as they get placed in relative young nonischemic heart failure patients who don’t have comorbidities that threaten a quick demise.
The DANISH results “tell us ICDs can benefit patients if we can be a little better in selecting the right patients,” said Lars Køber, MD, while presenting the results at the annual congress of the European Society of Cardiology.
He noted that “for us [in Denmark] the results actually mean we’ll implant more ICDs. We had not been using ICDs [in patients with nonischemic systolic heart failure] because we were not convinced we should use them on everyone,” said Dr. Køber, a professor of cardiology at the University of Copenhagen.
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so placing an ICD should be taken into consideration,” commented Michel Komajda, MD, professor of cardiology at Pierre and Marie Curie University in Paris.
“This is the first trial to look at ICDs in the setting of modern therapy. Most of the ICD trials are very old now,” commented Mariell L. Jessup, MD, a heart failure specialist and professor of medicine at the University of Pennsylvania in Philadelphia. “In DANISH the ICDs significantly reduced the incidence of sudden cardiac death; that is what ICDs do.”
DANISH randomized 1,116 patients with nonischemic systolic heart failure at any of five Danish hospitals to either receive or not receive an ICD on top of optimal medical therapy and, when judged appropriate, placement of a cardiac resynchronization therapy (CRT) device. The patients averaged about 64 years of age, they all had New York Heart Association class II or III heart failure, and their maximum left ventricular ejection fraction was 35%. The researchers followed patients for a median of about 68 months (5.7 years).
The study’s primary endpoint, death from any cause, occurred in 22% of the ICD recipients and in 23% of control patients, a nonsignificant difference. The two prespecified secondary endpoints were cardiovascular death, which was a relative 23% lower in the ICD patients and also not statistically significant, but the rate of sudden cardiac death during follow-up was 4% in the ICD patients and 8% in the controls, a statistically significant 50% relative risk reduction. Concurrent with Dr. Køber’s report of these results at the meeting they also appeared online (N Engl J Med. 2016 Aug 28;doi: 10.1056/NEJMoa1608029).
The study design also included a set of prespecified subset analyses, and one of these showed a statistically significant interaction: When the analysis stratified patients into tertiles by age, those younger than 59 years old had a statistically significant 49% cut in all-cause mortality with ICD use, and patients 59-67 years old had a nonsignificant 25% reduction in all cause mortality when on ICD treatment. A second analysis that included all these patients less than 68 years old showed that ICD use linked with a statistically significant 36% relative cut in all-cause death, compared with the patients who did not receive an ICD. Older patients, those at least age 68 years, had a relative 20% increased rate of all-cause mortality with ICD use but not a statistically significant difference.
The results also showed a downside to ICD use. Among the 42% of patients who did not receive a CRT device, the rate of serious infection was 2.6% in the ICD recipients and 0.8% in the control. Serious infection rates with and without ICD placement were similar in the subgroup of patients who received a CRT device.
The results underscored the ability of ICDs to provide a substantial benefit to well-selected patients based on factors such as age. “Clearly we need more accurate selection of nonischemic systolic heart failure patients before implanting ICDs,” said Christophe Leclerqc, MD, designated discussant for the study and professor of cardiology at Central University Hospital of Rennes, France.
“It’s all about patient selection,” agreed Dr. Jessup, who added that currently many nonischemic heart failure patients worldwide who could benefit from an ICD and have a life expectancy beyond 1 year do not receive a device.
On Twitter @mitchelzoler
The message from this study is that in younger, nonischemic heart failure patients at risk for sudden cardiac death but with relatively less morbidity and more life expectancy, the placement of an implantable cardioverter-defibrillator produced a substantial reduction in all-cause mortality.
Although the all-cause mortality benefit was not statistically significant in the entire study population, the study results were very consistent with what we know about sudden cardiac death and why we give ICD therapy to heart failure patients. In DANISH the ICDs did what they are supposed to do, which is prevent sudden cardiac death.
The guidelines say that ICD treatment is appropriate when a patient’s life expectancy is “substantially” more than 1 year. They don’t specify an age cutoff because some 80-year-olds can have a good life expectancy while some younger patients may have comorbidities that make them unlikely to live more than 6 months. ICDs should be targeted to patients at high enough risk from sudden cardiac death to potentially get benefit from the device but not so high-risk that an ICD would be unlikely to make a difference in survival.
Many heart failure patients who could potentially get a benefit from an ICD still do not receive them. ICDs remain an underused treatment for heart failure patients in U.S. practice including patients with nonischemic systolic heart failure.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Javed Butler, MD, is a professor of medicine and chief of cardiology at Stony Brook (N.Y.) University. He made these comments in an interview. He has been a consultant to several drug and therapeutics companies but had no relevant disclosures.
The message from this study is that in younger, nonischemic heart failure patients at risk for sudden cardiac death but with relatively less morbidity and more life expectancy, the placement of an implantable cardioverter-defibrillator produced a substantial reduction in all-cause mortality.
