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PIONEER-HF called “practice changing” for acute decompensated heart failure
CHICAGO – Initiation of angiotensin-neprilysin inhibition using sacubitril/valsartan during hospitalization for acute decompensated heart failure, instead of relying upon enalapril, resulted in a substantially greater reduction in N-terminal of the prohormone brain natriuretic peptide concentration and a markedly lower rate of rehospitalization with no safety downside in the PIONEER-HF trial, Eric J. Velazquez, MD, reported at the American Heart Association scientific sessions.
“We believe these results have clinical implications that support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced ejection fraction irrespective of prior ACE inhibitor or ARB [angiotensin II receptor blocker] use or prior diagnosis of heart failure,” said Dr. Velazquez, a professor of medicine and chief of the section of cardiovascular medicine at Yale University, New Haven, Conn., and physician in chief of the Heart and Vascular Center for the Yale-New Haven Health System.
Sacubitril/valsartan (Entresto) has a class I indication for treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) in the AHA/American College of Cardiology guidelines. This strong recommendation is based largely upon the impressive results of the PARADIGM-HF trial, which in ambulatory outpatients demonstrated a lower risk of cardiovascular mortality or hospitalization for heart failure than enalapril (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
However, since patients with acute decompensated heart failure (ADHF) were excluded from PARADIGM-HF, the safety and effectiveness of starting such patients on the drug while hospitalized for acute decompensation was unknown.
PIONEER-HF was carried out to shed light on that issue and thereby address a major unmet need for better treatments for ADHF. Even though this condition accounts for more than 1 million hospitalizations annually in the United States, short-term rehospitalization and mortality rates in affected patients remain unacceptably high at 21% and 12%, respectively. And the standard-of-care treatment – decongestion with intravenous diuretics and hemodynamic support with inotropes and vasodilators – hasn’t changed in nearly half a century, Dr. Velazquez noted.
The trial included 881 patients hospitalized for acute decompensated HFrEF at 129 U.S. centers. The study population was diverse: 36% of participants were black and one-third of subjects had no diagnosis of heart failure prior to their hospitalization. After achieving hemodynamic stabilization, patients were randomized to receive sacubitril/valsartan or enalapril.
Key outcomes
The primary endpoint was change in N-terminal of the prohormone brain natriuretic peptide concentration from baseline to week 8. There was a 25% reduction in the enalapril group and a 45% reduction with sacubitril/valsartan. This translated to a highly significant 29% greater relative risk reduction with sacubitril/valsartan.
More eye opening was the between-group difference in the prespecified composite clinical endpoint comprising death, rehospitalization for heart failure, implantation of a left ventricular assist device, or listing for heart transplant during the 8-week study.
The rate was 16.8% in the enalapril group and 9.3% with sacubitril/valsartan. This worked out to a 46% relative risk reduction, with a number needed to treat of 13.
The composite result was driven by a 44% reduction in risk of heart failure rehospitalization in the sacubitril/valsartan group: 8.0% versus 13.8%. The sacubitril/valsartan group also had a numerically lower mortality rate: 2.3% versus 3.4%, although the number of fatalities was small and this 34% relative risk reduction didn’t achieve statistical significance.
Rates of the key safety outcomes – symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema – didn’t differ between the two study arms. Of interest, however, all six cases of angioedema in the enalapril group occurred in black patients, while the only case in the sacubitril/valsartan group was in a white patient.
PIONEER-HF treatment strategy
Hemodynamic stabilization as a prelude to randomization to sacubitril/valsartan or enalapril required maintaining a systolic blood pressure of at least 100 mm Hg in the previous 6 hours, with no symptomatic hypotension, intensification of intravenous diuretics, or use of intravenous vasodilators during that time period, and no intravenous inotropes in the previous 24 hours.
Enalapril was titrated to a target dose of 10 mg twice daily. Sacubitril/valsartan was titrated to a target dose of 97/103 mg twice daily. Titration was carried out using an algorithm based upon systolic BP. If the SBP was at least 100 and less than 120 mm Hg at baseline, sacubitril/valsartan was initiated at 24/26 mg twice daily, enalapril at 2.5 mg b.i.d. If the SBP at randomization was 120 mm Hg or higher, the initial dosing was sacubitril/valsartan at 49/51 mm Hg b.i.d. or enalapril at 5 mg b.i.d. Up-titration occurred after 1 week, then biweekly through week 8.
PIONEER in perspective
Discussant Larry A. Allen, MD, a heart failure specialist at the University of Colorado at Denver, Aurora, predicted that this will be a practice-changing study.
“There has been a need for a study like PIONEER in heart failure,” he observed. While multiple randomized trials have advanced the treatment of ambulatory HFrEF patients, demonstrating benefit for initiation and intensification of treatment with ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, the treatment of patients with ADHF has remained relatively static, marked by failed trials of once-promising novel agents including tolvaptan, nesiritide, and serelaxin.
“All the data is in ambulatory patients, but the action for the care of heart failure patients actually occurs largely in the hospital. Seventy percent of care provided in the U.S. to patients with heart failure occurs in the hospital setting. These patients are a captive audience at that time, and the transitions from inpatient to outpatient care are fragile,” Dr. Allen said.
He noted that the use of sacubitril/valsartan in routine practice as reflected in national registries has been “extremely low” – less than 15% among eligible patients – despite the drug having been approved more than 3 years ago. One major reason for the low uptake, in his view, is clinical inertia. That should melt away in what he termed “the post-PIONEER world.”
“I think one of the great things about this study is it keeps it simple. We now have a simpler algorithm for inpatient and subsequent outpatient management of heart failure with reduced ejection fraction. It’s easier for us to start with the treatment we want patients to be on, and it’s better for patients, too. Most importantly, this study reinforces the importance and safety of aggressive guideline-directed medical therapy starting from the beginning in most patients,” Dr. Allen said.
The study findings were published simultaneously in the New England Journal of Medicine (2018 Nov 11. doi: 10.1056/NEJMoa1812851).
