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Allogeneic stem cells show promise for treating nonischemic dilated cardiomyopathy
NEW ORLEANS – Allogeneic stem cells appear to be a safe treatment option for nonischemic dilated cardiomyopathy and show somewhat greater efficacy than autologous stem cells, according to the results of the randomized POSEIDON-DCM trial.
“Nonischemic dilated cardiomyopathy is an incurable condition with significant genetic and immunologic underpinnings,” noted lead investigator Joshua M. Hare, MD, director of the Interdisciplinary Stem Cell Institute and professor of medicine at the University of Miami. 
The phase I/II trial undertook a head-to-head comparison of allogeneic and autologous bone marrow–derived mesenchymal stem cells in 37 patients with nonischemic dilated cardiomyopathy.
Results presented at the American Heart Association scientific sessions and simultaneously published (J Am Coll Cardiol. 2016. doi: 10.1016/j.jacc.2016.11.009) showed that none of the patients in either group experienced a 30-day treatment-emergent serious adverse event, the trial’s primary endpoint.
The allogeneic group had a greater shift to a lesser inflammatory immune profile, and, at 12 months, a lower rate of major adverse cardiac events and more improvement in walk test distance. Additionally, half of patients in the allogeneic group no longer met the ejection fraction cutoff typically used to define dilated cardiomyopathy, compared with only about one-fifth of those in the autologous group.
“Immunomodulation may contribute to the efficacy of allogeneic human mesenchymal stem cells in nonischemic dilated cardiomyopathy, as we have shown suppression of immune activation to a greater degree with the allo versus auto cells,” Dr. Hare said.
“We argue that these data support the use of allogeneic mesenchymal stem cell therapy in future pivotal placebo-controlled clinical trials for this patient population, an important patient population with significant unmet need.”
Trial details
The patients enrolled in POSEIDON-DCM had left ventricular dysfunction due to nonischemic dilated cardiomyopathy and were randomized evenly to allogeneic or autologous stem cell therapy. Stem cells were delivered by transendocardial injection into 10 left ventricular sites using a catheter.
In the first 30 days after treatment, there were no treatment-emergent serious adverse events, defined as death, nonfatal myocardial infarction, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias. “The 30-day safety and tolerability was excellent in both groups receiving either allogeneic or autologous therapy,” Dr. Hare said.
At 12 months, the allogeneic group had lower rates than the autologous group of major adverse cardiac events (20.3% vs. 57.1%, P = .0186) and all-cause rehospitalizations (28.2% vs. 70.0%, P = .0447).
In terms of efficacy, ejection fraction at 12 months had improved by a significant 8.0 Units in the allogeneic group and a nonsignificant 5.4 Units in the autologous group (P not significant for difference between groups). Roughly half of patients in the allogeneic group had achieved an ejection fraction of greater than 40%, compared with only two patients in the autologous group. “This is meaningful because the clinical definition of dilated cardiomyopathy typically uses an ejection fraction cutoff of 40%,” he noted.
The 6-minute walk test distance increased by a significant 37.0 m for the allogeneic group and by a nonsignificant 7.3 m for the autologous group (P = .0168 for difference between groups). Scores on the Minnesota Living With Heart Failure Questionnaire fell significantly in the former group and nonsignificantly in the latter group (P not significant for difference between groups).
Patients in the allogeneic group were more likely to have an improvement from baseline in New York Heart Association class (66.7% vs. 27.3%, P = .0527).
“An issue of concern in this field has been the formation of ectopic tissue with mesenchymal stem cells, so patients received whole-body CT scanning over 12 months,” Dr. Hare reported. “There was no ectopic tissue formation or tumor formation in any patient.”
In terms of biologic endpoints, two measures of endothelial function known to be suppressed in the setting of circulatory failure – endothelial progenitor cell colony-forming units and flow-mediated vasodilation – had increased significantly at 3 months in the allogeneic group only. Tumor necrosis factor–alpha levels fell by roughly 70% with allogeneic therapy versus 50% with autologous therapy (P = .05).
Both groups had a lessening of the immunosuppression that is common in heart failure, but benefit in several markers, such as the percentage of switched memory B cells, was greater with the allogeneic therapy. Additionally, there was a trend toward greater reduction of early T-cell activation in the allogeneic group.
“Of importance in the field of allogeneic cell therapy is [whether] the allogeneic cells mount a panel-reactive antigen [PRA],” commented Dr. Hare, who disclosed that he has an ownership interest in and is a consultant or advisory board member for Vestion.
Results showed that one patient in the allogeneic group developed a high-risk PRA, compared with none in the autologous group. Another four patients in the former group developed a moderate-risk PRA, compared with one in the latter group (P less than or equal to .05).
NEW ORLEANS – Allogeneic stem cells appear to be a safe treatment option for nonischemic dilated cardiomyopathy and show somewhat greater efficacy than autologous stem cells, according to the results of the randomized POSEIDON-DCM trial.
“Nonischemic dilated cardiomyopathy is an incurable condition with significant genetic and immunologic underpinnings,” noted lead investigator Joshua M. Hare, MD, director of the Interdisciplinary Stem Cell Institute and professor of medicine at the University of Miami.
The phase I/II trial undertook a head-to-head comparison of allogeneic and autologous bone marrow–derived mesenchymal stem cells in 37 patients with nonischemic dilated cardiomyopathy.
Results presented at the American Heart Association scientific sessions and simultaneously published (J Am Coll Cardiol. 2016. doi: 10.1016/j.jacc.2016.11.009) showed that none of the patients in either group experienced a 30-day treatment-emergent serious adverse event, the trial’s primary endpoint.
The allogeneic group had a greater shift to a lesser inflammatory immune profile, and, at 12 months, a lower rate of major adverse cardiac events and more improvement in walk test distance. Additionally, half of patients in the allogeneic group no longer met the ejection fraction cutoff typically used to define dilated cardiomyopathy, compared with only about one-fifth of those in the autologous group.
“Immunomodulation may contribute to the efficacy of allogeneic human mesenchymal stem cells in nonischemic dilated cardiomyopathy, as we have shown suppression of immune activation to a greater degree with the allo versus auto cells,” Dr. Hare said.
“We argue that these data support the use of allogeneic mesenchymal stem cell therapy in future pivotal placebo-controlled clinical trials for this patient population, an important patient population with significant unmet need.”
Trial details
The patients enrolled in POSEIDON-DCM had left ventricular dysfunction due to nonischemic dilated cardiomyopathy and were randomized evenly to allogeneic or autologous stem cell therapy. Stem cells were delivered by transendocardial injection into 10 left ventricular sites using a catheter.
In the first 30 days after treatment, there were no treatment-emergent serious adverse events, defined as death, nonfatal myocardial infarction, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias. “The 30-day safety and tolerability was excellent in both groups receiving either allogeneic or autologous therapy,” Dr. Hare said.
At 12 months, the allogeneic group had lower rates than the autologous group of major adverse cardiac events (20.3% vs. 57.1%, P = .0186) and all-cause rehospitalizations (28.2% vs. 70.0%, P = .0447).
In terms of efficacy, ejection fraction at 12 months had improved by a significant 8.0 Units in the allogeneic group and a nonsignificant 5.4 Units in the autologous group (P not significant for difference between groups). Roughly half of patients in the allogeneic group had achieved an ejection fraction of greater than 40%, compared with only two patients in the autologous group. “This is meaningful because the clinical definition of dilated cardiomyopathy typically uses an ejection fraction cutoff of 40%,” he noted.
The 6-minute walk test distance increased by a significant 37.0 m for the allogeneic group and by a nonsignificant 7.3 m for the autologous group (P = .0168 for difference between groups). Scores on the Minnesota Living With Heart Failure Questionnaire fell significantly in the former group and nonsignificantly in the latter group (P not significant for difference between groups).
Patients in the allogeneic group were more likely to have an improvement from baseline in New York Heart Association class (66.7% vs. 27.3%, P = .0527).
“An issue of concern in this field has been the formation of ectopic tissue with mesenchymal stem cells, so patients received whole-body CT scanning over 12 months,” Dr. Hare reported. “There was no ectopic tissue formation or tumor formation in any patient.”
In terms of biologic endpoints, two measures of endothelial function known to be suppressed in the setting of circulatory failure – endothelial progenitor cell colony-forming units and flow-mediated vasodilation – had increased significantly at 3 months in the allogeneic group only. Tumor necrosis factor–alpha levels fell by roughly 70% with allogeneic therapy versus 50% with autologous therapy (P = .05).
Both groups had a lessening of the immunosuppression that is common in heart failure, but benefit in several markers, such as the percentage of switched memory B cells, was greater with the allogeneic therapy. Additionally, there was a trend toward greater reduction of early T-cell activation in the allogeneic group.
“Of importance in the field of allogeneic cell therapy is [whether] the allogeneic cells mount a panel-reactive antigen [PRA],” commented Dr. Hare, who disclosed that he has an ownership interest in and is a consultant or advisory board member for Vestion.
Results showed that one patient in the allogeneic group developed a high-risk PRA, compared with none in the autologous group. Another four patients in the former group developed a moderate-risk PRA, compared with one in the latter group (P less than or equal to .05).
NEW ORLEANS – Allogeneic stem cells appear to be a safe treatment option for nonischemic dilated cardiomyopathy and show somewhat greater efficacy than autologous stem cells, according to the results of the randomized POSEIDON-DCM trial.
“Nonischemic dilated cardiomyopathy is an incurable condition with significant genetic and immunologic underpinnings,” noted lead investigator Joshua M. Hare, MD, director of the Interdisciplinary Stem Cell Institute and professor of medicine at the University of Miami.
The phase I/II trial undertook a head-to-head comparison of allogeneic and autologous bone marrow–derived mesenchymal stem cells in 37 patients with nonischemic dilated cardiomyopathy.
Results presented at the American Heart Association scientific sessions and simultaneously published (J Am Coll Cardiol. 2016. doi: 10.1016/j.jacc.2016.11.009) showed that none of the patients in either group experienced a 30-day treatment-emergent serious adverse event, the trial’s primary endpoint.
The allogeneic group had a greater shift to a lesser inflammatory immune profile, and, at 12 months, a lower rate of major adverse cardiac events and more improvement in walk test distance. Additionally, half of patients in the allogeneic group no longer met the ejection fraction cutoff typically used to define dilated cardiomyopathy, compared with only about one-fifth of those in the autologous group.
“Immunomodulation may contribute to the efficacy of allogeneic human mesenchymal stem cells in nonischemic dilated cardiomyopathy, as we have shown suppression of immune activation to a greater degree with the allo versus auto cells,” Dr. Hare said.
“We argue that these data support the use of allogeneic mesenchymal stem cell therapy in future pivotal placebo-controlled clinical trials for this patient population, an important patient population with significant unmet need.”
Trial details
The patients enrolled in POSEIDON-DCM had left ventricular dysfunction due to nonischemic dilated cardiomyopathy and were randomized evenly to allogeneic or autologous stem cell therapy. Stem cells were delivered by transendocardial injection into 10 left ventricular sites using a catheter.
In the first 30 days after treatment, there were no treatment-emergent serious adverse events, defined as death, nonfatal myocardial infarction, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias. “The 30-day safety and tolerability was excellent in both groups receiving either allogeneic or autologous therapy,” Dr. Hare said.
At 12 months, the allogeneic group had lower rates than the autologous group of major adverse cardiac events (20.3% vs. 57.1%, P = .0186) and all-cause rehospitalizations (28.2% vs. 70.0%, P = .0447).
In terms of efficacy, ejection fraction at 12 months had improved by a significant 8.0 Units in the allogeneic group and a nonsignificant 5.4 Units in the autologous group (P not significant for difference between groups). Roughly half of patients in the allogeneic group had achieved an ejection fraction of greater than 40%, compared with only two patients in the autologous group. “This is meaningful because the clinical definition of dilated cardiomyopathy typically uses an ejection fraction cutoff of 40%,” he noted.
The 6-minute walk test distance increased by a significant 37.0 m for the allogeneic group and by a nonsignificant 7.3 m for the autologous group (P = .0168 for difference between groups). Scores on the Minnesota Living With Heart Failure Questionnaire fell significantly in the former group and nonsignificantly in the latter group (P not significant for difference between groups).
Patients in the allogeneic group were more likely to have an improvement from baseline in New York Heart Association class (66.7% vs. 27.3%, P = .0527).
“An issue of concern in this field has been the formation of ectopic tissue with mesenchymal stem cells, so patients received whole-body CT scanning over 12 months,” Dr. Hare reported. “There was no ectopic tissue formation or tumor formation in any patient.”
In terms of biologic endpoints, two measures of endothelial function known to be suppressed in the setting of circulatory failure – endothelial progenitor cell colony-forming units and flow-mediated vasodilation – had increased significantly at 3 months in the allogeneic group only. Tumor necrosis factor–alpha levels fell by roughly 70% with allogeneic therapy versus 50% with autologous therapy (P = .05).
Both groups had a lessening of the immunosuppression that is common in heart failure, but benefit in several markers, such as the percentage of switched memory B cells, was greater with the allogeneic therapy. Additionally, there was a trend toward greater reduction of early T-cell activation in the allogeneic group.