Although the all-cause mortality benefit was not statistically significant in the entire study population, the study results were very consistent with what we know about sudden cardiac death and why we give ICD therapy to heart failure patients. In DANISH the ICDs did what they are supposed to do, which is prevent sudden cardiac death.
The guidelines say that ICD treatment is appropriate when a patient’s life expectancy is “substantially” more than 1 year. They don’t specify an age cutoff because some 80-year-olds can have a good life expectancy while some younger patients may have comorbidities that make them unlikely to live more than 6 months. ICDs should be targeted to patients at high enough risk from sudden cardiac death to potentially get benefit from the device but not so high-risk that an ICD would be unlikely to make a difference in survival.
Many heart failure patients who could potentially get a benefit from an ICD still do not receive them. ICDs remain an underused treatment for heart failure patients in U.S. practice including patients with nonischemic systolic heart failure.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Javed Butler, MD, is a professor of medicine and chief of cardiology at Stony Brook (N.Y.) University. He made these comments in an interview. He has been a consultant to several drug and therapeutics companies but had no relevant disclosures.
The message from this study is that in younger, nonischemic heart failure patients at risk for sudden cardiac death but with relatively less morbidity and more life expectancy, the placement of an implantable cardioverter-defibrillator produced a substantial reduction in all-cause mortality.
Although the all-cause mortality benefit was not statistically significant in the entire study population, the study results were very consistent with what we know about sudden cardiac death and why we give ICD therapy to heart failure patients. In DANISH the ICDs did what they are supposed to do, which is prevent sudden cardiac death.
The guidelines say that ICD treatment is appropriate when a patient’s life expectancy is “substantially” more than 1 year. They don’t specify an age cutoff because some 80-year-olds can have a good life expectancy while some younger patients may have comorbidities that make them unlikely to live more than 6 months. ICDs should be targeted to patients at high enough risk from sudden cardiac death to potentially get benefit from the device but not so high-risk that an ICD would be unlikely to make a difference in survival.
Many heart failure patients who could potentially get a benefit from an ICD still do not receive them. ICDs remain an underused treatment for heart failure patients in U.S. practice including patients with nonischemic systolic heart failure.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Javed Butler, MD, is a professor of medicine and chief of cardiology at Stony Brook (N.Y.) University. He made these comments in an interview. He has been a consultant to several drug and therapeutics companies but had no relevant disclosures.
ROME – Implantable cardioverter-defibrillators failed to significantly cut total mortality in patients with nonischemic systolic heart failure in the first large, randomized trial designed specifically to test the treatment in this setting. But the devices did show significant efficacy for doing what thy are specifically designed to do: prevent sudden cardiac death.
Results from the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) also highlighted the importance of targeting implantable cardioverter-defibrillator (ICD) treatment to the patients with nonischemic systolic heart failure who are most likely to benefit from it, younger patients who can be expected to live substantially longer than 1 year after they receive the device.
As a consequence, although the DANISH outcome was neutral for the study’s primary endpoint of decreased all-cause mortality several experts who commented on the findings as well as its lead investigator saw the overall results as providing important new evidence that ICDs are beneficial as long as they get placed in relative young nonischemic heart failure patients who don’t have comorbidities that threaten a quick demise.
The DANISH results “tell us ICDs can benefit patients if we can be a little better in selecting the right patients,” said Lars Køber, MD, while presenting the results at the annual congress of the European Society of Cardiology.
He noted that “for us [in Denmark] the results actually mean we’ll implant more ICDs. We had not been using ICDs [in patients with nonischemic systolic heart failure] because we were not convinced we should use them on everyone,” said Dr. Køber, a professor of cardiology at the University of Copenhagen.
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so placing an ICD should be taken into consideration,” commented Michel Komajda, MD, professor of cardiology at Pierre and Marie Curie University in Paris.
“This is the first trial to look at ICDs in the setting of modern therapy. Most of the ICD trials are very old now,” commented Mariell L. Jessup, MD, a heart failure specialist and professor of medicine at the University of Pennsylvania in Philadelphia. “In DANISH the ICDs significantly reduced the incidence of sudden cardiac death; that is what ICDs do.”
DANISH randomized 1,116 patients with nonischemic systolic heart failure at any of five Danish hospitals to either receive or not receive an ICD on top of optimal medical therapy and, when judged appropriate, placement of a cardiac resynchronization therapy (CRT) device. The patients averaged about 64 years of age, they all had New York Heart Association class II or III heart failure, and their maximum left ventricular ejection fraction was 35%. The researchers followed patients for a median of about 68 months (5.7 years).