PIONEER-HF was sponsored by Novartis. Dr. Velazquez reported receiving research grants from and serving as a consultant to that company and others. Dr. Allen reported having no financial conflicts.
CHICAGO – Initiation of angiotensin-neprilysin inhibition using sacubitril/valsartan during hospitalization for acute decompensated heart failure, instead of relying upon enalapril, resulted in a substantially greater reduction in N-terminal of the prohormone brain natriuretic peptide concentration and a markedly lower rate of rehospitalization with no safety downside in the PIONEER-HF trial, Eric J. Velazquez, MD, reported at the American Heart Association scientific sessions.
“We believe these results have clinical implications that support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced ejection fraction irrespective of prior ACE inhibitor or ARB [angiotensin II receptor blocker] use or prior diagnosis of heart failure,” said Dr. Velazquez, a professor of medicine and chief of the section of cardiovascular medicine at Yale University, New Haven, Conn., and physician in chief of the Heart and Vascular Center for the Yale-New Haven Health System.
Sacubitril/valsartan (Entresto) has a class I indication for treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) in the AHA/American College of Cardiology guidelines. This strong recommendation is based largely upon the impressive results of the PARADIGM-HF trial, which in ambulatory outpatients demonstrated a lower risk of cardiovascular mortality or hospitalization for heart failure than enalapril (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
However, since patients with acute decompensated heart failure (ADHF) were excluded from PARADIGM-HF, the safety and effectiveness of starting such patients on the drug while hospitalized for acute decompensation was unknown.
PIONEER-HF was carried out to shed light on that issue and thereby address a major unmet need for better treatments for ADHF. Even though this condition accounts for more than 1 million hospitalizations annually in the United States, short-term rehospitalization and mortality rates in affected patients remain unacceptably high at 21% and 12%, respectively. And the standard-of-care treatment – decongestion with intravenous diuretics and hemodynamic support with inotropes and vasodilators – hasn’t changed in nearly half a century, Dr. Velazquez noted.
The trial included 881 patients hospitalized for acute decompensated HFrEF at 129 U.S. centers. The study population was diverse: 36% of participants were black and one-third of subjects had no diagnosis of heart failure prior to their hospitalization. After achieving hemodynamic stabilization, patients were randomized to receive sacubitril/valsartan or enalapril.
Key outcomes
The primary endpoint was change in N-terminal of the prohormone brain natriuretic peptide concentration from baseline to week 8. There was a 25% reduction in the enalapril group and a 45% reduction with sacubitril/valsartan. This translated to a highly significant 29% greater relative risk reduction with sacubitril/valsartan.
More eye opening was the between-group difference in the prespecified composite clinical endpoint comprising death, rehospitalization for heart failure, implantation of a left ventricular assist device, or listing for heart transplant during the 8-week study.
The rate was 16.8% in the enalapril group and 9.3% with sacubitril/valsartan. This worked out to a 46% relative risk reduction, with a number needed to treat of 13.
The composite result was driven by a 44% reduction in risk of heart failure rehospitalization in the sacubitril/valsartan group: 8.0% versus 13.8%. The sacubitril/valsartan group also had a numerically lower mortality rate: 2.3% versus 3.4%, although the number of fatalities was small and this 34% relative risk reduction didn’t achieve statistical significance.
Rates of the key safety outcomes – symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema – didn’t differ between the two study arms. Of interest, however, all six cases of angioedema in the enalapril group occurred in black patients, while the only case in the sacubitril/valsartan group was in a white patient.
PIONEER-HF treatment strategy
Hemodynamic stabilization as a prelude to randomization to sacubitril/valsartan or enalapril required maintaining a systolic blood pressure of at least 100 mm Hg in the previous 6 hours, with no symptomatic hypotension, intensification of intravenous diuretics, or use of intravenous vasodilators during that time period, and no intravenous inotropes in the previous 24 hours.
Enalapril was titrated to a target dose of 10 mg twice daily. Sacubitril/valsartan was titrated to a target dose of 97/103 mg twice daily. Titration was carried out using an algorithm based upon systolic BP. If the SBP was at least 100 and less than 120 mm Hg at baseline, sacubitril/valsartan was initiated at 24/26 mg twice daily, enalapril at 2.5 mg b.i.d. If the SBP at randomization was 120 mm Hg or higher, the initial dosing was sacubitril/valsartan at 49/51 mm Hg b.i.d. or enalapril at 5 mg b.i.d. Up-titration occurred after 1 week, then biweekly through week 8.
PIONEER in perspective
Discussant Larry A. Allen, MD, a heart failure specialist at the University of Colorado at Denver, Aurora, predicted that this will be a practice-changing study.
“There has been a need for a study like PIONEER in heart failure,” he observed. While multiple randomized trials have advanced the treatment of ambulatory HFrEF patients, demonstrating benefit for initiation and intensification of treatment with ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, the treatment of patients with ADHF has remained relatively static, marked by failed trials of once-promising novel agents including tolvaptan, nesiritide, and serelaxin.
“All the data is in ambulatory patients, but the action for the care of heart failure patients actually occurs largely in the hospital. Seventy percent of care provided in the U.S. to patients with heart failure occurs in the hospital setting. These patients are a captive audience at that time, and the transitions from inpatient to outpatient care are fragile,” Dr. Allen said.
He noted that the use of sacubitril/valsartan in routine practice as reflected in national registries has been “extremely low” – less than 15% among eligible patients – despite the drug having been approved more than 3 years ago. One major reason for the low uptake, in his view, is clinical inertia. That should melt away in what he termed “the post-PIONEER world.”
“I think one of the great things about this study is it keeps it simple. We now have a simpler algorithm for inpatient and subsequent outpatient management of heart failure with reduced ejection fraction. It’s easier for us to start with the treatment we want patients to be on, and it’s better for patients, too. Most importantly, this study reinforces the importance and safety of aggressive guideline-directed medical therapy starting from the beginning in most patients,” Dr. Allen said.