“Of importance in the field of allogeneic cell therapy is [whether] the allogeneic cells mount a panel-reactive antigen [PRA],” commented Dr. Hare, who disclosed that he has an ownership interest in and is a consultant or advisory board member for Vestion.
Results showed that one patient in the allogeneic group developed a high-risk PRA, compared with none in the autologous group. Another four patients in the former group developed a moderate-risk PRA, compared with one in the latter group (P less than or equal to .05).
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: At 12 months, the allogeneic group had lower rates than the autologous group of major adverse cardiac events (20.3% vs. 57.1%, P = .0186) and all-cause rehospitalizations (28.2% vs. 70.0%, P = .0447).
Data source: A randomized phase I/II trial among 37 patients with nonischemic dilated cardiomyopathy (POSEIDON-DCM trial).
Disclosures: Dr. Hare disclosed that he has an ownership interest in and is a consultant or advisory board member for Vestion.
TRUE-AHF: Urgent vasodilator therapy in acute HF provides no long-term benefit
NEW ORLEANS – An investigational synthetic natriuretic peptide given early during hospitalization for acute decompensated heart failure didn’t produce any of the hoped-for intermediate- or long-term clinical benefits in the phase III TRUE-AHF study, Milton Packer, MD, reported at the American Heart Association scientific sessions.
The failure of this investigational vasodilator, ularitide, to influence downstream cardiovascular mortality or early readmission for heart failure closes the door on the once-promising hypothesis that myocardial microinjury occurring during ADHF is due to ventricular distension, observed Dr. Packer, the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, Dallas. “Ularitide did exactly what we expected it to do while we were giving it: we caused intravascular decompression, we reduced cardiac wall stress, but we did not affect cardiac microinjury, and we didn’t change long-term cardiovascular mortality or any of our secondary endpoints, including and in particular the 30-day risk of rehospitalization for heart failure,” he said.
During a median follow-up of 15 months there were 236 cardiovascular deaths in the ularitide group and 225 in the control group, a nonsignificant difference. Nor were there any differences between the two groups in secondary endpoints including length of stay in the ICU during the index hospitalization, rehospitalization for ADHF within 30 days of discharge, or the composite of all-cause mortality or cardiovascular hospitalization within 6 months, which occurred in 40.7% of the ularitide group and 37.2% of controls.
The explanation for this lack of long-term benefit lies in the finding that myocardial microinjury wasn’t prevented by the rapid reduction of cardiac distension produced by ularitide. This was evident in the therapy’s inability to dampen the rise in high-sensitivity cardiac troponin T which occurred in the initial 48 hours of the study.
“The trial demonstrated the effects and safety of ularitide. However, to gain long-term benefits on hospitalizations and death in patients following a hospital admission for heart failure, physicians must focus on the drugs that patients take as an outpatient rather than the drugs they receive as an inpatient,” Dr. Packer concluded.
“Readmission rates remain stubbornly at 20% within 30 days and near 50% at 6 months. Acute decompensation is an inflection point in the natural history of heart failure with subsequent 1-year mortality rates consistently approximating 25%. Clearly there is something about the hospitalization that is a herald event which speaks to much worse outcomes, compared with chronic ambulatory heart failure,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University in Chicago.
He agreed with Dr. Packer that in light of the TRUE-AHF results, what Dr. Yancy termed “the early injury hypothesis” isn’t worth further pursuit.
Ularitide thus joins a long list of failed therapies for ADHF. Treatments that have convincingly been shown to have no significant impact on mortality and at best only modest impact on morbidity include continuous IV infusion of loop diuretics in the DOSE trial; the arginine vasopressin antagonists, which failed to impress in EVEREST, SECRET, and TACTICS; nesiritide (Natrecor) in the ASCEND-HF trial; and levosimendan (Simdax), which proved disappointing in the SURVIVE and REVIVE II studies, according to Dr. Yancy.
The jury is still out on serelaxin, he added. The drug showed a favorable signal in the RELAX-AHF trial. The results of RELAX II are awaited with interest.
“Today we still don’t have an effective single intervention for acute decompensated heart failure other than process-of-care improvement,” the cardiologist noted.
What holds promise for improved long-term outcomes in ADHF at this point? Dr. Yancy said sacubitril/valsartan (Entresto) is intriguing based upon the results of the PARADIGM-HF trial (N Engl J Med. 2014;371:993-1004). But the drug needs to be studied prospectively in patients in the throes of ADHF before it can appropriately be recommended for the purpose of changing the natural history of this disorder, Dr. Yancy stressed.
Devices such as the implantable pulmonary catheter are under study as a promising means of altering the natural history of ADHF by identifying actionable signals of impending decompensation weeks beforehand, he added.
The TRUE-AHF trial was sponsored by Cardiorentis. Dr. Packer reported serving as a consultant to that company and more than a dozen other pharmaceutical and medical device companies.
[email protected]
NEW ORLEANS – An investigational synthetic natriuretic peptide given early during hospitalization for acute decompensated heart failure didn’t produce any of the hoped-for intermediate- or long-term clinical benefits in the phase III TRUE-AHF study, Milton Packer, MD, reported at the American Heart Association scientific sessions.
The failure of this investigational vasodilator, ularitide, to influence downstream cardiovascular mortality or early readmission for heart failure closes the door on the once-promising hypothesis that myocardial microinjury occurring during ADHF is due to ventricular distension, observed Dr. Packer, the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, Dallas. “Ularitide did exactly what we expected it to do while we were giving it: we caused intravascular decompression, we reduced cardiac wall stress, but we did not affect cardiac microinjury, and we didn’t change long-term cardiovascular mortality or any of our secondary endpoints, including and in particular the 30-day risk of rehospitalization for heart failure,” he said.
During a median follow-up of 15 months there were 236 cardiovascular deaths in the ularitide group and 225 in the control group, a nonsignificant difference. Nor were there any differences between the two groups in secondary endpoints including length of stay in the ICU during the index hospitalization, rehospitalization for ADHF within 30 days of discharge, or the composite of all-cause mortality or cardiovascular hospitalization within 6 months, which occurred in 40.7% of the ularitide group and 37.2% of controls.
The explanation for this lack of long-term benefit lies in the finding that myocardial microinjury wasn’t prevented by the rapid reduction of cardiac distension produced by ularitide. This was evident in the therapy’s inability to dampen the rise in high-sensitivity cardiac troponin T which occurred in the initial 48 hours of the study.
“The trial demonstrated the effects and safety of ularitide. However, to gain long-term benefits on hospitalizations and death in patients following a hospital admission for heart failure, physicians must focus on the drugs that patients take as an outpatient rather than the drugs they receive as an inpatient,” Dr. Packer concluded.
“Readmission rates remain stubbornly at 20% within 30 days and near 50% at 6 months. Acute decompensation is an inflection point in the natural history of heart failure with subsequent 1-year mortality rates consistently approximating 25%. Clearly there is something about the hospitalization that is a herald event which speaks to much worse outcomes, compared with chronic ambulatory heart failure,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University in Chicago.
He agreed with Dr. Packer that in light of the TRUE-AHF results, what Dr. Yancy termed “the early injury hypothesis” isn’t worth further pursuit.
Ularitide thus joins a long list of failed therapies for ADHF. Treatments that have convincingly been shown to have no significant impact on mortality and at best only modest impact on morbidity include continuous IV infusion of loop diuretics in the DOSE trial; the arginine vasopressin antagonists, which failed to impress in EVEREST, SECRET, and TACTICS; nesiritide (Natrecor) in the ASCEND-HF trial; and levosimendan (Simdax), which proved disappointing in the SURVIVE and REVIVE II studies, according to Dr. Yancy.
The jury is still out on serelaxin, he added. The drug showed a favorable signal in the RELAX-AHF trial. The results of RELAX II are awaited with interest.
“Today we still don’t have an effective single intervention for acute decompensated heart failure other than process-of-care improvement,” the cardiologist noted.
What holds promise for improved long-term outcomes in ADHF at this point? Dr. Yancy said sacubitril/valsartan (Entresto) is intriguing based upon the results of the PARADIGM-HF trial (N Engl J Med. 2014;371:993-1004). But the drug needs to be studied prospectively in patients in the throes of ADHF before it can appropriately be recommended for the purpose of changing the natural history of this disorder, Dr. Yancy stressed.
Devices such as the implantable pulmonary catheter are under study as a promising means of altering the natural history of ADHF by identifying actionable signals of impending decompensation weeks beforehand, he added.
The TRUE-AHF trial was sponsored by Cardiorentis. Dr. Packer reported serving as a consultant to that company and more than a dozen other pharmaceutical and medical device companies.
[email protected]
NEW ORLEANS – An investigational synthetic natriuretic peptide given early during hospitalization for acute decompensated heart failure didn’t produce any of the hoped-for intermediate- or long-term clinical benefits in the phase III TRUE-AHF study, Milton Packer, MD, reported at the American Heart Association scientific sessions.
The failure of this investigational vasodilator, ularitide, to influence downstream cardiovascular mortality or early readmission for heart failure closes the door on the once-promising hypothesis that myocardial microinjury occurring during ADHF is due to ventricular distension, observed Dr. Packer, the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, Dallas. “Ularitide did exactly what we expected it to do while we were giving it: we caused intravascular decompression, we reduced cardiac wall stress, but we did not affect cardiac microinjury, and we didn’t change long-term cardiovascular mortality or any of our secondary endpoints, including and in particular the 30-day risk of rehospitalization for heart failure,” he said.
During a median follow-up of 15 months there were 236 cardiovascular deaths in the ularitide group and 225 in the control group, a nonsignificant difference. Nor were there any differences between the two groups in secondary endpoints including length of stay in the ICU during the index hospitalization, rehospitalization for ADHF within 30 days of discharge, or the composite of all-cause mortality or cardiovascular hospitalization within 6 months, which occurred in 40.7% of the ularitide group and 37.2% of controls.
The explanation for this lack of long-term benefit lies in the finding that myocardial microinjury wasn’t prevented by the rapid reduction of cardiac distension produced by ularitide. This was evident in the therapy’s inability to dampen the rise in high-sensitivity cardiac troponin T which occurred in the initial 48 hours of the study.
“The trial demonstrated the effects and safety of ularitide. However, to gain long-term benefits on hospitalizations and death in patients following a hospital admission for heart failure, physicians must focus on the drugs that patients take as an outpatient rather than the drugs they receive as an inpatient,” Dr. Packer concluded.
“Readmission rates remain stubbornly at 20% within 30 days and near 50% at 6 months. Acute decompensation is an inflection point in the natural history of heart failure with subsequent 1-year mortality rates consistently approximating 25%. Clearly there is something about the hospitalization that is a herald event which speaks to much worse outcomes, compared with chronic ambulatory heart failure,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University in Chicago.
He agreed with Dr. Packer that in light of the TRUE-AHF results, what Dr. Yancy termed “the early injury hypothesis” isn’t worth further pursuit.
Ularitide thus joins a long list of failed therapies for ADHF. Treatments that have convincingly been shown to have no significant impact on mortality and at best only modest impact on morbidity include continuous IV infusion of loop diuretics in the DOSE trial; the arginine vasopressin antagonists, which failed to impress in EVEREST, SECRET, and TACTICS; nesiritide (Natrecor) in the ASCEND-HF trial; and levosimendan (Simdax), which proved disappointing in the SURVIVE and REVIVE II studies, according to Dr. Yancy.
The jury is still out on serelaxin, he added. The drug showed a favorable signal in the RELAX-AHF trial. The results of RELAX II are awaited with interest.
“Today we still don’t have an effective single intervention for acute decompensated heart failure other than process-of-care improvement,” the cardiologist noted.
What holds promise for improved long-term outcomes in ADHF at this point? Dr. Yancy said sacubitril/valsartan (Entresto) is intriguing based upon the results of the PARADIGM-HF trial (N Engl J Med. 2014;371:993-1004). But the drug needs to be studied prospectively in patients in the throes of ADHF before it can appropriately be recommended for the purpose of changing the natural history of this disorder, Dr. Yancy stressed.
Devices such as the implantable pulmonary catheter are under study as a promising means of altering the natural history of ADHF by identifying actionable signals of impending decompensation weeks beforehand, he added.
The TRUE-AHF trial was sponsored by Cardiorentis. Dr. Packer reported serving as a consultant to that company and more than a dozen other pharmaceutical and medical device companies.
[email protected]
Key clinical point:
Major finding: Early administration of ularitide during hospitalization for acute decompensated heart failure failed to achieve any long-term clinical benefits.
Data source: The TRUE-AHF trial was a double-blind, placebo-controlled, randomized trial including 2,157 patients hospitalized for acute decompensated heart failure at 156 centers in 23 countries.
Disclosures: The study was sponsored by Cardiorentis. The presenter reported serving as a consultant to that company and more than a dozen other pharmaceutical and medical device companies.
Cardiac rehab also slashes stroke risk
ROME – Cardiac rehabilitation programs have a previously unappreciated benefit: participants enjoy a 60% reduction in the risk of stroke, Gijs van Halewijn, MD, reported at the annual congress of the European Society of Cardiology.
“I think cardiologists are really focused on cardiovascular deaths, especially from MI. But we’ve shown that cardiac rehabilitation also has an effect on cerebrovascular events,” said Dr. van Halewijn of Erasmus University in Rotterdam (the Netherlands).