The study’s primary endpoint, death from any cause, occurred in 22% of the ICD recipients and in 23% of control patients, a nonsignificant difference. The two prespecified secondary endpoints were cardiovascular death, which was a relative 23% lower in the ICD patients and also not statistically significant, but the rate of sudden cardiac death during follow-up was 4% in the ICD patients and 8% in the controls, a statistically significant 50% relative risk reduction. Concurrent with Dr. Køber’s report of these results at the meeting they also appeared online (N Engl J Med. 2016 Aug 28;doi: 10.1056/NEJMoa1608029).
The study design also included a set of prespecified subset analyses, and one of these showed a statistically significant interaction: When the analysis stratified patients into tertiles by age, those younger than 59 years old had a statistically significant 49% cut in all-cause mortality with ICD use, and patients 59-67 years old had a nonsignificant 25% reduction in all cause mortality when on ICD treatment. A second analysis that included all these patients less than 68 years old showed that ICD use linked with a statistically significant 36% relative cut in all-cause death, compared with the patients who did not receive an ICD. Older patients, those at least age 68 years, had a relative 20% increased rate of all-cause mortality with ICD use but not a statistically significant difference.
The results also showed a downside to ICD use. Among the 42% of patients who did not receive a CRT device, the rate of serious infection was 2.6% in the ICD recipients and 0.8% in the control. Serious infection rates with and without ICD placement were similar in the subgroup of patients who received a CRT device.
The results underscored the ability of ICDs to provide a substantial benefit to well-selected patients based on factors such as age. “Clearly we need more accurate selection of nonischemic systolic heart failure patients before implanting ICDs,” said Christophe Leclerqc, MD, designated discussant for the study and professor of cardiology at Central University Hospital of Rennes, France.
“It’s all about patient selection,” agreed Dr. Jessup, who added that currently many nonischemic heart failure patients worldwide who could benefit from an ICD and have a life expectancy beyond 1 year do not receive a device.
On Twitter @mitchelzoler
ROME – Implantable cardioverter-defibrillators failed to significantly cut total mortality in patients with nonischemic systolic heart failure in the first large, randomized trial designed specifically to test the treatment in this setting. But the devices did show significant efficacy for doing what thy are specifically designed to do: prevent sudden cardiac death.
Results from the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) also highlighted the importance of targeting implantable cardioverter-defibrillator (ICD) treatment to the patients with nonischemic systolic heart failure who are most likely to benefit from it, younger patients who can be expected to live substantially longer than 1 year after they receive the device.
As a consequence, although the DANISH outcome was neutral for the study’s primary endpoint of decreased all-cause mortality several experts who commented on the findings as well as its lead investigator saw the overall results as providing important new evidence that ICDs are beneficial as long as they get placed in relative young nonischemic heart failure patients who don’t have comorbidities that threaten a quick demise.
The DANISH results “tell us ICDs can benefit patients if we can be a little better in selecting the right patients,” said Lars Køber, MD, while presenting the results at the annual congress of the European Society of Cardiology.
He noted that “for us [in Denmark] the results actually mean we’ll implant more ICDs. We had not been using ICDs [in patients with nonischemic systolic heart failure] because we were not convinced we should use them on everyone,” said Dr. Køber, a professor of cardiology at the University of Copenhagen.
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so placing an ICD should be taken into consideration,” commented Michel Komajda, MD, professor of cardiology at Pierre and Marie Curie University in Paris.
“This is the first trial to look at ICDs in the setting of modern therapy. Most of the ICD trials are very old now,” commented Mariell L. Jessup, MD, a heart failure specialist and professor of medicine at the University of Pennsylvania in Philadelphia. “In DANISH the ICDs significantly reduced the incidence of sudden cardiac death; that is what ICDs do.”
DANISH randomized 1,116 patients with nonischemic systolic heart failure at any of five Danish hospitals to either receive or not receive an ICD on top of optimal medical therapy and, when judged appropriate, placement of a cardiac resynchronization therapy (CRT) device. The patients averaged about 64 years of age, they all had New York Heart Association class II or III heart failure, and their maximum left ventricular ejection fraction was 35%. The researchers followed patients for a median of about 68 months (5.7 years).
The study’s primary endpoint, death from any cause, occurred in 22% of the ICD recipients and in 23% of control patients, a nonsignificant difference. The two prespecified secondary endpoints were cardiovascular death, which was a relative 23% lower in the ICD patients and also not statistically significant, but the rate of sudden cardiac death during follow-up was 4% in the ICD patients and 8% in the controls, a statistically significant 50% relative risk reduction. Concurrent with Dr. Køber’s report of these results at the meeting they also appeared online (N Engl J Med. 2016 Aug 28;doi: 10.1056/NEJMoa1608029).
The study design also included a set of prespecified subset analyses, and one of these showed a statistically significant interaction: When the analysis stratified patients into tertiles by age, those younger than 59 years old had a statistically significant 49% cut in all-cause mortality with ICD use, and patients 59-67 years old had a nonsignificant 25% reduction in all cause mortality when on ICD treatment. A second analysis that included all these patients less than 68 years old showed that ICD use linked with a statistically significant 36% relative cut in all-cause death, compared with the patients who did not receive an ICD. Older patients, those at least age 68 years, had a relative 20% increased rate of all-cause mortality with ICD use but not a statistically significant difference.