The study findings were published simultaneously in the New England Journal of Medicine (2018 Nov 11. doi: 10.1056/NEJMoa1812851).
PIONEER-HF was sponsored by Novartis. Dr. Velazquez reported receiving research grants from and serving as a consultant to that company and others. Dr. Allen reported having no financial conflicts.
CHICAGO – Initiation of angiotensin-neprilysin inhibition using sacubitril/valsartan during hospitalization for acute decompensated heart failure, instead of relying upon enalapril, resulted in a substantially greater reduction in N-terminal of the prohormone brain natriuretic peptide concentration and a markedly lower rate of rehospitalization with no safety downside in the PIONEER-HF trial, Eric J. Velazquez, MD, reported at the American Heart Association scientific sessions.
“We believe these results have clinical implications that support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced ejection fraction irrespective of prior ACE inhibitor or ARB [angiotensin II receptor blocker] use or prior diagnosis of heart failure,” said Dr. Velazquez, a professor of medicine and chief of the section of cardiovascular medicine at Yale University, New Haven, Conn., and physician in chief of the Heart and Vascular Center for the Yale-New Haven Health System.
Sacubitril/valsartan (Entresto) has a class I indication for treatment of symptomatic heart failure with reduced ejection fraction (HFrEF) in the AHA/American College of Cardiology guidelines. This strong recommendation is based largely upon the impressive results of the PARADIGM-HF trial, which in ambulatory outpatients demonstrated a lower risk of cardiovascular mortality or hospitalization for heart failure than enalapril (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
However, since patients with acute decompensated heart failure (ADHF) were excluded from PARADIGM-HF, the safety and effectiveness of starting such patients on the drug while hospitalized for acute decompensation was unknown.
PIONEER-HF was carried out to shed light on that issue and thereby address a major unmet need for better treatments for ADHF. Even though this condition accounts for more than 1 million hospitalizations annually in the United States, short-term rehospitalization and mortality rates in affected patients remain unacceptably high at 21% and 12%, respectively. And the standard-of-care treatment – decongestion with intravenous diuretics and hemodynamic support with inotropes and vasodilators – hasn’t changed in nearly half a century, Dr. Velazquez noted.
The trial included 881 patients hospitalized for acute decompensated HFrEF at 129 U.S. centers. The study population was diverse: 36% of participants were black and one-third of subjects had no diagnosis of heart failure prior to their hospitalization. After achieving hemodynamic stabilization, patients were randomized to receive sacubitril/valsartan or enalapril.
Key outcomes
The primary endpoint was change in N-terminal of the prohormone brain natriuretic peptide concentration from baseline to week 8. There was a 25% reduction in the enalapril group and a 45% reduction with sacubitril/valsartan. This translated to a highly significant 29% greater relative risk reduction with sacubitril/valsartan.
More eye opening was the between-group difference in the prespecified composite clinical endpoint comprising death, rehospitalization for heart failure, implantation of a left ventricular assist device, or listing for heart transplant during the 8-week study.
The rate was 16.8% in the enalapril group and 9.3% with sacubitril/valsartan. This worked out to a 46% relative risk reduction, with a number needed to treat of 13.
The composite result was driven by a 44% reduction in risk of heart failure rehospitalization in the sacubitril/valsartan group: 8.0% versus 13.8%. The sacubitril/valsartan group also had a numerically lower mortality rate: 2.3% versus 3.4%, although the number of fatalities was small and this 34% relative risk reduction didn’t achieve statistical significance.
Rates of the key safety outcomes – symptomatic hypotension, worsening renal function, hyperkalemia, and angioedema – didn’t differ between the two study arms. Of interest, however, all six cases of angioedema in the enalapril group occurred in black patients, while the only case in the sacubitril/valsartan group was in a white patient.
PIONEER-HF treatment strategy
Hemodynamic stabilization as a prelude to randomization to sacubitril/valsartan or enalapril required maintaining a systolic blood pressure of at least 100 mm Hg in the previous 6 hours, with no symptomatic hypotension, intensification of intravenous diuretics, or use of intravenous vasodilators during that time period, and no intravenous inotropes in the previous 24 hours.
Enalapril was titrated to a target dose of 10 mg twice daily. Sacubitril/valsartan was titrated to a target dose of 97/103 mg twice daily. Titration was carried out using an algorithm based upon systolic BP. If the SBP was at least 100 and less than 120 mm Hg at baseline, sacubitril/valsartan was initiated at 24/26 mg twice daily, enalapril at 2.5 mg b.i.d. If the SBP at randomization was 120 mm Hg or higher, the initial dosing was sacubitril/valsartan at 49/51 mm Hg b.i.d. or enalapril at 5 mg b.i.d. Up-titration occurred after 1 week, then biweekly through week 8.
PIONEER in perspective
Discussant Larry A. Allen, MD, a heart failure specialist at the University of Colorado at Denver, Aurora, predicted that this will be a practice-changing study.
“There has been a need for a study like PIONEER in heart failure,” he observed. While multiple randomized trials have advanced the treatment of ambulatory HFrEF patients, demonstrating benefit for initiation and intensification of treatment with ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, the treatment of patients with ADHF has remained relatively static, marked by failed trials of once-promising novel agents including tolvaptan, nesiritide, and serelaxin.
“All the data is in ambulatory patients, but the action for the care of heart failure patients actually occurs largely in the hospital. Seventy percent of care provided in the U.S. to patients with heart failure occurs in the hospital setting. These patients are a captive audience at that time, and the transitions from inpatient to outpatient care are fragile,” Dr. Allen said.
He noted that the use of sacubitril/valsartan in routine practice as reflected in national registries has been “extremely low” – less than 15% among eligible patients – despite the drug having been approved more than 3 years ago. One major reason for the low uptake, in his view, is clinical inertia. That should melt away in what he termed “the post-PIONEER world.”