He presented a meta-analysis of randomized controlled trials of cardiac rehab conducted during 2010-2015. The purpose was to assess the value provided by cardiac rehab in the contemporary era of acute coronary syndrome management featuring primary percutaneous coronary intervention, drug-eluting stents, and potent medications for secondary cardiovascular prevention. That hadn’t previously been looked at systematically.
“The standard meta-analyses cited in the field include randomized trials from as far back as just after World War II,” Dr. van Halewijn noted in an interview.
He employed the same search and analytic methods utilized by the Cochrane Collaboration in evaluating 18 randomized controlled trials of lifestyle- or exercise-based cardiac rehab, compared with usual care, in a total of 7,691 participants.
The results of the meta-analysis indicate cardiac rehab provides powerful secondary prevention benefits above and beyond those obtained through contemporary interventional procedures and preventive medications.
Cardiovascular mortality was reduced by 58% in cardiac rehab participants compared with usual care controls. The risk of acute MI was decreased by 30%. And in a new observation, cerebrovascular events were reduced by 60% in the four randomized trials in which that was an endpoint. All of these differences were highly statistically significant.
“Interestingly, the number needed to treat was 45 for MI, so if you have 45 patients included in your cardiac rehabilitation program, you can prevent one MI. And you can prevent one cerebrovascular event with 82 participants,” according to Dr. van Halewijn.
Cardiac rehab had no effect on all-cause mortality in the overall meta-analysis. However, in the trials involving comprehensive cardiac rehab programs targeting six or more of the components of secondary cardiovascular prevention described by the British Association for Cardiac Prevention and Rehabilitation (Heart. 2013 Aug;99[15]:1069-71), participation was associated with a 37% reduction in the risk of all-cause mortality, compared with usual care.
Those components are smoking, blood pressure, cholesterol, HbA1c, exercise training, counseling about the importance of exercise, stress management, and checking medications.
In addition, Dr. van Halewijn continued, cardiac rehab programs in which a physician or nurse made sure participants were on guideline-directed cardiovascular medications had a 65% reduction in all-cause mortality, compared with usual care.
“Cardiac rehabilitation’s opportunity is to evolve into comprehensive programs addressing all aspects of lifestyle, risk factor management, and prescription of medications to reduce death and nonfatal events,” the physician concluded.
This study was supported by Erasmus University Medical Center, Imperial College London, and the Dutch Heart Foundation. Dr. van Halewijn reported having no financial conflicts of interest.
[email protected]
ROME – Cardiac rehabilitation programs have a previously unappreciated benefit: participants enjoy a 60% reduction in the risk of stroke, Gijs van Halewijn, MD, reported at the annual congress of the European Society of Cardiology.
“I think cardiologists are really focused on cardiovascular deaths, especially from MI. But we’ve shown that cardiac rehabilitation also has an effect on cerebrovascular events,” said Dr. van Halewijn of Erasmus University in Rotterdam (the Netherlands).
He presented a meta-analysis of randomized controlled trials of cardiac rehab conducted during 2010-2015. The purpose was to assess the value provided by cardiac rehab in the contemporary era of acute coronary syndrome management featuring primary percutaneous coronary intervention, drug-eluting stents, and potent medications for secondary cardiovascular prevention. That hadn’t previously been looked at systematically.
“The standard meta-analyses cited in the field include randomized trials from as far back as just after World War II,” Dr. van Halewijn noted in an interview.
He employed the same search and analytic methods utilized by the Cochrane Collaboration in evaluating 18 randomized controlled trials of lifestyle- or exercise-based cardiac rehab, compared with usual care, in a total of 7,691 participants.
The results of the meta-analysis indicate cardiac rehab provides powerful secondary prevention benefits above and beyond those obtained through contemporary interventional procedures and preventive medications.
Cardiovascular mortality was reduced by 58% in cardiac rehab participants compared with usual care controls. The risk of acute MI was decreased by 30%. And in a new observation, cerebrovascular events were reduced by 60% in the four randomized trials in which that was an endpoint. All of these differences were highly statistically significant.
“Interestingly, the number needed to treat was 45 for MI, so if you have 45 patients included in your cardiac rehabilitation program, you can prevent one MI. And you can prevent one cerebrovascular event with 82 participants,” according to Dr. van Halewijn.
Cardiac rehab had no effect on all-cause mortality in the overall meta-analysis. However, in the trials involving comprehensive cardiac rehab programs targeting six or more of the components of secondary cardiovascular prevention described by the British Association for Cardiac Prevention and Rehabilitation (Heart. 2013 Aug;99[15]:1069-71), participation was associated with a 37% reduction in the risk of all-cause mortality, compared with usual care.
Those components are smoking, blood pressure, cholesterol, HbA1c, exercise training, counseling about the importance of exercise, stress management, and checking medications.
In addition, Dr. van Halewijn continued, cardiac rehab programs in which a physician or nurse made sure participants were on guideline-directed cardiovascular medications had a 65% reduction in all-cause mortality, compared with usual care.
“Cardiac rehabilitation’s opportunity is to evolve into comprehensive programs addressing all aspects of lifestyle, risk factor management, and prescription of medications to reduce death and nonfatal events,” the physician concluded.
This study was supported by Erasmus University Medical Center, Imperial College London, and the Dutch Heart Foundation. Dr. van Halewijn reported having no financial conflicts of interest.
[email protected]
ROME – Cardiac rehabilitation programs have a previously unappreciated benefit: participants enjoy a 60% reduction in the risk of stroke, Gijs van Halewijn, MD, reported at the annual congress of the European Society of Cardiology.
“I think cardiologists are really focused on cardiovascular deaths, especially from MI. But we’ve shown that cardiac rehabilitation also has an effect on cerebrovascular events,” said Dr. van Halewijn of Erasmus University in Rotterdam (the Netherlands).
He presented a meta-analysis of randomized controlled trials of cardiac rehab conducted during 2010-2015. The purpose was to assess the value provided by cardiac rehab in the contemporary era of acute coronary syndrome management featuring primary percutaneous coronary intervention, drug-eluting stents, and potent medications for secondary cardiovascular prevention. That hadn’t previously been looked at systematically.
“The standard meta-analyses cited in the field include randomized trials from as far back as just after World War II,” Dr. van Halewijn noted in an interview.
He employed the same search and analytic methods utilized by the Cochrane Collaboration in evaluating 18 randomized controlled trials of lifestyle- or exercise-based cardiac rehab, compared with usual care, in a total of 7,691 participants.
The results of the meta-analysis indicate cardiac rehab provides powerful secondary prevention benefits above and beyond those obtained through contemporary interventional procedures and preventive medications.
Cardiovascular mortality was reduced by 58% in cardiac rehab participants compared with usual care controls. The risk of acute MI was decreased by 30%. And in a new observation, cerebrovascular events were reduced by 60% in the four randomized trials in which that was an endpoint. All of these differences were highly statistically significant.
“Interestingly, the number needed to treat was 45 for MI, so if you have 45 patients included in your cardiac rehabilitation program, you can prevent one MI. And you can prevent one cerebrovascular event with 82 participants,” according to Dr. van Halewijn.
Cardiac rehab had no effect on all-cause mortality in the overall meta-analysis. However, in the trials involving comprehensive cardiac rehab programs targeting six or more of the components of secondary cardiovascular prevention described by the British Association for Cardiac Prevention and Rehabilitation (Heart. 2013 Aug;99[15]:1069-71), participation was associated with a 37% reduction in the risk of all-cause mortality, compared with usual care.
Those components are smoking, blood pressure, cholesterol, HbA1c, exercise training, counseling about the importance of exercise, stress management, and checking medications.
In addition, Dr. van Halewijn continued, cardiac rehab programs in which a physician or nurse made sure participants were on guideline-directed cardiovascular medications had a 65% reduction in all-cause mortality, compared with usual care.
“Cardiac rehabilitation’s opportunity is to evolve into comprehensive programs addressing all aspects of lifestyle, risk factor management, and prescription of medications to reduce death and nonfatal events,” the physician concluded.
This study was supported by Erasmus University Medical Center, Imperial College London, and the Dutch Heart Foundation. Dr. van Halewijn reported having no financial conflicts of interest.
[email protected]
AT THE ESC CONGRESS 2016
Key clinical point:
Major finding: The number of patients who need to participate in a cardiac rehabilitation program following an ACS in order to prevent one cerebrovascular event is 85.
Data source: This was a meta-analysis of 18 randomized trials carried out in 2010-2015 comparing contemporary cardiac rehabilitation to usual care in 7,691 patients.
Disclosures: This study was supported by Erasmus University (Rotterdam, the Netherlands) Medical Center, Imperial College London, and the Dutch Heart Foundation. The presenter reported having no financial conflicts of interest.
Risk stratification important for aortic valve disease in pregnancy
CHICAGO – Pregnancy-associated hemodynamic and physiologic changes can challenge hearts with diseased aortic valves. Understanding pregnancy’s toll on the body can help physicians take better care of pregnant women with aortic stenosis or aortic regurgitation, said Patrick T. O’Gara, MD. “This is a relatively infrequent condition, and it causes all of us a great deal of apprehension,” he said.
Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital, Boston, walked attendees through current recommendations for caring for pregnant women with aortic valve disease in a presentation at the annual Heart Valve Summit.
When talking to women with aortic valve disease, it’s important to let them know that a pregnancy during which they experience an adverse maternal cardiac event appears to increase their risk for later events as well, said Dr. O’Gara. One study of pregnancy in women with aortic valve disease, said Dr. O’Gara, found that the risk of later events for women who had had a cardiac event in pregnancy was 27% plus or minus 9 percentage points in the 5 years following pregnancy, while the risk was just 15% plus or minus 3 percentage points for women whose pregnancies were not complicated by cardiac adverse events (P = .02) (Heart. 2010 Oct;96(20):1656-61).
The World Health Organization classification of pregnancy risk, said Dr. O’Gara, provides some guidance. Patients who are WHO class III are considered to be high risk; pregnancy in these individuals calls for counseling and a multidisciplinary care team. Patients who fall into this class are those with mechanical heart valves, those with Marfan syndrome and aortic involvement with a valve diameter of 40-45 mm, and those with bicuspid aortic valve disease with a valve diameter of 45-50 mm.
WHO class IV patients, according to the guidelines, are at prohibitive risk. These patients should consider terminating a pregnancy if one occurs. Conditions that place women into WHO class IV include symptomatic severe aortic stenosis (AS), severe left ventricular dysfunction with an ejection fraction less than 40%, and severe coarctation of the aorta. Women with Marfan syndrome with aortic valve diameters greater than 45 mm and women with bicuspid aortic valves and a diameter over 50 mm also fall into this category of prohibitive risk.
If a physician is lucky enough to have a pre-conception relationship with a patient, then a host of considerations can come into play. In addition to cardiac risk stratification, obstetric and intrapartum risk to the mother as well as neonatal risk should be considered. Some factors to take into account are maternal life expectancy and potential long-term complications to the mother from pregnancy and childbirth.
Plasma volume increases rapidly through the first trimester, plateauing about halfway through pregnancy. With this normal dilutional anemia, “Most normal pregnancies are accompanied by a grade II systolic murmur, best heard at the upper left sternal border,” said Dr. O’Gara. Since stroke volume and heart rate both also increase through pregnancy, cardiac output goes up as well.
“Importantly, systemic vascular resistance is reduced throughout pregnancy,” said Dr. O’Gara. Consequently, “regurgitant heart valve problems are generally much better tolerated than stenotic lesions in pregnancy. That’s physiologic principle number one.”
In labor, abrupt hemodynamic changes include increases in cardiac output, heart rate, blood pressure, and venous return. “Labor and delivery are very stressful hemodynamic times for women,” said Dr. O’Gara.
In the immediate postpartum period, uterine contraction results in a return of a significant amount of blood to the maternal circulation. This effectively creates an autotransfusion, with resulting increased preload and cardiac output. The inferior vena cava is also freed from the pressure of a gravid uterus, increasing venous return further. Finally, there’s also a marked increase in systemic vascular resistance.
Aside from the risk of adverse cardiac events, other adverse outcomes for women can include an increased risk of premature rupture of membranes and postpartum hemorrhage. For the neonate, preterm birth and respiratory distress are more likely. Newborns are more likely to be small for gestational age, to suffer intraventricular hemorrhage, and to die. Depending on the parental genetic status, the infant may be at risk of congenital heart disease as well.
Neonatal risk may also be increased, said Dr. O’Gara. Some maternal conditions that can increase risk for the infant include a baseline New York Heart Association (NYHA) class of greater than II or having cyanosis; having a left heart obstruction; being a smoker; having a multiple gestation; having a mechanical heart valve; and taking an oral anticoagulant.
Ideally, a full discussion would include a genetic referral if indicated, as well as coordination with a gynecologist or primary care provider to provide contraception and to assist with planning for and optimizing outcomes of a pregnancy.
The American College of Cardiology and the American Heart Association have issued guidelines that include a class I recommendation regarding valve intervention before pregnancy for symptomatic patients with severe AS (those with aortic velocity of at least 4.0 m/sec, or mean pressure gradient greater than 41 mm Hg; stage D). For patients who meet the same hemodynamic criteria for severe AS but who are asymptomatic (stage C), the guidelines have a class IIa recommendation that pre-pregnancy valve intervention is “reasonable.” These recommendations have level C evidence supporting them.