The results also showed a downside to ICD use. Among the 42% of patients who did not receive a CRT device, the rate of serious infection was 2.6% in the ICD recipients and 0.8% in the control. Serious infection rates with and without ICD placement were similar in the subgroup of patients who received a CRT device.
The results underscored the ability of ICDs to provide a substantial benefit to well-selected patients based on factors such as age. “Clearly we need more accurate selection of nonischemic systolic heart failure patients before implanting ICDs,” said Christophe Leclerqc, MD, designated discussant for the study and professor of cardiology at Central University Hospital of Rennes, France.
“It’s all about patient selection,” agreed Dr. Jessup, who added that currently many nonischemic heart failure patients worldwide who could benefit from an ICD and have a life expectancy beyond 1 year do not receive a device.
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2016
Key clinical point: Implantable cardioverter-defibrillators significantly cut the rate of sudden cardiac death in patients with nonishemic systolic heart failure, and reduced all-cause mortality in patients younger than 68 years.
Major finding: Sudden cardiac death was halved in patients who received an ICD compared with control patients.
Data source: DANISH, a multicenter, randomized trial in 1,116 patients with nonischemic systolic heart failure.
Disclosures: DANISH received partial funding from Medtronic and St. Jude, companies that market ICDs. Dr. Køber, Dr. Komajda, and Dr. Jessup had no relevant disclosures. Dr. Leclercq has been a consultant to or spoken on behalf of Biotronik, Boston Scientific, Medtronic, St. Jude, Livanova and several drug companies.
Inadequate diversity snags hypertrophic cardiomyopathy genetic linkages
The genetic tests used for more than a decade to identify patients or family members who carry genetic mutations linked to hypertrophic cardiomyopathy are seriously flawed.
The tests have been erroneously flagging people as genetically positive for hypertrophic cardiomyopathy (HC) when they actually carried benign genetic variants, according to a new reassessment of the genetic linkages by researchers using a more genetically diverse database. Five genetic variants now reclassified as benign were collectively responsible for flagging 74% of people flagged at genetic risk for HC in the more than 8,500 cases examined.
The results call into question any genetic diagnosis of HC made since genetic testing entered the mainstream in 2003, especially among African Americans who seem to have been disproportionately affected by these mislabeled genetic markers because of inadequate population diversity when the markers were first established.
In addition, the results more broadly cast a shadow over the full spectrum of genetic tests for disease-linked variants now in routine medical practice because of the possibility that other linkage determinations derived from an inadequately-representative reference population, reported Arjun K. Manrai, PhD, and his associates (N Engl J Med. 2016 Aug 18;375[7]:655-65). The researchers call the HC experience they document a “cautionary tale of broad relevance to genetic diagnosis.”
The findings “powerfully illustrate the importance of racial and genetic diversity” when running linkage studies aimed at validating genetic markers for widespread clinical use, Isaac S. Kohane, MD, senior author of the study, said in a written statement. “Racial and ethnic inclusiveness improves the validity and accuracy” of genetic tests, said Dr. Kohane, professor of biomedical informatics and pediatrics at Harvard Medical School in Boston.
“We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” Dr. Manrai, a biomedical informatics researcher at Harvard, said in the same statement. “Much genetic assessment today relies on historical links between a disorder and variant, sometimes decades old. We believe our findings illustrate the critical need to systematically reevaluate prior assertions about genetic variants,” Dr. Manrai added in an interview.
The two researchers and their associates reexamined the link between genetic variants and HC in three genetic databases that involved a total of more than 8,500 people. One database included 4,300 white Americans and 2,203 black Americans. A second database included genetic data from 1,092 people from 14 worldwide populations, and the third had genetic data from 938 people from 51 worldwide populations.
The analysis showed that although 94 distinct genetic variants that had previously been reported as associated with HC were confirmed as linked, just 5 met the study’s definition of a “high-frequency” variant with an allele frequent of more than 1%. These five variants together accounted for 74% of the overall total of linkages seen in these 8,533 people. Further analysis classified all five of these high-frequency genetic variants as benign with no discernible link to HC.
These five high-frequency variants occurred disproportionately higher among black Americans, and the consequences of this showed up in the patient records the researchers reviewed from one large U.S. genetic testing laboratory. They examined in detail HC genetic test results during 2004-2013 from 2,912 unrelated people. The records showed seven people had been labeled as carrying either a pathogenic or “presumed pathogenic” variant when in fact they had one of the five high-frequency variants now declared benign. Five of the seven mislabeled people were of African ancestry; the other two had unknown ancestry.