“I think one of the great things about this study is it keeps it simple. We now have a simpler algorithm for inpatient and subsequent outpatient management of heart failure with reduced ejection fraction. It’s easier for us to start with the treatment we want patients to be on, and it’s better for patients, too. Most importantly, this study reinforces the importance and safety of aggressive guideline-directed medical therapy starting from the beginning in most patients,” Dr. Allen said.
The study findings were published simultaneously in the New England Journal of Medicine (2018 Nov 11. doi: 10.1056/NEJMoa1812851).
PIONEER-HF was sponsored by Novartis. Dr. Velazquez reported receiving research grants from and serving as a consultant to that company and others. Dr. Allen reported having no financial conflicts.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The rate of rehospitalization for heart failure during the next 2 months after initiation of sacubitril/valsartan during hospitalization for acute decompensated heart failure was 44% lower than with enalapril.
Study details: A randomized, multicenter trial involving 881 patients hospitalized for acute decompensated heart failure.
Disclosures: The PIONEER-HF trial was sponsored by Novartis. The presenter reported receiving research grants from and serving as a consultant to that company and others.
Is prehospital cooling in cardiac arrest ready for prime time?
CHICAGO – Starting transnasal evaporative cooling before patients in cardiac arrest arrive at the hospital has been found to be safe, according to study results presented at the American Heart Association scientific sessions.
The European trial didn’t determine any benefit in the out-of-hospital approach, compared with in-hospital cooling across all study patients. But it did suggest that patients with ventricular fibrillation may achieve higher rates of complete neurologic recovery with the prehospital cooling approach.
“Transnasal evaporative cooling in out-of-hospital cardiac arrest is hemodynamically safe,” said Per Nordberg, MD, PhD, of Karolinska Institute in Stockholm, reporting for the Prehospital Resuscitation Intra-arrest Cooling Effectiveness Survival Study (PRINCESS). “I think this an important message, because guidelines state at the moment that you shouldn’t cool patients outside the hospital. We have shown that this is possible with this new method.”
Transnasal evaporative cooling (RhinoChill) is a noninvasive method that involves cooling of the brain and provides continuous cooling without volume loading.
Centers in seven European countries participated in the trial, randomizing 677 patients to the transnasal, early cooling protocol or standard in-hospital hypothermia. The final analysis evaluated 671 patients: 337 in the intervention group and 334 in the control group. In the intervention group, the transnasal cooling technique was started on patients during CPR in their homes or in the ambulance.
The study found that the rate of 90-day survival with good neurological outcome was 16.6% in the intervention group, compared with 13.5% in the control group, a nonsignificant difference (P = .26).
“However, we could see a signal or a clinical trend toward an improved neurologic outcome in patients with ventricular fibrillation,” Dr. Nordberg said: 34.8% vs. 25.9% for the intervention vs. control populations, a relative, nonsignificant difference of 25% (P = .11).
In terms of complete neurologic recovery, the differences between the treatment groups among those with ventricular fibrillation were even more profound, and significant: 32.6% vs. 20% (P = .002).
Rates of cardiovascular complications – ventricular fibrillation, cardiogenic shock, pulmonary edema, and need for vasopressor – were similar between both groups, although the intervention group had low rates of nasal-related problems such as nose bleed and white nose tip that the control group didn’t have.
Transnasal evaporative cooling “could significantly shorten the time to the target temperature; we have shown that in previous safety feasibility trials,” Dr. Nordberg said. “Now, we can confirm that this method is effective to cool patients with cardiac arrest outside the hospital.”
In his discussion of the trial, Christopher B. Granger, MD, of Duke University, Durham, N.C., noted that the trial was well conducted and that it confirmed that patients can be rapidly cooled during or immediately after cardiac arrest. “But we still do not know if this has meaningful improvement in clinical outcomes,” he cautioned. A strength of the trial is its size, particularly “in a very challenging setting,” Dr. Granger added.
But he questioned the potential for neurological benefit in patients with ventricular fibrillation, particularly because the finding conflicts with a previously published trial (Crit Care Med. 2009 Dec;37[12]:3062-9). “With the primary outcome not significantly reduced, the subgroup analysis may not be reliable,” he said.
What’s needed next? “This trial provides some suggestion of the benefit of early rapid cooling in the ventricular fibrillation population,” Dr. Granger said, “but another trial is needed to justify a widespread change in practice.”
He reported receiving funding from the Swedish Heart-Lung Foundation. The makers of RhinoChill provided the cooling device used in the study at no cost to the participating sites.
Dr. Granger reported financial relationships with AbbVie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic and the Medtronic Foundation, Merck, National Institutes of Health, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex, and Verseon.
SOURCE: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.
CHICAGO – Starting transnasal evaporative cooling before patients in cardiac arrest arrive at the hospital has been found to be safe, according to study results presented at the American Heart Association scientific sessions.
The European trial didn’t determine any benefit in the out-of-hospital approach, compared with in-hospital cooling across all study patients. But it did suggest that patients with ventricular fibrillation may achieve higher rates of complete neurologic recovery with the prehospital cooling approach.
“Transnasal evaporative cooling in out-of-hospital cardiac arrest is hemodynamically safe,” said Per Nordberg, MD, PhD, of Karolinska Institute in Stockholm, reporting for the Prehospital Resuscitation Intra-arrest Cooling Effectiveness Survival Study (PRINCESS). “I think this an important message, because guidelines state at the moment that you shouldn’t cool patients outside the hospital. We have shown that this is possible with this new method.”
Transnasal evaporative cooling (RhinoChill) is a noninvasive method that involves cooling of the brain and provides continuous cooling without volume loading.
Centers in seven European countries participated in the trial, randomizing 677 patients to the transnasal, early cooling protocol or standard in-hospital hypothermia. The final analysis evaluated 671 patients: 337 in the intervention group and 334 in the control group. In the intervention group, the transnasal cooling technique was started on patients during CPR in their homes or in the ambulance.