However, another class IIa recommendation for patients with severe AS who are already pregnant advises valve intervention only in the case of hemodynamic deterioration, or the development of NYHA class III to IV heart failure symptoms. This is backed by grade B evidence, according to the associations.
For aortic regurgitation (AR), a level I recommendation advises valve repair or replacement before pregnancy if patients are symptomatic and have severe (stage D) regurgitation. Pregnant patients with severe regurgitation should only be considered for a valve operation if they have refractory NYHA class IV heart failure symptoms. These recommendations have level C evidence supporting them.
Since AR is better tolerated in pregnancy than AS, the nature of the valve disease is one of many factors to consider when deciding whether to perform intervention before the patient becomes pregnant. Plans for future pregnancy may also affect the choice of prosthesis, as anticoagulation management during pregnancy can be extremely tricky.
The recommendations overall make clear that, based on available evidence, “there should be a high threshold for intervention during pregnancy,” said Dr. O’Gara. And no one should go it alone when taking care of these complicated patients. “Care of pregnant women with heart disease requires coordination with a multidisciplinary team,” he said.
Dr. O’Gara reported no relevant disclosures.
[email protected]
On Twitter @karioakes
CHICAGO – Pregnancy-associated hemodynamic and physiologic changes can challenge hearts with diseased aortic valves. Understanding pregnancy’s toll on the body can help physicians take better care of pregnant women with aortic stenosis or aortic regurgitation, said Patrick T. O’Gara, MD. “This is a relatively infrequent condition, and it causes all of us a great deal of apprehension,” he said.
Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital, Boston, walked attendees through current recommendations for caring for pregnant women with aortic valve disease in a presentation at the annual Heart Valve Summit.
When talking to women with aortic valve disease, it’s important to let them know that a pregnancy during which they experience an adverse maternal cardiac event appears to increase their risk for later events as well, said Dr. O’Gara. One study of pregnancy in women with aortic valve disease, said Dr. O’Gara, found that the risk of later events for women who had had a cardiac event in pregnancy was 27% plus or minus 9 percentage points in the 5 years following pregnancy, while the risk was just 15% plus or minus 3 percentage points for women whose pregnancies were not complicated by cardiac adverse events (P = .02) (Heart. 2010 Oct;96(20):1656-61).
The World Health Organization classification of pregnancy risk, said Dr. O’Gara, provides some guidance. Patients who are WHO class III are considered to be high risk; pregnancy in these individuals calls for counseling and a multidisciplinary care team. Patients who fall into this class are those with mechanical heart valves, those with Marfan syndrome and aortic involvement with a valve diameter of 40-45 mm, and those with bicuspid aortic valve disease with a valve diameter of 45-50 mm.
WHO class IV patients, according to the guidelines, are at prohibitive risk. These patients should consider terminating a pregnancy if one occurs. Conditions that place women into WHO class IV include symptomatic severe aortic stenosis (AS), severe left ventricular dysfunction with an ejection fraction less than 40%, and severe coarctation of the aorta. Women with Marfan syndrome with aortic valve diameters greater than 45 mm and women with bicuspid aortic valves and a diameter over 50 mm also fall into this category of prohibitive risk.
If a physician is lucky enough to have a pre-conception relationship with a patient, then a host of considerations can come into play. In addition to cardiac risk stratification, obstetric and intrapartum risk to the mother as well as neonatal risk should be considered. Some factors to take into account are maternal life expectancy and potential long-term complications to the mother from pregnancy and childbirth.
Plasma volume increases rapidly through the first trimester, plateauing about halfway through pregnancy. With this normal dilutional anemia, “Most normal pregnancies are accompanied by a grade II systolic murmur, best heard at the upper left sternal border,” said Dr. O’Gara. Since stroke volume and heart rate both also increase through pregnancy, cardiac output goes up as well.
“Importantly, systemic vascular resistance is reduced throughout pregnancy,” said Dr. O’Gara. Consequently, “regurgitant heart valve problems are generally much better tolerated than stenotic lesions in pregnancy. That’s physiologic principle number one.”
In labor, abrupt hemodynamic changes include increases in cardiac output, heart rate, blood pressure, and venous return. “Labor and delivery are very stressful hemodynamic times for women,” said Dr. O’Gara.
In the immediate postpartum period, uterine contraction results in a return of a significant amount of blood to the maternal circulation. This effectively creates an autotransfusion, with resulting increased preload and cardiac output. The inferior vena cava is also freed from the pressure of a gravid uterus, increasing venous return further. Finally, there’s also a marked increase in systemic vascular resistance.
Aside from the risk of adverse cardiac events, other adverse outcomes for women can include an increased risk of premature rupture of membranes and postpartum hemorrhage. For the neonate, preterm birth and respiratory distress are more likely. Newborns are more likely to be small for gestational age, to suffer intraventricular hemorrhage, and to die. Depending on the parental genetic status, the infant may be at risk of congenital heart disease as well.
Neonatal risk may also be increased, said Dr. O’Gara. Some maternal conditions that can increase risk for the infant include a baseline New York Heart Association (NYHA) class of greater than II or having cyanosis; having a left heart obstruction; being a smoker; having a multiple gestation; having a mechanical heart valve; and taking an oral anticoagulant.
Ideally, a full discussion would include a genetic referral if indicated, as well as coordination with a gynecologist or primary care provider to provide contraception and to assist with planning for and optimizing outcomes of a pregnancy.
The American College of Cardiology and the American Heart Association have issued guidelines that include a class I recommendation regarding valve intervention before pregnancy for symptomatic patients with severe AS (those with aortic velocity of at least 4.0 m/sec, or mean pressure gradient greater than 41 mm Hg; stage D). For patients who meet the same hemodynamic criteria for severe AS but who are asymptomatic (stage C), the guidelines have a class IIa recommendation that pre-pregnancy valve intervention is “reasonable.” These recommendations have level C evidence supporting them.
However, another class IIa recommendation for patients with severe AS who are already pregnant advises valve intervention only in the case of hemodynamic deterioration, or the development of NYHA class III to IV heart failure symptoms. This is backed by grade B evidence, according to the associations.
For aortic regurgitation (AR), a level I recommendation advises valve repair or replacement before pregnancy if patients are symptomatic and have severe (stage D) regurgitation. Pregnant patients with severe regurgitation should only be considered for a valve operation if they have refractory NYHA class IV heart failure symptoms. These recommendations have level C evidence supporting them.
Since AR is better tolerated in pregnancy than AS, the nature of the valve disease is one of many factors to consider when deciding whether to perform intervention before the patient becomes pregnant. Plans for future pregnancy may also affect the choice of prosthesis, as anticoagulation management during pregnancy can be extremely tricky.
The recommendations overall make clear that, based on available evidence, “there should be a high threshold for intervention during pregnancy,” said Dr. O’Gara. And no one should go it alone when taking care of these complicated patients. “Care of pregnant women with heart disease requires coordination with a multidisciplinary team,” he said.
Dr. O’Gara reported no relevant disclosures.
[email protected]
On Twitter @karioakes
CHICAGO – Pregnancy-associated hemodynamic and physiologic changes can challenge hearts with diseased aortic valves. Understanding pregnancy’s toll on the body can help physicians take better care of pregnant women with aortic stenosis or aortic regurgitation, said Patrick T. O’Gara, MD. “This is a relatively infrequent condition, and it causes all of us a great deal of apprehension,” he said.
Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital, Boston, walked attendees through current recommendations for caring for pregnant women with aortic valve disease in a presentation at the annual Heart Valve Summit.
When talking to women with aortic valve disease, it’s important to let them know that a pregnancy during which they experience an adverse maternal cardiac event appears to increase their risk for later events as well, said Dr. O’Gara. One study of pregnancy in women with aortic valve disease, said Dr. O’Gara, found that the risk of later events for women who had had a cardiac event in pregnancy was 27% plus or minus 9 percentage points in the 5 years following pregnancy, while the risk was just 15% plus or minus 3 percentage points for women whose pregnancies were not complicated by cardiac adverse events (P = .02) (Heart. 2010 Oct;96(20):1656-61).
The World Health Organization classification of pregnancy risk, said Dr. O’Gara, provides some guidance. Patients who are WHO class III are considered to be high risk; pregnancy in these individuals calls for counseling and a multidisciplinary care team. Patients who fall into this class are those with mechanical heart valves, those with Marfan syndrome and aortic involvement with a valve diameter of 40-45 mm, and those with bicuspid aortic valve disease with a valve diameter of 45-50 mm.
WHO class IV patients, according to the guidelines, are at prohibitive risk. These patients should consider terminating a pregnancy if one occurs. Conditions that place women into WHO class IV include symptomatic severe aortic stenosis (AS), severe left ventricular dysfunction with an ejection fraction less than 40%, and severe coarctation of the aorta. Women with Marfan syndrome with aortic valve diameters greater than 45 mm and women with bicuspid aortic valves and a diameter over 50 mm also fall into this category of prohibitive risk.
If a physician is lucky enough to have a pre-conception relationship with a patient, then a host of considerations can come into play. In addition to cardiac risk stratification, obstetric and intrapartum risk to the mother as well as neonatal risk should be considered. Some factors to take into account are maternal life expectancy and potential long-term complications to the mother from pregnancy and childbirth.
Plasma volume increases rapidly through the first trimester, plateauing about halfway through pregnancy. With this normal dilutional anemia, “Most normal pregnancies are accompanied by a grade II systolic murmur, best heard at the upper left sternal border,” said Dr. O’Gara. Since stroke volume and heart rate both also increase through pregnancy, cardiac output goes up as well.
“Importantly, systemic vascular resistance is reduced throughout pregnancy,” said Dr. O’Gara. Consequently, “regurgitant heart valve problems are generally much better tolerated than stenotic lesions in pregnancy. That’s physiologic principle number one.”
In labor, abrupt hemodynamic changes include increases in cardiac output, heart rate, blood pressure, and venous return. “Labor and delivery are very stressful hemodynamic times for women,” said Dr. O’Gara.
In the immediate postpartum period, uterine contraction results in a return of a significant amount of blood to the maternal circulation. This effectively creates an autotransfusion, with resulting increased preload and cardiac output. The inferior vena cava is also freed from the pressure of a gravid uterus, increasing venous return further. Finally, there’s also a marked increase in systemic vascular resistance.
Aside from the risk of adverse cardiac events, other adverse outcomes for women can include an increased risk of premature rupture of membranes and postpartum hemorrhage. For the neonate, preterm birth and respiratory distress are more likely. Newborns are more likely to be small for gestational age, to suffer intraventricular hemorrhage, and to die. Depending on the parental genetic status, the infant may be at risk of congenital heart disease as well.
Neonatal risk may also be increased, said Dr. O’Gara. Some maternal conditions that can increase risk for the infant include a baseline New York Heart Association (NYHA) class of greater than II or having cyanosis; having a left heart obstruction; being a smoker; having a multiple gestation; having a mechanical heart valve; and taking an oral anticoagulant.
Ideally, a full discussion would include a genetic referral if indicated, as well as coordination with a gynecologist or primary care provider to provide contraception and to assist with planning for and optimizing outcomes of a pregnancy.
The American College of Cardiology and the American Heart Association have issued guidelines that include a class I recommendation regarding valve intervention before pregnancy for symptomatic patients with severe AS (those with aortic velocity of at least 4.0 m/sec, or mean pressure gradient greater than 41 mm Hg; stage D). For patients who meet the same hemodynamic criteria for severe AS but who are asymptomatic (stage C), the guidelines have a class IIa recommendation that pre-pregnancy valve intervention is “reasonable.” These recommendations have level C evidence supporting them.
However, another class IIa recommendation for patients with severe AS who are already pregnant advises valve intervention only in the case of hemodynamic deterioration, or the development of NYHA class III to IV heart failure symptoms. This is backed by grade B evidence, according to the associations.
For aortic regurgitation (AR), a level I recommendation advises valve repair or replacement before pregnancy if patients are symptomatic and have severe (stage D) regurgitation. Pregnant patients with severe regurgitation should only be considered for a valve operation if they have refractory NYHA class IV heart failure symptoms. These recommendations have level C evidence supporting them.
Since AR is better tolerated in pregnancy than AS, the nature of the valve disease is one of many factors to consider when deciding whether to perform intervention before the patient becomes pregnant. Plans for future pregnancy may also affect the choice of prosthesis, as anticoagulation management during pregnancy can be extremely tricky.
The recommendations overall make clear that, based on available evidence, “there should be a high threshold for intervention during pregnancy,” said Dr. O’Gara. And no one should go it alone when taking care of these complicated patients. “Care of pregnant women with heart disease requires coordination with a multidisciplinary team,” he said.
Dr. O’Gara reported no relevant disclosures.
[email protected]
On Twitter @karioakes
EXPERT ANALYSIS FROM THE HEART VALVE SUMMIT
Interatrial shunt benefits sustained for 1 year in HFpEF patients
NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.
The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).