The researchers called for reevaluating known variants for all genetic diseases in more diverse populations and to immediately release the results of updated linkage assessments. This has the potential to meaningfully rewrite current gospel for many genetic variants and linkages.
“Our findings point to the value of patients staying in contact with their genetic counselors and physicians, even years after genetic testing,” Dr. Manrai said. Reassessments using more diverse populations will take time, he acknowledged, but tools are available to allow clinical geneticists to update old variants and apply new ones in real time, as soon as a new assessment completes.
Dr. Manrai and Dr. Kohane had no disclosures.
On Twitter @mitchelzoler
The genetic tests used for more than a decade to identify patients or family members who carry genetic mutations linked to hypertrophic cardiomyopathy are seriously flawed.
The tests have been erroneously flagging people as genetically positive for hypertrophic cardiomyopathy (HC) when they actually carried benign genetic variants, according to a new reassessment of the genetic linkages by researchers using a more genetically diverse database. Five genetic variants now reclassified as benign were collectively responsible for flagging 74% of people flagged at genetic risk for HC in the more than 8,500 cases examined.
The results call into question any genetic diagnosis of HC made since genetic testing entered the mainstream in 2003, especially among African Americans who seem to have been disproportionately affected by these mislabeled genetic markers because of inadequate population diversity when the markers were first established.
In addition, the results more broadly cast a shadow over the full spectrum of genetic tests for disease-linked variants now in routine medical practice because of the possibility that other linkage determinations derived from an inadequately-representative reference population, reported Arjun K. Manrai, PhD, and his associates (N Engl J Med. 2016 Aug 18;375[7]:655-65). The researchers call the HC experience they document a “cautionary tale of broad relevance to genetic diagnosis.”
The findings “powerfully illustrate the importance of racial and genetic diversity” when running linkage studies aimed at validating genetic markers for widespread clinical use, Isaac S. Kohane, MD, senior author of the study, said in a written statement. “Racial and ethnic inclusiveness improves the validity and accuracy” of genetic tests, said Dr. Kohane, professor of biomedical informatics and pediatrics at Harvard Medical School in Boston.
“We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” Dr. Manrai, a biomedical informatics researcher at Harvard, said in the same statement. “Much genetic assessment today relies on historical links between a disorder and variant, sometimes decades old. We believe our findings illustrate the critical need to systematically reevaluate prior assertions about genetic variants,” Dr. Manrai added in an interview.
The two researchers and their associates reexamined the link between genetic variants and HC in three genetic databases that involved a total of more than 8,500 people. One database included 4,300 white Americans and 2,203 black Americans. A second database included genetic data from 1,092 people from 14 worldwide populations, and the third had genetic data from 938 people from 51 worldwide populations.
The analysis showed that although 94 distinct genetic variants that had previously been reported as associated with HC were confirmed as linked, just 5 met the study’s definition of a “high-frequency” variant with an allele frequent of more than 1%. These five variants together accounted for 74% of the overall total of linkages seen in these 8,533 people. Further analysis classified all five of these high-frequency genetic variants as benign with no discernible link to HC.
These five high-frequency variants occurred disproportionately higher among black Americans, and the consequences of this showed up in the patient records the researchers reviewed from one large U.S. genetic testing laboratory. They examined in detail HC genetic test results during 2004-2013 from 2,912 unrelated people. The records showed seven people had been labeled as carrying either a pathogenic or “presumed pathogenic” variant when in fact they had one of the five high-frequency variants now declared benign. Five of the seven mislabeled people were of African ancestry; the other two had unknown ancestry.
The researchers called for reevaluating known variants for all genetic diseases in more diverse populations and to immediately release the results of updated linkage assessments. This has the potential to meaningfully rewrite current gospel for many genetic variants and linkages.
“Our findings point to the value of patients staying in contact with their genetic counselors and physicians, even years after genetic testing,” Dr. Manrai said. Reassessments using more diverse populations will take time, he acknowledged, but tools are available to allow clinical geneticists to update old variants and apply new ones in real time, as soon as a new assessment completes.
Dr. Manrai and Dr. Kohane had no disclosures.
On Twitter @mitchelzoler
The genetic tests used for more than a decade to identify patients or family members who carry genetic mutations linked to hypertrophic cardiomyopathy are seriously flawed.
The tests have been erroneously flagging people as genetically positive for hypertrophic cardiomyopathy (HC) when they actually carried benign genetic variants, according to a new reassessment of the genetic linkages by researchers using a more genetically diverse database. Five genetic variants now reclassified as benign were collectively responsible for flagging 74% of people flagged at genetic risk for HC in the more than 8,500 cases examined.
The results call into question any genetic diagnosis of HC made since genetic testing entered the mainstream in 2003, especially among African Americans who seem to have been disproportionately affected by these mislabeled genetic markers because of inadequate population diversity when the markers were first established.