The study found that the rate of 90-day survival with good neurological outcome was 16.6% in the intervention group, compared with 13.5% in the control group, a nonsignificant difference (P = .26).
“However, we could see a signal or a clinical trend toward an improved neurologic outcome in patients with ventricular fibrillation,” Dr. Nordberg said: 34.8% vs. 25.9% for the intervention vs. control populations, a relative, nonsignificant difference of 25% (P = .11).
In terms of complete neurologic recovery, the differences between the treatment groups among those with ventricular fibrillation were even more profound, and significant: 32.6% vs. 20% (P = .002).
Rates of cardiovascular complications – ventricular fibrillation, cardiogenic shock, pulmonary edema, and need for vasopressor – were similar between both groups, although the intervention group had low rates of nasal-related problems such as nose bleed and white nose tip that the control group didn’t have.
Transnasal evaporative cooling “could significantly shorten the time to the target temperature; we have shown that in previous safety feasibility trials,” Dr. Nordberg said. “Now, we can confirm that this method is effective to cool patients with cardiac arrest outside the hospital.”
In his discussion of the trial, Christopher B. Granger, MD, of Duke University, Durham, N.C., noted that the trial was well conducted and that it confirmed that patients can be rapidly cooled during or immediately after cardiac arrest. “But we still do not know if this has meaningful improvement in clinical outcomes,” he cautioned. A strength of the trial is its size, particularly “in a very challenging setting,” Dr. Granger added.
But he questioned the potential for neurological benefit in patients with ventricular fibrillation, particularly because the finding conflicts with a previously published trial (Crit Care Med. 2009 Dec;37[12]:3062-9). “With the primary outcome not significantly reduced, the subgroup analysis may not be reliable,” he said.
What’s needed next? “This trial provides some suggestion of the benefit of early rapid cooling in the ventricular fibrillation population,” Dr. Granger said, “but another trial is needed to justify a widespread change in practice.”
He reported receiving funding from the Swedish Heart-Lung Foundation. The makers of RhinoChill provided the cooling device used in the study at no cost to the participating sites.
Dr. Granger reported financial relationships with AbbVie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic and the Medtronic Foundation, Merck, National Institutes of Health, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex, and Verseon.
SOURCE: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.
CHICAGO – Starting transnasal evaporative cooling before patients in cardiac arrest arrive at the hospital has been found to be safe, according to study results presented at the American Heart Association scientific sessions.
The European trial didn’t determine any benefit in the out-of-hospital approach, compared with in-hospital cooling across all study patients. But it did suggest that patients with ventricular fibrillation may achieve higher rates of complete neurologic recovery with the prehospital cooling approach.
“Transnasal evaporative cooling in out-of-hospital cardiac arrest is hemodynamically safe,” said Per Nordberg, MD, PhD, of Karolinska Institute in Stockholm, reporting for the Prehospital Resuscitation Intra-arrest Cooling Effectiveness Survival Study (PRINCESS). “I think this an important message, because guidelines state at the moment that you shouldn’t cool patients outside the hospital. We have shown that this is possible with this new method.”
Transnasal evaporative cooling (RhinoChill) is a noninvasive method that involves cooling of the brain and provides continuous cooling without volume loading.
Centers in seven European countries participated in the trial, randomizing 677 patients to the transnasal, early cooling protocol or standard in-hospital hypothermia. The final analysis evaluated 671 patients: 337 in the intervention group and 334 in the control group. In the intervention group, the transnasal cooling technique was started on patients during CPR in their homes or in the ambulance.
The study found that the rate of 90-day survival with good neurological outcome was 16.6% in the intervention group, compared with 13.5% in the control group, a nonsignificant difference (P = .26).
“However, we could see a signal or a clinical trend toward an improved neurologic outcome in patients with ventricular fibrillation,” Dr. Nordberg said: 34.8% vs. 25.9% for the intervention vs. control populations, a relative, nonsignificant difference of 25% (P = .11).
In terms of complete neurologic recovery, the differences between the treatment groups among those with ventricular fibrillation were even more profound, and significant: 32.6% vs. 20% (P = .002).
Rates of cardiovascular complications – ventricular fibrillation, cardiogenic shock, pulmonary edema, and need for vasopressor – were similar between both groups, although the intervention group had low rates of nasal-related problems such as nose bleed and white nose tip that the control group didn’t have.
Transnasal evaporative cooling “could significantly shorten the time to the target temperature; we have shown that in previous safety feasibility trials,” Dr. Nordberg said. “Now, we can confirm that this method is effective to cool patients with cardiac arrest outside the hospital.”
In his discussion of the trial, Christopher B. Granger, MD, of Duke University, Durham, N.C., noted that the trial was well conducted and that it confirmed that patients can be rapidly cooled during or immediately after cardiac arrest. “But we still do not know if this has meaningful improvement in clinical outcomes,” he cautioned. A strength of the trial is its size, particularly “in a very challenging setting,” Dr. Granger added.
But he questioned the potential for neurological benefit in patients with ventricular fibrillation, particularly because the finding conflicts with a previously published trial (Crit Care Med. 2009 Dec;37[12]:3062-9). “With the primary outcome not significantly reduced, the subgroup analysis may not be reliable,” he said.
What’s needed next? “This trial provides some suggestion of the benefit of early rapid cooling in the ventricular fibrillation population,” Dr. Granger said, “but another trial is needed to justify a widespread change in practice.”
He reported receiving funding from the Swedish Heart-Lung Foundation. The makers of RhinoChill provided the cooling device used in the study at no cost to the participating sites.
Dr. Granger reported financial relationships with AbbVie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Medtronic and the Medtronic Foundation, Merck, National Institutes of Health, Novartis, Pfizer, Rho Pharmaceuticals, Sirtex, and Verseon.
SOURCE: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: Prehospital hypothermia therapy for cardiac arrest patients is safe.
Major finding: Ninety-day survival was 16.6% in the intervention group vs. 13.5% in controls (P = .26).