Overall survival at 1 year was 95%. Three patients died (one from combined pneumonia and renal failure, one from a fatal stroke, and one from an undetermined cause) and one was lost to follow-up. Thirteen patients required 17 hospitalizations for heart failure.
Six-minute walk distance improved from 331 meters at baseline to 363 meters. NYHA classification improved dramatically, as did quality of life scores as assessed by the Minnesota Living with HF questionnaire.
All 48 devices that were evaluable on echocardiographic imaging remained patent, showing continued left-to-right shunting. Left ventricular ejection fraction remained unchanged while right ventricular ejection fraction was significantly elevated over baseline levels. “In conjunction, there were modest but stable reductions in LV end-diastolic volume index with a concomitant rise in RV end-diastolic index,” he said.
A subset of 18 study participants underwent heart catheterization during both rest and exercise so that hemodynamics could be assessed. Exercise time increased significantly, from 8.2 minutes at baseline to 9.7 minutes at 6 months and to 10.4 minutes at 1 year. Similarly, peak work capacity during supine cycling increased from 48 watts at baseline to 60 watts at 6 months and 55 watts at 1 year. These benefits occurred without any increase in pulmonary capillary wedge pressure.
Systemic blood pressure did not change over time, either at rest or during exercise. Left and right atrial volumes also remained unchanged.
Perhaps most importantly, Dr. Kaye said, right-sided cardiac output increased significantly, while left-sided cardiac output remained unchanged. There was no evidence of increased pulmonary pressure or pulmonary vascular resistance. This meant that patients could do more physical activity for a given level of left atrial pressure, he said.
Furthermore, 1-year mortality was lower in this trial, at 4.6%, than in the placebo groups of the I-PRESERVE trial in irbesartan (5.2%) and the U.S. group of the TOPCAT trial in spironolactone (7.7%), said Dr. Kaye, professor and chief of cardiology at the University of Arizona, Tuscon.
Device therapy could have an enormous impact in carefully selected patients with HFpEF, for whom there are no medical treatments, despite the nonrandomized nature of the trial.
REDUCE LAP-HF was funded by Corvia Medical, maker of the shunt device. Dr. Kaye is an unpaid member of Corvia’s scientific advisory group. Dr. Sweitzer is an investigator in the ongoing randomized trial of the interatrial shunt.
NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.
The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).
Overall survival at 1 year was 95%. Three patients died (one from combined pneumonia and renal failure, one from a fatal stroke, and one from an undetermined cause) and one was lost to follow-up. Thirteen patients required 17 hospitalizations for heart failure.
Six-minute walk distance improved from 331 meters at baseline to 363 meters. NYHA classification improved dramatically, as did quality of life scores as assessed by the Minnesota Living with HF questionnaire.
All 48 devices that were evaluable on echocardiographic imaging remained patent, showing continued left-to-right shunting. Left ventricular ejection fraction remained unchanged while right ventricular ejection fraction was significantly elevated over baseline levels. “In conjunction, there were modest but stable reductions in LV end-diastolic volume index with a concomitant rise in RV end-diastolic index,” he said.
A subset of 18 study participants underwent heart catheterization during both rest and exercise so that hemodynamics could be assessed. Exercise time increased significantly, from 8.2 minutes at baseline to 9.7 minutes at 6 months and to 10.4 minutes at 1 year. Similarly, peak work capacity during supine cycling increased from 48 watts at baseline to 60 watts at 6 months and 55 watts at 1 year. These benefits occurred without any increase in pulmonary capillary wedge pressure.
Systemic blood pressure did not change over time, either at rest or during exercise. Left and right atrial volumes also remained unchanged.
Perhaps most importantly, Dr. Kaye said, right-sided cardiac output increased significantly, while left-sided cardiac output remained unchanged. There was no evidence of increased pulmonary pressure or pulmonary vascular resistance. This meant that patients could do more physical activity for a given level of left atrial pressure, he said.
Furthermore, 1-year mortality was lower in this trial, at 4.6%, than in the placebo groups of the I-PRESERVE trial in irbesartan (5.2%) and the U.S. group of the TOPCAT trial in spironolactone (7.7%), said Dr. Kaye, professor and chief of cardiology at the University of Arizona, Tuscon.
Device therapy could have an enormous impact in carefully selected patients with HFpEF, for whom there are no medical treatments, despite the nonrandomized nature of the trial.
REDUCE LAP-HF was funded by Corvia Medical, maker of the shunt device. Dr. Kaye is an unpaid member of Corvia’s scientific advisory group. Dr. Sweitzer is an investigator in the ongoing randomized trial of the interatrial shunt.
NEW ORLEANS – An interatrial septal shunt device continued to provide “sustained and meaningful clinical benefit” at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction (HFpEF), David M. Kaye, MD, PhD, reported at the American Heart Association scientific sessions.
The device is implanted via cardiac catheterization and is intended to reduce elevated left atrial pressure, particularly that associated with exertion, by allowing a small amount but not excessive left-to-right shunting. Patients showed improvements in 6-minute walk distance, New York Heart Association class, and HF-related quality of life scores at 6 months, and those effects persisted at the most recent (12-month) follow-up, he said in a presentation that was simultaneously published online in Circulation (2016 Nov 16).
Overall survival at 1 year was 95%. Three patients died (one from combined pneumonia and renal failure, one from a fatal stroke, and one from an undetermined cause) and one was lost to follow-up. Thirteen patients required 17 hospitalizations for heart failure.
Six-minute walk distance improved from 331 meters at baseline to 363 meters. NYHA classification improved dramatically, as did quality of life scores as assessed by the Minnesota Living with HF questionnaire.
All 48 devices that were evaluable on echocardiographic imaging remained patent, showing continued left-to-right shunting. Left ventricular ejection fraction remained unchanged while right ventricular ejection fraction was significantly elevated over baseline levels. “In conjunction, there were modest but stable reductions in LV end-diastolic volume index with a concomitant rise in RV end-diastolic index,” he said.
A subset of 18 study participants underwent heart catheterization during both rest and exercise so that hemodynamics could be assessed. Exercise time increased significantly, from 8.2 minutes at baseline to 9.7 minutes at 6 months and to 10.4 minutes at 1 year. Similarly, peak work capacity during supine cycling increased from 48 watts at baseline to 60 watts at 6 months and 55 watts at 1 year. These benefits occurred without any increase in pulmonary capillary wedge pressure.
Systemic blood pressure did not change over time, either at rest or during exercise. Left and right atrial volumes also remained unchanged.
Perhaps most importantly, Dr. Kaye said, right-sided cardiac output increased significantly, while left-sided cardiac output remained unchanged. There was no evidence of increased pulmonary pressure or pulmonary vascular resistance. This meant that patients could do more physical activity for a given level of left atrial pressure, he said.
Furthermore, 1-year mortality was lower in this trial, at 4.6%, than in the placebo groups of the I-PRESERVE trial in irbesartan (5.2%) and the U.S. group of the TOPCAT trial in spironolactone (7.7%), said Dr. Kaye, professor and chief of cardiology at the University of Arizona, Tuscon.
Device therapy could have an enormous impact in carefully selected patients with HFpEF, for whom there are no medical treatments, despite the nonrandomized nature of the trial.
REDUCE LAP-HF was funded by Corvia Medical, maker of the shunt device. Dr. Kaye is an unpaid member of Corvia’s scientific advisory group. Dr. Sweitzer is an investigator in the ongoing randomized trial of the interatrial shunt.
AT THE AHA SCIENTIFIC SESSIONS 2016
Key clinical point: An interatrial septal shunt device continued to provide sustained and meaningful clinical benefit at 1-year follow-up for 64 patients who had heart failure with preserved ejection fraction.
Major finding: Six-minute walk distance improved from 331 meters at baseline to 363 meters at 1 year, NYHA classification improved dramatically, and HF-related quality of life scores also improved.
Data source: REDUCE LAP-HF, a multicenter, prospective, open-label study involving 64 patients followed for 1 year after transcatheter implantation of a shunt device.
Disclosures: REDUCE LAP-HF was funded by Corvia Medical, maker of the shunt device. Dr. Kaye is an unpaid member of Corvia’s scientific advisory group.
CSL112 enhances cholesterol efflux capacity after acute MI
CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.
Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.
An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).
The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.
The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.
Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.
This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.
As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.
The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.
CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.
Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.
An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).
The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.
The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.
Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.
This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.
As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.
The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.
CSL112, a plasma-derived apolipoprotein A-1 (apoA-1) that enhances cholesterol efflux capacity, was found safe for use after acute MI in a manufacturer-sponsored phase IIb trial, Michael Gibson, MD, reported at the American Heart Association scientific sessions.
Cholesterol efflux capacity is a measure of HDL cholesterol’s ability to remove excess cholesterol from atherosclerotic plaque for transport to the liver. Drugs that improve this capacity rather than simply raising HDL cholesterol are expected to reduce plaque burden and stabilize vulnerable plaque immediately following acute MI, when cholesterol efflux is significantly impaired. But they have not been tested in this patient population until now, said Dr. Gibson of Beth Israel Deaconess Medical Center and Harvard, both in Boston.
An earlier prototype formulation of CSL112 was discontinued because of concerns about transient elevations in liver enzymes and the potential for renal toxicity due to the agent’s high sucrose content. Dr. Gibson and his associates in the AEGIS-1 trial (ApoA-1 Event Reducing in Ischemic Syndromes 1) now report their findings for the current formulation of CSL112, which contains lower phosphatidylcholine and lower sucrose levels, in 1,258 patients who had MI during the preceding week and who had normal or only mildly impaired renal function. These results were reported at the meeting and simultaneously published online in Circulation (2016, Nov 15. doi: 10.1161/CIRCULATION AHA.116.025687).
The study participants were enrolled in 16 countries during an 11-month period. They were randomly assigned to receive low-dose (2 g) CSL112 (419 patients), high-dose (6 g) CSL112 (421 patients), or a matching placebo (418 patients) via IV infusion every week for 4 consecutive weeks. The median duration of follow-up at the time of this report was 7.5 months.
The two primary safety end points – the rate of hepatic impairment and the rate of renal impairment during treatment – were not significantly different across the three study groups. Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group. Renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group.
Similarly, rates of major adverse cardiovascular events were comparable across the three study groups, as were rates of any grade of bleeding, rates of serious and life-threatening adverse events, and rates of adverse events leading to drug discontinuation.
This study focused on safety and tolerability and was not designed or powered to assess efficacy. Nevertheless, CSL112 caused a substantial and dose-dependent increase in both apoA-1 and cholesterol efflux capacity. The low-dose drug raised total cholesterol efflux capacity by 1.87-fold, and the high-dose drug raised it 2.45-fold.
As the first study to establish the safety and feasibility of adding CSL112 to standard care for acute MI, this trial demonstrates that an adequately powered, multicenter, phase III trial is warranted, Dr. Gibson said.
The current formulation of CSL112 didn’t provoke hepatic toxicity, and even though it was given shortly after contrast studies in MI patients, it also didn’t provoke renal toxicity. “This demonstrates the feasibility of administering CSL112 to patients with MI who have normal renal function or mild renal impairment shortly after angiography. A study in MI patients who have moderate renal impairment is now under way,” he noted.
This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.
FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: CSL112, a plasma-derived apolipoprotein A-1 that enhances cholesterol efflux capacity, was found safe for use after acute MI in an international phase IIb trial.
Major finding: Hepatic impairment developed in 1.0% of the low-dose group, 0.5% of the high-dose group, and 0.0% of the placebo group, while renal impairment developed in 0.0% of the low-dose group, 0.7% of the high-dose group, and 0.2% of the placebo group – all nonsignificant differences.
Data source: A manufacturer-sponsored randomized double-blind placebo-controlled phase IIb trial involving 1,258 patients in 16 countries.
Disclosures: This study was sponsored by CSL Behring, maker of CSL112. Dr. Gibson and his associates reported financial ties to Behring and numerous other industry sources.
VIDEO: For CABG, double arterial grafts found no better than single
NEW ORLEANS – Patients undergoing coronary artery bypass graft (CABG) surgery do not see any 5-year survival advantage when their surgeon uses both internal mammary (thoracic) arteries for grafting rather than just one of them along with a vein, finds an interim analysis from the randomized Arterial Revascularization Trial (ART).
Overall, about 8.5% of the 3,102 patients randomized had died 5 years after surgery, with no significant difference between the bilateral graft and single graft groups, according to data reported at the American Heart Association scientific sessions and simultaneously published (N Engl J Med. 2016 Nov 14. doi: 10.1056/NEJMoa1610021). The former had roughly triple the rate of sternal reconstruction, mainly driven by complications in insulin-dependent diabetes patients having high body mass index.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
There is strong angiographic evidence that vein grafts have a high rate of failure over time because of atherosclerosis, but internal mammary artery grafts retain excellent patency, he elaborated. “People have speculated that this superior patency of internal mammary arteries will translate into a clinical survival benefit,” and observational data indeed suggest that the bilateral artery strategy reduces mortality by about one-fifth relative to the single artery strategy.
Yet uptake of the bilateral procedure has been low. It is used in fewer than 5% of patients undergoing CABG in the United States and fewer than 10% of those in Europe, reflecting concerns about its greater technical complexity, potentially increased mortality and morbidity, and – until now – lack of evidence from randomized trials.