In addition, the results more broadly cast a shadow over the full spectrum of genetic tests for disease-linked variants now in routine medical practice because of the possibility that other linkage determinations derived from an inadequately-representative reference population, reported Arjun K. Manrai, PhD, and his associates (N Engl J Med. 2016 Aug 18;375[7]:655-65). The researchers call the HC experience they document a “cautionary tale of broad relevance to genetic diagnosis.”
The findings “powerfully illustrate the importance of racial and genetic diversity” when running linkage studies aimed at validating genetic markers for widespread clinical use, Isaac S. Kohane, MD, senior author of the study, said in a written statement. “Racial and ethnic inclusiveness improves the validity and accuracy” of genetic tests, said Dr. Kohane, professor of biomedical informatics and pediatrics at Harvard Medical School in Boston.
“We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” Dr. Manrai, a biomedical informatics researcher at Harvard, said in the same statement. “Much genetic assessment today relies on historical links between a disorder and variant, sometimes decades old. We believe our findings illustrate the critical need to systematically reevaluate prior assertions about genetic variants,” Dr. Manrai added in an interview.
The two researchers and their associates reexamined the link between genetic variants and HC in three genetic databases that involved a total of more than 8,500 people. One database included 4,300 white Americans and 2,203 black Americans. A second database included genetic data from 1,092 people from 14 worldwide populations, and the third had genetic data from 938 people from 51 worldwide populations.
The analysis showed that although 94 distinct genetic variants that had previously been reported as associated with HC were confirmed as linked, just 5 met the study’s definition of a “high-frequency” variant with an allele frequent of more than 1%. These five variants together accounted for 74% of the overall total of linkages seen in these 8,533 people. Further analysis classified all five of these high-frequency genetic variants as benign with no discernible link to HC.
These five high-frequency variants occurred disproportionately higher among black Americans, and the consequences of this showed up in the patient records the researchers reviewed from one large U.S. genetic testing laboratory. They examined in detail HC genetic test results during 2004-2013 from 2,912 unrelated people. The records showed seven people had been labeled as carrying either a pathogenic or “presumed pathogenic” variant when in fact they had one of the five high-frequency variants now declared benign. Five of the seven mislabeled people were of African ancestry; the other two had unknown ancestry.
The researchers called for reevaluating known variants for all genetic diseases in more diverse populations and to immediately release the results of updated linkage assessments. This has the potential to meaningfully rewrite current gospel for many genetic variants and linkages.
“Our findings point to the value of patients staying in contact with their genetic counselors and physicians, even years after genetic testing,” Dr. Manrai said. Reassessments using more diverse populations will take time, he acknowledged, but tools are available to allow clinical geneticists to update old variants and apply new ones in real time, as soon as a new assessment completes.
Dr. Manrai and Dr. Kohane had no disclosures.
On Twitter @mitchelzoler
Key clinical point: Five high-frequency genetic variants that collectively had been linked to 74% of hypertrophic cardiomyopathy cases are actually benign with no detectable pathologic linkage.
Major finding: Inaccurate linkage data mislabeled seven people as having a hypertrophic cardiomyopathy–causing genetic variant.
Data source: Three genomic sequence databases that included 8,533 people and a genetic laboratory’s records for 2,912 clients.
Disclosures: Dr. Manrai and Dr. Kohane had no disclosures.
Solid INRs on warfarin don’t predict future stability
Six months of stable international normalized ratio values [INRs] while on warfarin therapy doesn’t predict continued INR stability, according to a Research Letter to the Editor published August 9 in JAMA.
Whether or not to switch patients with atrial fibrillation from warfarin to non–vitamin K anticoagulants remains controversial. “A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non–vitamin K oral anticoagulants,” said Sean D. Pokorney, MD, of the division of cardiology, Duke University Medical Center, Durham, N.C., and his associates.
But the results of their observational study of 3,749 patients enrolled in an atrial fibrillation registry show that such stability cannot be predicted, and “challenge the notion that patients who have done well taking warfarin should maintain taking warfarin,” the investigators said (JAMA. 2016;316:661-3).
They assessed INRs over the course of 3 years of follow-up using data from patients enrolled in the registry through 176 clinics. INR stability was defined as having 80% or more of INRs in the therapeutic range (2-3). The mean patient age was 75 years, and 43% were women.
A total of 968 patients showed such INR stability throughout the first 6 months of the study. However, 36% of them went on to have at least one “well out of range” INR during the following year. Even in the subgroup of 376 patients who had 100% of their INRs within the therapeutic range during the first 6 months, 33% went on to have at least one “well out of range” INR during the following year, according to Dr. Pokorney and his associates.
No sponsor was cited for this study. Dr. Pokorney reported ties to AstraZeneca, Boston Scientific, Gilead, Janssen, and Medtronic; his associates reported ties to numerous industry sources.
Six months of stable international normalized ratio values [INRs] while on warfarin therapy doesn’t predict continued INR stability, according to a Research Letter to the Editor published August 9 in JAMA.