Study details: A randomized clinical trial of 677 patients who had cardiac arrest outside the hospital.
Disclosures: Dr. Nordberg receives funding from the Swedish Heart-Lung Foundation. The makers of RhinoChill provided the cooling device used in the study at no cost to the participating sites.
Source: Nordberg P et al. Abstract 2018-LBCT-18598-AHA.
PIONEER-HF secures place for sacubitril/valsartan in this heart failure doc’s practice
CHICAGO – Dr. Larry A. Allen will now have an easier time of treating hospitalized patients with acute decompensated heart failure because of the results of the PIONEER-HF trial.
That study examined whether in-hospital initiation of sacubitril/valsartan compared to enalapril is safe and effective in ADHF, a treatment that hasn’t been studied well or taken up in clinical practice.
, showed comparable safety, and reduced composite endpoint of death, rehospitalization for heart failure, implantation of a left-ventricular implant device, and need for a transplant by 46%.
Dr. Allen, of the University of Colorado, Denver, was the designated discussant for the PIONEER-HF presentation at the American Heart Association scientific sessions. In an interview, he explained how these results will change his practice as a heart failure specialist. “It simplifies things: I don’t have to start on an old therapy in the hospital, get the patients back in clinic, and switch the over to this newer therapy. I can just start from the beginning with the therapy that I think will be most effective.”
To find out why, watch the complete interview.
CHICAGO – Dr. Larry A. Allen will now have an easier time of treating hospitalized patients with acute decompensated heart failure because of the results of the PIONEER-HF trial.
That study examined whether in-hospital initiation of sacubitril/valsartan compared to enalapril is safe and effective in ADHF, a treatment that hasn’t been studied well or taken up in clinical practice.
, showed comparable safety, and reduced composite endpoint of death, rehospitalization for heart failure, implantation of a left-ventricular implant device, and need for a transplant by 46%.
Dr. Allen, of the University of Colorado, Denver, was the designated discussant for the PIONEER-HF presentation at the American Heart Association scientific sessions. In an interview, he explained how these results will change his practice as a heart failure specialist. “It simplifies things: I don’t have to start on an old therapy in the hospital, get the patients back in clinic, and switch the over to this newer therapy. I can just start from the beginning with the therapy that I think will be most effective.”
To find out why, watch the complete interview.
CHICAGO – Dr. Larry A. Allen will now have an easier time of treating hospitalized patients with acute decompensated heart failure because of the results of the PIONEER-HF trial.
That study examined whether in-hospital initiation of sacubitril/valsartan compared to enalapril is safe and effective in ADHF, a treatment that hasn’t been studied well or taken up in clinical practice.
, showed comparable safety, and reduced composite endpoint of death, rehospitalization for heart failure, implantation of a left-ventricular implant device, and need for a transplant by 46%.
Dr. Allen, of the University of Colorado, Denver, was the designated discussant for the PIONEER-HF presentation at the American Heart Association scientific sessions. In an interview, he explained how these results will change his practice as a heart failure specialist. “It simplifies things: I don’t have to start on an old therapy in the hospital, get the patients back in clinic, and switch the over to this newer therapy. I can just start from the beginning with the therapy that I think will be most effective.”
To find out why, watch the complete interview.
REPORTING FROM AHA 2018
Revised U.S. cholesterol guidelines promote personalized risk assessment
CHICAGO – The latest cholesterol management guideline for U.S. practice has a core treatment principal that propels the field from its long-held focus on “know your cholesterol number,” that then became “know your risk” with the 2013 guideline, to what is now “personalize your risk.”
“The new guideline put special focus not just on risk, but on risk assessment that uses ‘enhancing factors’ to help patients understand their risk in a personal way and decide whether statin treatment is right for them” Neil J. Stone, MD, said at the American Heart Association scientific sessions.
Other novel features of the 2018 edition of the cholesterol management guideline included: specification of the role for two types of drugs other than statins – ezetimibe and PCSK9 inhibitors (including mention of the cost-value consideration when prescribing an expensive PCSK9 inhibitor); inclusion of coronary artery calcium (CAC) score assessment for patients with intermediate risk who are unsure whether statin treatment is right for them; and acknowledgment that nonfasting measurement of blood cholesterol levels is fine for most screening circumstances.
“Nonfasting is okay for many situations,” said Dr. Stone, a professor of medicine at Northwestern University here, and vice-chair of the writing panel for the guidelines, released by the American College of Cardiology, the American Heart Association, and 10 additional endorsing societies (J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.11.003)
But among the changes in the 2018 guideline that distinguish it from the preceding, 2013 version (Circulation. 2014 June 24;129[25, suppl 2]:S1-S45), the expanded approach to risk assessment in the primary-prevention setting stood out as the biggest shift.
“In 2013 we said calculate a person’s risk” for atherosclerotic cardiovascular disease. “Now that is much more fleshed out,” said Donald M. Lloyd-Jones, MD, a member of the guideline-writing group who helped develop the risk assessment tools used by the guideline.*
“The risk equations now are the same as we introduced in 2013,” he noted, and research done by Dr. Lloyd-Jones and others since that introduction showed that the “pooled cohort equations” are “well calibrated” for estimating a person’s 10-year risk for a cardiovascular event, especially at a risk level around 7.5%, which serves as the threshold for identifying a person with enough risk to warrant statin treatment. “But there are subgroups where the risk calculator clearly over- or under-estimates risk,” and that’s why the new guideline introduced the concept of risk enhancers--additional features not included in the basic risk calculation that enhance risk: family history; metabolic syndrome; chronic kidney disease; chronic inflammatory diseases such as psoriasis, rheumatoid arthritis, or HIV infection; a history of premature menopause or preeclampsia, certain ethnicity, or high levels of Lp(a) or apolipoprotein B.
“We didn’t need new risk scores; we needed to understand how to use the scores better, and the new guideline goes a long way toward helping clinicians do that,” Dr. Lloyd-Jones said in an interview.