“What I think we can conclude today is that there are excellent 5-year outcomes of CABG in both groups. This study confirms that it’s at least safe to use bilateral grafts over the medium term,” Dr. Taggart commented. He discussed the results in a video interview conducted at the meeting.
These interim ART data probably won’t sway practice one way or the other, he said. “People who believe in arterial grafts will continue to do them, and those who are not enthusiastic about the prospect of a slightly technically more difficult operation [can now] remain comfortable as to why they are not using both internal mammary arteries.”
Pointed questions
The lack of difference was possibly due to a very high level of guideline-based medical therapy in the trial (which may have especially protected the vein grafts) or to the fact that the annual failure rate of vein grafts is modest and steady up to 5 years but accelerates thereafter, Dr. Taggart proposed. The trial’s primary outcome of 10-year survival, expected in 2018, will likely differ, speculated Dr. Sellke, who is also program chair for the AHA scientific sessions.
“Do you think multiple arterial grafting is superior to single internal mammary artery grafting considering the lack of improvement in survival and other outcomes in the study, with the increase in sternal wound infections?” he asked.
“I personally, if I needed the operation, would insist on having bilateral internal mammary artery grafts done by an experienced operator because it is totally counterintuitive to believe that having more patent grafts in your heart at 10 to 20 years of follow-up is of no benefit,” Dr. Taggart maintained.
When data meet clinical practice
It may require time for the benefit of the bilateral artery graft to emerge, he agreed. “I’m undeterred from my belief that ... in patients who are getting CABG done in their 40s or 50s or early 60s, betting on a graft that’s going to outperform vein grafts is the better strategy.”
Until the trial’s 10-year results become available, physicians may wish to put these interim results in the context when counseling patients, according to Dr. Gardner.
“We have indisputable evidence that arterial grafts have better long-term patency than vein grafts,” he elaborated. “If we had a very sophisticated patient, we might tell them that we were a little surprised that this head-to-head trial of single versus double didn’t show any survival benefit at 5 years, but we still are persuaded by the data that shows the better patency, and we think in the situation that the patient’s in, that we would still recommend a double mammary, assuming that the patient doesn’t have comorbidities that would make that more dangerous.”
Trial details
ART enrolled patients from 28 cardiac surgical centers in seven countries. The patients, all of whom had multivessel coronary disease and were scheduled to undergo CABG, were randomized evenly to single or bilateral internal thoracic artery grafts.
The interim results showed differences in nonadherence to the randomized operation: 2.4% of patients in the single graft group ultimately underwent got bilateral grafts, whereas 14% of patients in the bilateral graft group ultimately got a single graft.
“This raises questions about how experienced some surgeons were with the use of bilateral internal mammary artery grafts,” Dr. Taggart commented.
At 5 years of follow-up, 8.7% of patients in the bilateral graft group and 8.4% of patients in the single graft group had died, a nonsignificant difference. “Those mortalities are similar to what has been observed in other contemporary trials of CABG,” he noted. There was no difference between diabetic and nondiabetic patients with respect to this outcome.
The rate of the composite outcome of death, myocardial infarction, or stroke was 12.2% in the bilateral graft group and 12.7% in the single graft group, also a nonsignificant difference.
On the other hand, patients in the bilateral graft group had higher rates of sternal wound complications (3.5% vs. 1.9%; P = .005) and sternal reconstruction (1.9% vs. 0.6%; P = .002).
The groups were statistically indistinguishable with respect to rates of mortality, major bleeding, or need for repeat revascularization, as well as angina status and quality of life measures, according to Dr. Taggart, who disclosed that he had no relevant conflicts of interest.
NEW ORLEANS – Patients undergoing coronary artery bypass graft (CABG) surgery do not see any 5-year survival advantage when their surgeon uses both internal mammary (thoracic) arteries for grafting rather than just one of them along with a vein, finds an interim analysis from the randomized Arterial Revascularization Trial (ART).
Overall, about 8.5% of the 3,102 patients randomized had died 5 years after surgery, with no significant difference between the bilateral graft and single graft groups, according to data reported at the American Heart Association scientific sessions and simultaneously published (N Engl J Med. 2016 Nov 14. doi: 10.1056/NEJMoa1610021). The former had roughly triple the rate of sternal reconstruction, mainly driven by complications in insulin-dependent diabetes patients having high body mass index.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
There is strong angiographic evidence that vein grafts have a high rate of failure over time because of atherosclerosis, but internal mammary artery grafts retain excellent patency, he elaborated. “People have speculated that this superior patency of internal mammary arteries will translate into a clinical survival benefit,” and observational data indeed suggest that the bilateral artery strategy reduces mortality by about one-fifth relative to the single artery strategy.
Yet uptake of the bilateral procedure has been low. It is used in fewer than 5% of patients undergoing CABG in the United States and fewer than 10% of those in Europe, reflecting concerns about its greater technical complexity, potentially increased mortality and morbidity, and – until now – lack of evidence from randomized trials.
“What I think we can conclude today is that there are excellent 5-year outcomes of CABG in both groups. This study confirms that it’s at least safe to use bilateral grafts over the medium term,” Dr. Taggart commented. He discussed the results in a video interview conducted at the meeting.
These interim ART data probably won’t sway practice one way or the other, he said. “People who believe in arterial grafts will continue to do them, and those who are not enthusiastic about the prospect of a slightly technically more difficult operation [can now] remain comfortable as to why they are not using both internal mammary arteries.”
Pointed questions
The lack of difference was possibly due to a very high level of guideline-based medical therapy in the trial (which may have especially protected the vein grafts) or to the fact that the annual failure rate of vein grafts is modest and steady up to 5 years but accelerates thereafter, Dr. Taggart proposed. The trial’s primary outcome of 10-year survival, expected in 2018, will likely differ, speculated Dr. Sellke, who is also program chair for the AHA scientific sessions.
“Do you think multiple arterial grafting is superior to single internal mammary artery grafting considering the lack of improvement in survival and other outcomes in the study, with the increase in sternal wound infections?” he asked.
“I personally, if I needed the operation, would insist on having bilateral internal mammary artery grafts done by an experienced operator because it is totally counterintuitive to believe that having more patent grafts in your heart at 10 to 20 years of follow-up is of no benefit,” Dr. Taggart maintained.
When data meet clinical practice
It may require time for the benefit of the bilateral artery graft to emerge, he agreed. “I’m undeterred from my belief that ... in patients who are getting CABG done in their 40s or 50s or early 60s, betting on a graft that’s going to outperform vein grafts is the better strategy.”
Until the trial’s 10-year results become available, physicians may wish to put these interim results in the context when counseling patients, according to Dr. Gardner.
“We have indisputable evidence that arterial grafts have better long-term patency than vein grafts,” he elaborated. “If we had a very sophisticated patient, we might tell them that we were a little surprised that this head-to-head trial of single versus double didn’t show any survival benefit at 5 years, but we still are persuaded by the data that shows the better patency, and we think in the situation that the patient’s in, that we would still recommend a double mammary, assuming that the patient doesn’t have comorbidities that would make that more dangerous.”
Trial details
ART enrolled patients from 28 cardiac surgical centers in seven countries. The patients, all of whom had multivessel coronary disease and were scheduled to undergo CABG, were randomized evenly to single or bilateral internal thoracic artery grafts.
The interim results showed differences in nonadherence to the randomized operation: 2.4% of patients in the single graft group ultimately underwent got bilateral grafts, whereas 14% of patients in the bilateral graft group ultimately got a single graft.
“This raises questions about how experienced some surgeons were with the use of bilateral internal mammary artery grafts,” Dr. Taggart commented.
At 5 years of follow-up, 8.7% of patients in the bilateral graft group and 8.4% of patients in the single graft group had died, a nonsignificant difference. “Those mortalities are similar to what has been observed in other contemporary trials of CABG,” he noted. There was no difference between diabetic and nondiabetic patients with respect to this outcome.
The rate of the composite outcome of death, myocardial infarction, or stroke was 12.2% in the bilateral graft group and 12.7% in the single graft group, also a nonsignificant difference.
On the other hand, patients in the bilateral graft group had higher rates of sternal wound complications (3.5% vs. 1.9%; P = .005) and sternal reconstruction (1.9% vs. 0.6%; P = .002).
The groups were statistically indistinguishable with respect to rates of mortality, major bleeding, or need for repeat revascularization, as well as angina status and quality of life measures, according to Dr. Taggart, who disclosed that he had no relevant conflicts of interest.
NEW ORLEANS – Patients undergoing coronary artery bypass graft (CABG) surgery do not see any 5-year survival advantage when their surgeon uses both internal mammary (thoracic) arteries for grafting rather than just one of them along with a vein, finds an interim analysis from the randomized Arterial Revascularization Trial (ART).
Overall, about 8.5% of the 3,102 patients randomized had died 5 years after surgery, with no significant difference between the bilateral graft and single graft groups, according to data reported at the American Heart Association scientific sessions and simultaneously published (N Engl J Med. 2016 Nov 14. doi: 10.1056/NEJMoa1610021). The former had roughly triple the rate of sternal reconstruction, mainly driven by complications in insulin-dependent diabetes patients having high body mass index.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
There is strong angiographic evidence that vein grafts have a high rate of failure over time because of atherosclerosis, but internal mammary artery grafts retain excellent patency, he elaborated. “People have speculated that this superior patency of internal mammary arteries will translate into a clinical survival benefit,” and observational data indeed suggest that the bilateral artery strategy reduces mortality by about one-fifth relative to the single artery strategy.
Yet uptake of the bilateral procedure has been low. It is used in fewer than 5% of patients undergoing CABG in the United States and fewer than 10% of those in Europe, reflecting concerns about its greater technical complexity, potentially increased mortality and morbidity, and – until now – lack of evidence from randomized trials.
“What I think we can conclude today is that there are excellent 5-year outcomes of CABG in both groups. This study confirms that it’s at least safe to use bilateral grafts over the medium term,” Dr. Taggart commented. He discussed the results in a video interview conducted at the meeting.
These interim ART data probably won’t sway practice one way or the other, he said. “People who believe in arterial grafts will continue to do them, and those who are not enthusiastic about the prospect of a slightly technically more difficult operation [can now] remain comfortable as to why they are not using both internal mammary arteries.”
Pointed questions
The lack of difference was possibly due to a very high level of guideline-based medical therapy in the trial (which may have especially protected the vein grafts) or to the fact that the annual failure rate of vein grafts is modest and steady up to 5 years but accelerates thereafter, Dr. Taggart proposed. The trial’s primary outcome of 10-year survival, expected in 2018, will likely differ, speculated Dr. Sellke, who is also program chair for the AHA scientific sessions.
“Do you think multiple arterial grafting is superior to single internal mammary artery grafting considering the lack of improvement in survival and other outcomes in the study, with the increase in sternal wound infections?” he asked.
“I personally, if I needed the operation, would insist on having bilateral internal mammary artery grafts done by an experienced operator because it is totally counterintuitive to believe that having more patent grafts in your heart at 10 to 20 years of follow-up is of no benefit,” Dr. Taggart maintained.
When data meet clinical practice
It may require time for the benefit of the bilateral artery graft to emerge, he agreed. “I’m undeterred from my belief that ... in patients who are getting CABG done in their 40s or 50s or early 60s, betting on a graft that’s going to outperform vein grafts is the better strategy.”
Until the trial’s 10-year results become available, physicians may wish to put these interim results in the context when counseling patients, according to Dr. Gardner.
“We have indisputable evidence that arterial grafts have better long-term patency than vein grafts,” he elaborated. “If we had a very sophisticated patient, we might tell them that we were a little surprised that this head-to-head trial of single versus double didn’t show any survival benefit at 5 years, but we still are persuaded by the data that shows the better patency, and we think in the situation that the patient’s in, that we would still recommend a double mammary, assuming that the patient doesn’t have comorbidities that would make that more dangerous.”
Trial details
ART enrolled patients from 28 cardiac surgical centers in seven countries. The patients, all of whom had multivessel coronary disease and were scheduled to undergo CABG, were randomized evenly to single or bilateral internal thoracic artery grafts.
The interim results showed differences in nonadherence to the randomized operation: 2.4% of patients in the single graft group ultimately underwent got bilateral grafts, whereas 14% of patients in the bilateral graft group ultimately got a single graft.
“This raises questions about how experienced some surgeons were with the use of bilateral internal mammary artery grafts,” Dr. Taggart commented.
At 5 years of follow-up, 8.7% of patients in the bilateral graft group and 8.4% of patients in the single graft group had died, a nonsignificant difference. “Those mortalities are similar to what has been observed in other contemporary trials of CABG,” he noted. There was no difference between diabetic and nondiabetic patients with respect to this outcome.
The rate of the composite outcome of death, myocardial infarction, or stroke was 12.2% in the bilateral graft group and 12.7% in the single graft group, also a nonsignificant difference.
On the other hand, patients in the bilateral graft group had higher rates of sternal wound complications (3.5% vs. 1.9%; P = .005) and sternal reconstruction (1.9% vs. 0.6%; P = .002).