Whether or not to switch patients with atrial fibrillation from warfarin to non–vitamin K anticoagulants remains controversial. “A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non–vitamin K oral anticoagulants,” said Sean D. Pokorney, MD, of the division of cardiology, Duke University Medical Center, Durham, N.C., and his associates.
But the results of their observational study of 3,749 patients enrolled in an atrial fibrillation registry show that such stability cannot be predicted, and “challenge the notion that patients who have done well taking warfarin should maintain taking warfarin,” the investigators said (JAMA. 2016;316:661-3).
They assessed INRs over the course of 3 years of follow-up using data from patients enrolled in the registry through 176 clinics. INR stability was defined as having 80% or more of INRs in the therapeutic range (2-3). The mean patient age was 75 years, and 43% were women.
A total of 968 patients showed such INR stability throughout the first 6 months of the study. However, 36% of them went on to have at least one “well out of range” INR during the following year. Even in the subgroup of 376 patients who had 100% of their INRs within the therapeutic range during the first 6 months, 33% went on to have at least one “well out of range” INR during the following year, according to Dr. Pokorney and his associates.
No sponsor was cited for this study. Dr. Pokorney reported ties to AstraZeneca, Boston Scientific, Gilead, Janssen, and Medtronic; his associates reported ties to numerous industry sources.
Six months of stable international normalized ratio values [INRs] while on warfarin therapy doesn’t predict continued INR stability, according to a Research Letter to the Editor published August 9 in JAMA.
Whether or not to switch patients with atrial fibrillation from warfarin to non–vitamin K anticoagulants remains controversial. “A common belief has been that patients with stable INRs while taking warfarin would continue to be stable and derive less benefit from switching to non–vitamin K oral anticoagulants,” said Sean D. Pokorney, MD, of the division of cardiology, Duke University Medical Center, Durham, N.C., and his associates.
But the results of their observational study of 3,749 patients enrolled in an atrial fibrillation registry show that such stability cannot be predicted, and “challenge the notion that patients who have done well taking warfarin should maintain taking warfarin,” the investigators said (JAMA. 2016;316:661-3).
They assessed INRs over the course of 3 years of follow-up using data from patients enrolled in the registry through 176 clinics. INR stability was defined as having 80% or more of INRs in the therapeutic range (2-3). The mean patient age was 75 years, and 43% were women.
A total of 968 patients showed such INR stability throughout the first 6 months of the study. However, 36% of them went on to have at least one “well out of range” INR during the following year. Even in the subgroup of 376 patients who had 100% of their INRs within the therapeutic range during the first 6 months, 33% went on to have at least one “well out of range” INR during the following year, according to Dr. Pokorney and his associates.
No sponsor was cited for this study. Dr. Pokorney reported ties to AstraZeneca, Boston Scientific, Gilead, Janssen, and Medtronic; his associates reported ties to numerous industry sources.
FROM JAMA
Key clinical point: Six months of stable INRs while on warfarin doesn’t predict continued INR stability.
Major finding: Of the 968 patients who showed INR stability throughout the first 6 months of the study, 36% went on to have at least one “well out of range” INR during the following year.
Data source: An observational cohort study involving 3,749 patients with atrial fibrillation who were followed for 3 years.
Disclosures: No sponsor was cited for this study. Dr. Pokorney reported ties to AstraZeneca, Boston Scientific, Gilead, Janssen, and Medtronic; his associates reported ties to numerous industry sources.
Statement warns of drugs causing or exacerbating heart failure
Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.
This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.
Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.
NSAIDs
The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).
“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.
Metformin
Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m2. The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.
Antihypertensives, biologics, and more
Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.
The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.
Managing myriad meds
The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.
“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”
Dr. Page had no disclosures.
On Twitter @mitchelzoler
Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.
This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.
Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.
NSAIDs
The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).
“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.
Metformin
Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m2. The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.
Antihypertensives, biologics, and more
Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.
The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.
Managing myriad meds
The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.
“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”
Dr. Page had no disclosures.
On Twitter @mitchelzoler
Many commonly used prescription drugs, many OTC agents, and also several complimentary or alternative medications, can either trigger heart failure or exacerbate the disease in patients with existing heart failure according to a Scientific Statement written by a committee of the American Heart Association and released on July 11.
This first-ever authoritative U.S. overview of what is known about drugs that can affect heart failure was compiled to address an important practice issue for the large and growing number of U.S. patients with heart failure, estimated to be nearly 6 million Americans, and “provide some guidance to health care providers in how to minimize polypharmacy, improve medication safety, as well as identify the medications that could exacerbate or cause heart failure,” said Robert L. Page II, PharmD, chair of the committee and a professor of clinical pharmacy at the University of Colorado at Denver, Aurora.