Another aspect of this new, more nuanced approach to individualized risk assessment is the introduction of the CAC score as a possible tie breaker when a person who is otherwise a candidate for statin treatment for primary prevention is unsure about committing to possibly decades of daily statin treatment.
The guideline does not endorse obtaining a person’s CAC score for everyone as screening, stressed Dr. Stone, but this score, obtained by noncontrast CT with a radiation dose of about 1 mSv – comparable to a mammography exam, received a IIa rating” – is reasonable” for helping patients decide. Dr. Stone and others cited the importance of a CAC score of zero for patients on the fence for statin treatment as a strong indicator for many people that they can safely defer treatment.
As a result of this new endorsement for selectively obtaining CAC scores, “I think the number of tests will increase, probably fairly substantially,” said Dr. Lloyd-Jones, professor and chair of preventive medicine at Northwestern University here. He also expressed hope that this acknowledgment of an evidenced-based role for selected CAC score imaging may prompt health insurers to start coving this expense, something they don’t now do. Patients generally pay out-of-pocket from $50 to $300 for CAC score imaging. “I hope they will start paying for this,” Dr. Lloyd-Jones said.
The guidelines also deal, at least in passing, with another financial issue that has loomed large for cholesterol treatment, the role of the notoriously expensive PCSK9 inhibitors, alirocumab (Praluent) and evolocumab (Repatha). For secondary prevention patients or for patients with familial hypercholesterolemia who do not reach their LDL cholesterol goal on statin treatment alone, the guideline recommended treatment first with generic ezetimibe. If the goal remains elusive, the next step is prescribing a PCSK9 inhibitor. The guideline also noted the poor cost-benefit ratio for the PCSK9 inhibitors at the U.S. list prices that existed in mid-2018, about $14,000 a year.
The guideline writers noted that this is one of the first times that cost considerations found their way into cardiology guidelines. Clinicians “need to be attuned to prescribing PCSK9 inhibitors only in those settings when it provides good value to patients,” explained Mark A. Hlatky, MD, a professor of medicine, cardiologist, and health policy specialist at Stanford (Calif.) University. The guideline “focuses on patient selection for PCSK9 inhibitors, limiting it to patients who get the most benefit,” said Dr. Hlatky, another member of the writing panel.
Although 10 medical groups joined the American College of Cardiology and American Heart Association in endorsing the guideline, conspicuously absent were the two largest U.S. societies representing primary care physicians, the American College of Physicians and American Academy of Family Practitioners. The guideline’s organizers invited both these societies to participate in the process and they declined, said Sidney C. Smith, Jr., MD, a member of the guideline committee.
Dr. Stone and Dr. Lloyd-Jones had no financial disclosures. The writing committee members’ disclosures can be found at jaccjacc.acc.org/Clinical_Document/Cholesterol_GL_Au_Comp_RWI.pdf.
*Correction, 11/13/18: An earlier version of this article misstated the name of Dr. Donald M. Lloyd-Jones.
SOURCE: AHA 2018 and Grundy S et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.11.003.
CHICAGO – The latest cholesterol management guideline for U.S. practice has a core treatment principal that propels the field from its long-held focus on “know your cholesterol number,” that then became “know your risk” with the 2013 guideline, to what is now “personalize your risk.”
“The new guideline put special focus not just on risk, but on risk assessment that uses ‘enhancing factors’ to help patients understand their risk in a personal way and decide whether statin treatment is right for them” Neil J. Stone, MD, said at the American Heart Association scientific sessions.
Other novel features of the 2018 edition of the cholesterol management guideline included: specification of the role for two types of drugs other than statins – ezetimibe and PCSK9 inhibitors (including mention of the cost-value consideration when prescribing an expensive PCSK9 inhibitor); inclusion of coronary artery calcium (CAC) score assessment for patients with intermediate risk who are unsure whether statin treatment is right for them; and acknowledgment that nonfasting measurement of blood cholesterol levels is fine for most screening circumstances.
“Nonfasting is okay for many situations,” said Dr. Stone, a professor of medicine at Northwestern University here, and vice-chair of the writing panel for the guidelines, released by the American College of Cardiology, the American Heart Association, and 10 additional endorsing societies (J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.11.003)
But among the changes in the 2018 guideline that distinguish it from the preceding, 2013 version (Circulation. 2014 June 24;129[25, suppl 2]:S1-S45), the expanded approach to risk assessment in the primary-prevention setting stood out as the biggest shift.
“In 2013 we said calculate a person’s risk” for atherosclerotic cardiovascular disease. “Now that is much more fleshed out,” said Donald M. Lloyd-Jones, MD, a member of the guideline-writing group who helped develop the risk assessment tools used by the guideline.*
“The risk equations now are the same as we introduced in 2013,” he noted, and research done by Dr. Lloyd-Jones and others since that introduction showed that the “pooled cohort equations” are “well calibrated” for estimating a person’s 10-year risk for a cardiovascular event, especially at a risk level around 7.5%, which serves as the threshold for identifying a person with enough risk to warrant statin treatment. “But there are subgroups where the risk calculator clearly over- or under-estimates risk,” and that’s why the new guideline introduced the concept of risk enhancers--additional features not included in the basic risk calculation that enhance risk: family history; metabolic syndrome; chronic kidney disease; chronic inflammatory diseases such as psoriasis, rheumatoid arthritis, or HIV infection; a history of premature menopause or preeclampsia, certain ethnicity, or high levels of Lp(a) or apolipoprotein B.
“We didn’t need new risk scores; we needed to understand how to use the scores better, and the new guideline goes a long way toward helping clinicians do that,” Dr. Lloyd-Jones said in an interview.
Another aspect of this new, more nuanced approach to individualized risk assessment is the introduction of the CAC score as a possible tie breaker when a person who is otherwise a candidate for statin treatment for primary prevention is unsure about committing to possibly decades of daily statin treatment.