The groups were statistically indistinguishable with respect to rates of mortality, major bleeding, or need for repeat revascularization, as well as angina status and quality of life measures, according to Dr. Taggart, who disclosed that he had no relevant conflicts of interest.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: At 5 years, the rate of all-cause mortality was 8.7% in the bilateral graft group and 8.4% in the single graft group, a nonsignificant difference.
Data source: ART, a randomized trial among 3,102 patients with multivessel coronary disease undergoing CABG.
Disclosures: Dr. Taggart had no relevant conflicts of interest. The trial was funded by the U.K. Medical Research Council, the British Heart Foundation, and the U.K. National Institute of Health Research Efficacy and Mechanistic Evaluation.
VIDEO: Celecoxib just as safe as naproxen or ibuprofen in OA and RA
WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.
But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.
“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”
PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.
The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:
• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).
• Renal events (acute kidney injury, including hospitalization for renal failure).
• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.
The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).
Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.
The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.
“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.
“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”
The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.
Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.
Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.
In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.
For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.
RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.
The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.
“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”
Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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On Twitter @alz_gal
WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.
But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.
“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”
PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.
The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:
• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).
• Renal events (acute kidney injury, including hospitalization for renal failure).
• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.
The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).
Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.
The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.
“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.
“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”
The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.
Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.
Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.
In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.
For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.
RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.
The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.
“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”
Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.
But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.
“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”
PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.
The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:
• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).
• Renal events (acute kidney injury, including hospitalization for renal failure).
• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.
The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).
Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.
The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.
“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.
“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”
The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.
Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.
Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.
In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.
For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.
RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.
The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.
“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”
Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
AT THE ACR ANNUAL MEETING
Key clinical point:
Major finding: Compared with naproxen, celecoxib was associated with a 53% lower risk of overall mortality, although the clinical impact of that finding remains unknown.
Data source: PRECISION, which randomized more than 24,000 patients to celecoxib, ibuprofen, or naproxen.
Disclosures: Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.
No primary prevention gains from low-dose aspirin in diabetes
Low-dose aspirin does not appear to reduce the risk of cardiovascular events in individuals with type 2 diabetes but without preexisting cardiovascular disease, according to a study presented at the American Heart Association scientific sessions and published simultaneously in the Nov. 15 edition of Circulation.
In the long-term follow-up of participants in an open-label controlled trial, Japanese researchers followed 2,539 patients with type 2 diabetes who were randomized to daily aspirin (81 mg or 100 mg) or no aspirin, for a median of 10.3 years to see the impact on the incidence of cardiovascular events.
In their study, they found that a daily regimen of low-dose aspirin was not associated with a significant change in the risk of cardiovascular events including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease (hazard ratio, 1.14; 95% confidence interval, 0.91-1.42). They also found no significant difference between the two groups in secondary outcomes, which were a composite of coronary artery, cerebrovascular, and vascular events.
This lack of impact persisted even after age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia were accounted for, and it was also seen in sensitivity analyses on the intention-to-treat cohort.
However, the investigators did find a significantly higher rate of gastrointestinal bleeding in patients taking aspirin, compared with the control group (2% vs. 0.9%, P = .03) but no difference in the rate of hemorrhagic stroke.
“Meta-analyses in patients with diabetes have reported that aspirin has a smaller benefit for primary prevention than in general populations, although patients with diabetes are at high risk for cardiovascular events,” the authors wrote. “It seems there are differential effects of low-dose aspirin therapy on preventing cardiovascular events in patients with and without diabetes.”
The study was supported by the Ministry of Health, Labour, and Welfare of Japan and the Japan Heart Foundation. Eight authors declared funding, grants, honoraria, and other support from the pharmaceutical industry. No other conflicts of interest were declared.
Low-dose aspirin does not appear to reduce the risk of cardiovascular events in individuals with type 2 diabetes but without preexisting cardiovascular disease, according to a study presented at the American Heart Association scientific sessions and published simultaneously in the Nov. 15 edition of Circulation.
In the long-term follow-up of participants in an open-label controlled trial, Japanese researchers followed 2,539 patients with type 2 diabetes who were randomized to daily aspirin (81 mg or 100 mg) or no aspirin, for a median of 10.3 years to see the impact on the incidence of cardiovascular events.
In their study, they found that a daily regimen of low-dose aspirin was not associated with a significant change in the risk of cardiovascular events including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease (hazard ratio, 1.14; 95% confidence interval, 0.91-1.42). They also found no significant difference between the two groups in secondary outcomes, which were a composite of coronary artery, cerebrovascular, and vascular events.
This lack of impact persisted even after age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia were accounted for, and it was also seen in sensitivity analyses on the intention-to-treat cohort.
However, the investigators did find a significantly higher rate of gastrointestinal bleeding in patients taking aspirin, compared with the control group (2% vs. 0.9%, P = .03) but no difference in the rate of hemorrhagic stroke.
“Meta-analyses in patients with diabetes have reported that aspirin has a smaller benefit for primary prevention than in general populations, although patients with diabetes are at high risk for cardiovascular events,” the authors wrote. “It seems there are differential effects of low-dose aspirin therapy on preventing cardiovascular events in patients with and without diabetes.”
The study was supported by the Ministry of Health, Labour, and Welfare of Japan and the Japan Heart Foundation. Eight authors declared funding, grants, honoraria, and other support from the pharmaceutical industry. No other conflicts of interest were declared.
Low-dose aspirin does not appear to reduce the risk of cardiovascular events in individuals with type 2 diabetes but without preexisting cardiovascular disease, according to a study presented at the American Heart Association scientific sessions and published simultaneously in the Nov. 15 edition of Circulation.
In the long-term follow-up of participants in an open-label controlled trial, Japanese researchers followed 2,539 patients with type 2 diabetes who were randomized to daily aspirin (81 mg or 100 mg) or no aspirin, for a median of 10.3 years to see the impact on the incidence of cardiovascular events.
In their study, they found that a daily regimen of low-dose aspirin was not associated with a significant change in the risk of cardiovascular events including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease (hazard ratio, 1.14; 95% confidence interval, 0.91-1.42). They also found no significant difference between the two groups in secondary outcomes, which were a composite of coronary artery, cerebrovascular, and vascular events.
This lack of impact persisted even after age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia were accounted for, and it was also seen in sensitivity analyses on the intention-to-treat cohort.
However, the investigators did find a significantly higher rate of gastrointestinal bleeding in patients taking aspirin, compared with the control group (2% vs. 0.9%, P = .03) but no difference in the rate of hemorrhagic stroke.
“Meta-analyses in patients with diabetes have reported that aspirin has a smaller benefit for primary prevention than in general populations, although patients with diabetes are at high risk for cardiovascular events,” the authors wrote. “It seems there are differential effects of low-dose aspirin therapy on preventing cardiovascular events in patients with and without diabetes.”
The study was supported by the Ministry of Health, Labour, and Welfare of Japan and the Japan Heart Foundation. Eight authors declared funding, grants, honoraria, and other support from the pharmaceutical industry. No other conflicts of interest were declared.
FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Patients with type 2 diabetes taking daily low-dose aspirin showed no significant reductions in cardiovascular events, compared with a control group not taking aspirin.
Data source: Long-term follow-up in a randomized controlled trial in 2,539 patients with type 2 diabetes in the absence of preexisting cardiovascular disease.
Disclosures: The study was supported by the Ministry of Health, Labour, and Welfare of Japan and the Japan Heart Foundation. Eight authors declared funding, grants, honoraria, and other support from the pharmaceutical industry. No other conflicts of interest were declared.
USPSTF: Expand statin use beyond lipids to CVD risk
Use of statins for the primary prevention of cardiovascular disease should be based on overall cardiovascular disease risk, not necessarily blood lipid levels, according to new recommendations from the United States Preventive Services Task Force.
Despite widespread use in the elderly, USPSTF also said there’s insufficient evidence to recommend starting statins for cardiovascular disease (CVD) prevention in patients 76 years or older (JAMA. 2016 Nov;316[19]:1997-2007).
USPSTF now recommends low- to moderate-dose statins for primary prevention in adults 40-75 years old who have at least one CVD risk factor – dyslipidemia, diabetes, hypertension, or smoking – and a 10-year CVD event risk of at least 10% (B grade). It also recommended “selectively” offering low- to moderate-dose statins if patients have a 7.5%-10% risk (C grade). The task force recommends using the online American College of Cardiology/American Heart Association risk calculator.
A B grade denotes that USPSTF recommends the service as one where there is “high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.” With a C grade, the task force recommends that the service be provided subject to professional judgment and patient preferences.
The new advices from USPSTF is consistent with the task force’s 2015 draft proposals, and is based on a pooled analysis of 19 randomized trials in 71,344 adults at risk for CVD but without prior events; 17 of the studies were sponsored at least in part by the companies that make statins. The median duration of follow-up was 3 years. Trials included atorvastatin (Lipitor) and six other statins from 1994-2016.
Few of the 19 trials enrolled patients older than 75 years, so “the balance of benefits and harms of initiating statin use for” primary prevention in elderly adults “cannot be determined.” The task force did not make a recommendation either way, and called for further investigation.
For younger patients, the scales tipped toward benefit when the group found no overall increased risk of cancer, liver damage, diabetes, or cognitive problems with statins for primary prevention. “Although muscle pain, soreness, or weakness are commonly reported with statin use, there were no statistically significant differences between the intervention and control groups for myalgia, myopathy, or rhabdomyolysis,” according to the task force.
Across the 19 trials, statin therapy was associated with a statistically significant 14% reduction in all-cause mortality; 31% reduction in cardiovascular mortality; 29% reduction in stroke; and a 36% reduction in myocardial infarction; 250 patients needed to be treated to prevent one death from any cause after 1-6 years, and 233 to prevent one cardiovascular death after 2-6 years.
The recommendations call for low to moderate doses because that’s what most of the studies used, and there were no clear benefits when trials stratified patients by dose.
USPSTF cautioned that “reliance on a risk calculator ... alone as a basis for prevention may be problematic, given its possible overestimation of risk in some populations” and noted that the benefits “of statin use may be linear according to a patient’s absolute risk level, and any cut points used are only population estimates of benefits.”
The recommendations do not pertain to adults with very high CVD risk, such as those with familial hypercholesterolemia or an LDL level greater than 190mg/dL, since they were excluded from primary prevention trials.
While the USPSTF was careful in its evidence review, “ the limitations of the evidence were not considered sufficiently, given the serious concerns about the harms of statins for primary prevention,” Rita Redberg, MD, and Mitchell Katz, MD, wrote in an editorial accompanying the recommendations.
“USPSTF also did not have access to patient-level data; they had to rely on peer-reviewed published reports,” according to the editorialists. “The actual trial data are largely held by the Cholesterol Treatment Trialists’ Collaboration on behalf of industry sponsors and have not been made available to other researchers, despite multiple requests over many years.” Further, many of the trials were industry sponsored.
Using the USPSTF data, only 2% of patients who take statins for 5 years will avoid a myocardial infarction; virtually all (98%) will not experience any benefit. At the same time, 5%-20% will experience side effects including rhabdomyolysis, cognitive dysfunction, and increased risk of diabetes (JAMA. 2016 Nov;316[19]:1979-81).
There are unintended consequences of widespread statin use in healthy persons, Dr. Redberg and Dr. Katz wrote. People taking statins are more likely to become obese and more sedentary over time, likely because they mistakenly think they do not need to eat a healthy diet and exercise.
The USPSTF analysis was funded by the Agency for Healthcare Research and Quality. Task force lead Kirsten Bibbins-Domingo, MD, PhD, of the University of California, San Francisco, has advised the Institute for Clinical and Economic Review, which is partly funded by industry, on the cost-effectiveness of lipid-lowering drugs. Another member reported comparing how well they worked. The other 15 task force members had no disclosures.
Dare cardiovascular experts consider a future in which there are near-universal statin recommendations for middle-aged adults?
[USPSTF analysis suggests] that statin recommendations could be based primarily on a patient’s underlying CVD risk rather than on his or her cholesterol level. Disseminating a treatment strategy based largely on CVD risk alone has been a difficult message for the clinical community to accept and implement.
Nearly a generation of physicians has considered high-cholesterol levels, rather than generalized CVD risk, the target for statin treatment. Only a minority of physicians consistently use complex, risk-based probabilistic calculations to determine therapy.
Several key questions deserve careful consideration. Should LDL be considered in treatment recommendations beyond CVD risk? The decision to use absolute risk to guide statin recommendations is based on the finding that the relative risk reduction seen with statin therapy is independent of baseline risk; thus, those with the highest absolute baseline CVD risk experience the greatest reduction in CVD events.
However, the relative risk reduction of lipid-lowering therapy is also proportional to mmol/dL reduction in LDL level. This supports the contention that those with the highest baseline LDL levels should benefit the most from treatment because they have the most potential decline in LDL with intervention. One way to reconcile these findings is to incorporate both LDL levels and CVD risk into treatment recommendations, as has been done in the European guidelines. This approach recognizes that the relative benefit of statins is proportional to LDL lowering but that the absolute treatment benefit is largely driven by baseline risk.
From the resource perspective, the vast majority of statins are now available as generic products and require limited monitoring, leading to quite modest therapeutic costs. For patients in the gray area not covered by the guidelines, clinicians should be cautioned against adopting either a “treat none” or a “treat all” strategy. Rather, gaps in the evidence provide opportunities for clinicians to practice the art of medicine and engage with patients in shared decision-making regarding strategies for CVD prevention.