Although the comprehensive statement lists 88 distinct prescription drugs or drug classes as agents that pose major or moderate threats for causing or worsening heart failure, “from the American public’s perspective, importance should be placed on educating patients regarding the impact that OTC medications can have on their heart failure,” Dr. Page said in an interview. “For example, nonsteroidal anti-inflammatory drugs like ibuprofen or naproxen can cause sodium and water retention and antagonize the effects of evidence-based heart failure pharmacotherapies. Additionally, OTC medications like pseudoephedrine, which many cough and cold products contain, can increase blood pressure and afterload,” he noted. The risks these drugs pose becomes even greater when they are taken at higher doses.
NSAIDs
The statement cites already existing guidance from the American College of Cardiology and American Heart Association that for patients with existing heart failure, use of NSAIDs should either be avoided or withdrawn when possible. The statement advises educating patients to communicate with their health care provider before taking any OTC medication or complimentary or alternative medication, avoid these agents when their efficacy and safety is uncertain, and evaluate the labels of these products for their sodium content (although the sodium content from inactive ingredients may be difficult to find in labeling).
“Currently, we teach patients to read food labels for sodium content, but we also need to educate patients on how to read OTC medication labels for both ingredients and sodium content. Many OTC antacids may have a large sodium load,” Dr. Page said. The statement includes a list of 14 prescription drugs and also highlights several OTC formulations that have an especially high sodium content.
Metformin
Among the many prescription drugs listed, one notable entry is for the oral hypoglycemic agent metformin that today is among the most widely used drugs for treating type 2 diabetes and is especially relevant for heart failure patients because, as the statement notes, 38% also have diabetes. The statement details the long history of metformin and heart failure, noting that until a decade ago, the drug had a contraindication for patients with heart failure, that metformin’s label still carries a black box warning for cautious use in heart failure patients, and that earlier in 2016, the Food and Drug Administration cautioned that metformin should not be used in patients with an estimated glomerular filtration rate of less than 30 mL/minute per 1.73 m2. The statement also endorsed a recommendation from the American Diabetes Association that metformin not be used in patients with unstable heart failure or those hospitalized for heart failure.
Antihypertensives, biologics, and more
Other notable prescription drugs listed as potentially having a major impact on causing or worsening heart failure include the antihypertensive drugs diltiazem, verapamil, and moxonidine, the tumor necrosis factor–inhibitors that are widely used to treat rheumatologic and gastroenterologic diseases, the antipsychotic clozapine, and a long list of anticancer medications, including several anthracyclines and many types of newer biologic agents.
The statement also lists several specific recommendations to health care providers for improving oversight of the drugs taken by patients with heart failure or those at risk for heart failure. These include a comprehensive medication review during each clinical encounter. The statement also suggests a “medication flow sheet” for each patient that contains the basic information regarding the regimen for each medication taken by a patient: the brand and generic name, the purpose of the medication, and its dosage. “These medication flow sheets should be used by patients as a tool to enhance safety and adherence, and they should show their flow sheets at each provider visit,” Dr. Page said.
Managing myriad meds
The statement also calls for stopping medications without a well defined indication for a patient, avoid prescribing new drugs to address side effects of other drugs, and suggests establishing a “captain” among the health care providers seen by each patient who would be particularly responsible for overseeing and keeping track of the medications the patient takes.
“Ideally, this ‘captain’ would be the patient’s primary care provider, who should be in contact with the other specialists that the patient may be seeing. However, this does not always happen,” said Dr. Page. “Therefore, I encourage each patient with heart failure to contact both their primary care provider and their health care provider who is managing their heart failure before taking or stopping any new medication including prescription, OTC, herbal, complimentary or alternative medication or supplement. Health care providers need to encourage patients to be actively engaged in their medication management.”
Dr. Page had no disclosures.
On Twitter @mitchelzoler
Insomnia in young men boosts cardiovascular and cerebrovascular risk
DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.
“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.
It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.
“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.
To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.
She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.
During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.
In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.
Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.
The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.
As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.
Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.
Dr. Petrov reported having no relevant financial conflicts.
DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.
“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.
It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.
“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.
To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.
She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.
During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.
In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.
Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.
The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.
As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.
Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.
Dr. Petrov reported having no relevant financial conflicts.
DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.
“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.
It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.
“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.
To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.
She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.
During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.
In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.
Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.
The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.
As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.
Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.
Dr. Petrov reported having no relevant financial conflicts.
AT SLEEP 2016
Key clinical point: Insomnia symptoms are associated with increased cardiovascular and cerebrovascular event rates in young to middle-aged men.
Major finding: Men aged 33-45 who reported frequent difficulty in falling asleep were at an adjusted 2.64-fold increased risk of a major cardiovascular or cerebrovascular event during subsequent follow-up.
Data source: The prospective, epidemiologic CARDIA study including 2,950 black or white subjects aged 33-45 at enrollment who were followed for a mean of 11.5 years.
Disclosures: The CARDIA study is supported by the National Institutes of Health. The presenter reported having no relevant financial conflicts.