Ann Marie Navar, MD, PhD, and Eric Peterson, MD, MPH, are both at the Duke Clinical Research Institute in Durham, N.C. Dr. Navar reported funding from Regeneron and Sanofi. Dr. Peterson reported funding from Merck, Sanofi, Regeneron, and AstraZeneca. They made their comments in an editorial to the USPSTF report (JAMA. 2016 Nov;316[19]:1981-3).
Dare cardiovascular experts consider a future in which there are near-universal statin recommendations for middle-aged adults?
[USPSTF analysis suggests] that statin recommendations could be based primarily on a patient’s underlying CVD risk rather than on his or her cholesterol level. Disseminating a treatment strategy based largely on CVD risk alone has been a difficult message for the clinical community to accept and implement.
Nearly a generation of physicians has considered high-cholesterol levels, rather than generalized CVD risk, the target for statin treatment. Only a minority of physicians consistently use complex, risk-based probabilistic calculations to determine therapy.
Several key questions deserve careful consideration. Should LDL be considered in treatment recommendations beyond CVD risk? The decision to use absolute risk to guide statin recommendations is based on the finding that the relative risk reduction seen with statin therapy is independent of baseline risk; thus, those with the highest absolute baseline CVD risk experience the greatest reduction in CVD events.
However, the relative risk reduction of lipid-lowering therapy is also proportional to mmol/dL reduction in LDL level. This supports the contention that those with the highest baseline LDL levels should benefit the most from treatment because they have the most potential decline in LDL with intervention. One way to reconcile these findings is to incorporate both LDL levels and CVD risk into treatment recommendations, as has been done in the European guidelines. This approach recognizes that the relative benefit of statins is proportional to LDL lowering but that the absolute treatment benefit is largely driven by baseline risk.
From the resource perspective, the vast majority of statins are now available as generic products and require limited monitoring, leading to quite modest therapeutic costs. For patients in the gray area not covered by the guidelines, clinicians should be cautioned against adopting either a “treat none” or a “treat all” strategy. Rather, gaps in the evidence provide opportunities for clinicians to practice the art of medicine and engage with patients in shared decision-making regarding strategies for CVD prevention.
Ann Marie Navar, MD, PhD, and Eric Peterson, MD, MPH, are both at the Duke Clinical Research Institute in Durham, N.C. Dr. Navar reported funding from Regeneron and Sanofi. Dr. Peterson reported funding from Merck, Sanofi, Regeneron, and AstraZeneca. They made their comments in an editorial to the USPSTF report (JAMA. 2016 Nov;316[19]:1981-3).
Dare cardiovascular experts consider a future in which there are near-universal statin recommendations for middle-aged adults?
[USPSTF analysis suggests] that statin recommendations could be based primarily on a patient’s underlying CVD risk rather than on his or her cholesterol level. Disseminating a treatment strategy based largely on CVD risk alone has been a difficult message for the clinical community to accept and implement.
Nearly a generation of physicians has considered high-cholesterol levels, rather than generalized CVD risk, the target for statin treatment. Only a minority of physicians consistently use complex, risk-based probabilistic calculations to determine therapy.
Several key questions deserve careful consideration. Should LDL be considered in treatment recommendations beyond CVD risk? The decision to use absolute risk to guide statin recommendations is based on the finding that the relative risk reduction seen with statin therapy is independent of baseline risk; thus, those with the highest absolute baseline CVD risk experience the greatest reduction in CVD events.
However, the relative risk reduction of lipid-lowering therapy is also proportional to mmol/dL reduction in LDL level. This supports the contention that those with the highest baseline LDL levels should benefit the most from treatment because they have the most potential decline in LDL with intervention. One way to reconcile these findings is to incorporate both LDL levels and CVD risk into treatment recommendations, as has been done in the European guidelines. This approach recognizes that the relative benefit of statins is proportional to LDL lowering but that the absolute treatment benefit is largely driven by baseline risk.
From the resource perspective, the vast majority of statins are now available as generic products and require limited monitoring, leading to quite modest therapeutic costs. For patients in the gray area not covered by the guidelines, clinicians should be cautioned against adopting either a “treat none” or a “treat all” strategy. Rather, gaps in the evidence provide opportunities for clinicians to practice the art of medicine and engage with patients in shared decision-making regarding strategies for CVD prevention.
Ann Marie Navar, MD, PhD, and Eric Peterson, MD, MPH, are both at the Duke Clinical Research Institute in Durham, N.C. Dr. Navar reported funding from Regeneron and Sanofi. Dr. Peterson reported funding from Merck, Sanofi, Regeneron, and AstraZeneca. They made their comments in an editorial to the USPSTF report (JAMA. 2016 Nov;316[19]:1981-3).
Use of statins for the primary prevention of cardiovascular disease should be based on overall cardiovascular disease risk, not necessarily blood lipid levels, according to new recommendations from the United States Preventive Services Task Force.
Despite widespread use in the elderly, USPSTF also said there’s insufficient evidence to recommend starting statins for cardiovascular disease (CVD) prevention in patients 76 years or older (JAMA. 2016 Nov;316[19]:1997-2007).
USPSTF now recommends low- to moderate-dose statins for primary prevention in adults 40-75 years old who have at least one CVD risk factor – dyslipidemia, diabetes, hypertension, or smoking – and a 10-year CVD event risk of at least 10% (B grade). It also recommended “selectively” offering low- to moderate-dose statins if patients have a 7.5%-10% risk (C grade). The task force recommends using the online American College of Cardiology/American Heart Association risk calculator.
A B grade denotes that USPSTF recommends the service as one where there is “high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.” With a C grade, the task force recommends that the service be provided subject to professional judgment and patient preferences.
The new advices from USPSTF is consistent with the task force’s 2015 draft proposals, and is based on a pooled analysis of 19 randomized trials in 71,344 adults at risk for CVD but without prior events; 17 of the studies were sponsored at least in part by the companies that make statins. The median duration of follow-up was 3 years. Trials included atorvastatin (Lipitor) and six other statins from 1994-2016.
Few of the 19 trials enrolled patients older than 75 years, so “the balance of benefits and harms of initiating statin use for” primary prevention in elderly adults “cannot be determined.” The task force did not make a recommendation either way, and called for further investigation.
For younger patients, the scales tipped toward benefit when the group found no overall increased risk of cancer, liver damage, diabetes, or cognitive problems with statins for primary prevention. “Although muscle pain, soreness, or weakness are commonly reported with statin use, there were no statistically significant differences between the intervention and control groups for myalgia, myopathy, or rhabdomyolysis,” according to the task force.
Across the 19 trials, statin therapy was associated with a statistically significant 14% reduction in all-cause mortality; 31% reduction in cardiovascular mortality; 29% reduction in stroke; and a 36% reduction in myocardial infarction; 250 patients needed to be treated to prevent one death from any cause after 1-6 years, and 233 to prevent one cardiovascular death after 2-6 years.
The recommendations call for low to moderate doses because that’s what most of the studies used, and there were no clear benefits when trials stratified patients by dose.
USPSTF cautioned that “reliance on a risk calculator ... alone as a basis for prevention may be problematic, given its possible overestimation of risk in some populations” and noted that the benefits “of statin use may be linear according to a patient’s absolute risk level, and any cut points used are only population estimates of benefits.”
The recommendations do not pertain to adults with very high CVD risk, such as those with familial hypercholesterolemia or an LDL level greater than 190mg/dL, since they were excluded from primary prevention trials.
While the USPSTF was careful in its evidence review, “ the limitations of the evidence were not considered sufficiently, given the serious concerns about the harms of statins for primary prevention,” Rita Redberg, MD, and Mitchell Katz, MD, wrote in an editorial accompanying the recommendations.
“USPSTF also did not have access to patient-level data; they had to rely on peer-reviewed published reports,” according to the editorialists. “The actual trial data are largely held by the Cholesterol Treatment Trialists’ Collaboration on behalf of industry sponsors and have not been made available to other researchers, despite multiple requests over many years.” Further, many of the trials were industry sponsored.
Using the USPSTF data, only 2% of patients who take statins for 5 years will avoid a myocardial infarction; virtually all (98%) will not experience any benefit. At the same time, 5%-20% will experience side effects including rhabdomyolysis, cognitive dysfunction, and increased risk of diabetes (JAMA. 2016 Nov;316[19]:1979-81).
There are unintended consequences of widespread statin use in healthy persons, Dr. Redberg and Dr. Katz wrote. People taking statins are more likely to become obese and more sedentary over time, likely because they mistakenly think they do not need to eat a healthy diet and exercise.
The USPSTF analysis was funded by the Agency for Healthcare Research and Quality. Task force lead Kirsten Bibbins-Domingo, MD, PhD, of the University of California, San Francisco, has advised the Institute for Clinical and Economic Review, which is partly funded by industry, on the cost-effectiveness of lipid-lowering drugs. Another member reported comparing how well they worked. The other 15 task force members had no disclosures.
Use of statins for the primary prevention of cardiovascular disease should be based on overall cardiovascular disease risk, not necessarily blood lipid levels, according to new recommendations from the United States Preventive Services Task Force.
Despite widespread use in the elderly, USPSTF also said there’s insufficient evidence to recommend starting statins for cardiovascular disease (CVD) prevention in patients 76 years or older (JAMA. 2016 Nov;316[19]:1997-2007).
USPSTF now recommends low- to moderate-dose statins for primary prevention in adults 40-75 years old who have at least one CVD risk factor – dyslipidemia, diabetes, hypertension, or smoking – and a 10-year CVD event risk of at least 10% (B grade). It also recommended “selectively” offering low- to moderate-dose statins if patients have a 7.5%-10% risk (C grade). The task force recommends using the online American College of Cardiology/American Heart Association risk calculator.
A B grade denotes that USPSTF recommends the service as one where there is “high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.” With a C grade, the task force recommends that the service be provided subject to professional judgment and patient preferences.
The new advices from USPSTF is consistent with the task force’s 2015 draft proposals, and is based on a pooled analysis of 19 randomized trials in 71,344 adults at risk for CVD but without prior events; 17 of the studies were sponsored at least in part by the companies that make statins. The median duration of follow-up was 3 years. Trials included atorvastatin (Lipitor) and six other statins from 1994-2016.
Few of the 19 trials enrolled patients older than 75 years, so “the balance of benefits and harms of initiating statin use for” primary prevention in elderly adults “cannot be determined.” The task force did not make a recommendation either way, and called for further investigation.
For younger patients, the scales tipped toward benefit when the group found no overall increased risk of cancer, liver damage, diabetes, or cognitive problems with statins for primary prevention. “Although muscle pain, soreness, or weakness are commonly reported with statin use, there were no statistically significant differences between the intervention and control groups for myalgia, myopathy, or rhabdomyolysis,” according to the task force.
Across the 19 trials, statin therapy was associated with a statistically significant 14% reduction in all-cause mortality; 31% reduction in cardiovascular mortality; 29% reduction in stroke; and a 36% reduction in myocardial infarction; 250 patients needed to be treated to prevent one death from any cause after 1-6 years, and 233 to prevent one cardiovascular death after 2-6 years.
The recommendations call for low to moderate doses because that’s what most of the studies used, and there were no clear benefits when trials stratified patients by dose.
USPSTF cautioned that “reliance on a risk calculator ... alone as a basis for prevention may be problematic, given its possible overestimation of risk in some populations” and noted that the benefits “of statin use may be linear according to a patient’s absolute risk level, and any cut points used are only population estimates of benefits.”
The recommendations do not pertain to adults with very high CVD risk, such as those with familial hypercholesterolemia or an LDL level greater than 190mg/dL, since they were excluded from primary prevention trials.
While the USPSTF was careful in its evidence review, “ the limitations of the evidence were not considered sufficiently, given the serious concerns about the harms of statins for primary prevention,” Rita Redberg, MD, and Mitchell Katz, MD, wrote in an editorial accompanying the recommendations.
“USPSTF also did not have access to patient-level data; they had to rely on peer-reviewed published reports,” according to the editorialists. “The actual trial data are largely held by the Cholesterol Treatment Trialists’ Collaboration on behalf of industry sponsors and have not been made available to other researchers, despite multiple requests over many years.” Further, many of the trials were industry sponsored.
Using the USPSTF data, only 2% of patients who take statins for 5 years will avoid a myocardial infarction; virtually all (98%) will not experience any benefit. At the same time, 5%-20% will experience side effects including rhabdomyolysis, cognitive dysfunction, and increased risk of diabetes (JAMA. 2016 Nov;316[19]:1979-81).
There are unintended consequences of widespread statin use in healthy persons, Dr. Redberg and Dr. Katz wrote. People taking statins are more likely to become obese and more sedentary over time, likely because they mistakenly think they do not need to eat a healthy diet and exercise.
The USPSTF analysis was funded by the Agency for Healthcare Research and Quality. Task force lead Kirsten Bibbins-Domingo, MD, PhD, of the University of California, San Francisco, has advised the Institute for Clinical and Economic Review, which is partly funded by industry, on the cost-effectiveness of lipid-lowering drugs. Another member reported comparing how well they worked. The other 15 task force members had no disclosures.