The guideline does not endorse obtaining a person’s CAC score for everyone as screening, stressed Dr. Stone, but this score, obtained by noncontrast CT with a radiation dose of about 1 mSv – comparable to a mammography exam, received a IIa rating” – is reasonable” for helping patients decide. Dr. Stone and others cited the importance of a CAC score of zero for patients on the fence for statin treatment as a strong indicator for many people that they can safely defer treatment.
As a result of this new endorsement for selectively obtaining CAC scores, “I think the number of tests will increase, probably fairly substantially,” said Dr. Lloyd-Jones, professor and chair of preventive medicine at Northwestern University here. He also expressed hope that this acknowledgment of an evidenced-based role for selected CAC score imaging may prompt health insurers to start coving this expense, something they don’t now do. Patients generally pay out-of-pocket from $50 to $300 for CAC score imaging. “I hope they will start paying for this,” Dr. Lloyd-Jones said.
The guidelines also deal, at least in passing, with another financial issue that has loomed large for cholesterol treatment, the role of the notoriously expensive PCSK9 inhibitors, alirocumab (Praluent) and evolocumab (Repatha). For secondary prevention patients or for patients with familial hypercholesterolemia who do not reach their LDL cholesterol goal on statin treatment alone, the guideline recommended treatment first with generic ezetimibe. If the goal remains elusive, the next step is prescribing a PCSK9 inhibitor. The guideline also noted the poor cost-benefit ratio for the PCSK9 inhibitors at the U.S. list prices that existed in mid-2018, about $14,000 a year.
The guideline writers noted that this is one of the first times that cost considerations found their way into cardiology guidelines. Clinicians “need to be attuned to prescribing PCSK9 inhibitors only in those settings when it provides good value to patients,” explained Mark A. Hlatky, MD, a professor of medicine, cardiologist, and health policy specialist at Stanford (Calif.) University. The guideline “focuses on patient selection for PCSK9 inhibitors, limiting it to patients who get the most benefit,” said Dr. Hlatky, another member of the writing panel.
Although 10 medical groups joined the American College of Cardiology and American Heart Association in endorsing the guideline, conspicuously absent were the two largest U.S. societies representing primary care physicians, the American College of Physicians and American Academy of Family Practitioners. The guideline’s organizers invited both these societies to participate in the process and they declined, said Sidney C. Smith, Jr., MD, a member of the guideline committee.
Dr. Stone and Dr. Lloyd-Jones had no financial disclosures. The writing committee members’ disclosures can be found at jaccjacc.acc.org/Clinical_Document/Cholesterol_GL_Au_Comp_RWI.pdf.
*Correction, 11/13/18: An earlier version of this article misstated the name of Dr. Donald M. Lloyd-Jones.
SOURCE: AHA 2018 and Grundy S et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.11.003.
CHICAGO – The latest cholesterol management guideline for U.S. practice has a core treatment principal that propels the field from its long-held focus on “know your cholesterol number,” that then became “know your risk” with the 2013 guideline, to what is now “personalize your risk.”
“The new guideline put special focus not just on risk, but on risk assessment that uses ‘enhancing factors’ to help patients understand their risk in a personal way and decide whether statin treatment is right for them” Neil J. Stone, MD, said at the American Heart Association scientific sessions.
Other novel features of the 2018 edition of the cholesterol management guideline included: specification of the role for two types of drugs other than statins – ezetimibe and PCSK9 inhibitors (including mention of the cost-value consideration when prescribing an expensive PCSK9 inhibitor); inclusion of coronary artery calcium (CAC) score assessment for patients with intermediate risk who are unsure whether statin treatment is right for them; and acknowledgment that nonfasting measurement of blood cholesterol levels is fine for most screening circumstances.
“Nonfasting is okay for many situations,” said Dr. Stone, a professor of medicine at Northwestern University here, and vice-chair of the writing panel for the guidelines, released by the American College of Cardiology, the American Heart Association, and 10 additional endorsing societies (J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.11.003)
But among the changes in the 2018 guideline that distinguish it from the preceding, 2013 version (Circulation. 2014 June 24;129[25, suppl 2]:S1-S45), the expanded approach to risk assessment in the primary-prevention setting stood out as the biggest shift.
“In 2013 we said calculate a person’s risk” for atherosclerotic cardiovascular disease. “Now that is much more fleshed out,” said Donald M. Lloyd-Jones, MD, a member of the guideline-writing group who helped develop the risk assessment tools used by the guideline.*
“The risk equations now are the same as we introduced in 2013,” he noted, and research done by Dr. Lloyd-Jones and others since that introduction showed that the “pooled cohort equations” are “well calibrated” for estimating a person’s 10-year risk for a cardiovascular event, especially at a risk level around 7.5%, which serves as the threshold for identifying a person with enough risk to warrant statin treatment. “But there are subgroups where the risk calculator clearly over- or under-estimates risk,” and that’s why the new guideline introduced the concept of risk enhancers--additional features not included in the basic risk calculation that enhance risk: family history; metabolic syndrome; chronic kidney disease; chronic inflammatory diseases such as psoriasis, rheumatoid arthritis, or HIV infection; a history of premature menopause or preeclampsia, certain ethnicity, or high levels of Lp(a) or apolipoprotein B.
“We didn’t need new risk scores; we needed to understand how to use the scores better, and the new guideline goes a long way toward helping clinicians do that,” Dr. Lloyd-Jones said in an interview.
Another aspect of this new, more nuanced approach to individualized risk assessment is the introduction of the CAC score as a possible tie breaker when a person who is otherwise a candidate for statin treatment for primary prevention is unsure about committing to possibly decades of daily statin treatment.
The guideline does not endorse obtaining a person’s CAC score for everyone as screening, stressed Dr. Stone, but this score, obtained by noncontrast CT with a radiation dose of about 1 mSv – comparable to a mammography exam, received a IIa rating” – is reasonable” for helping patients decide. Dr. Stone and others cited the importance of a CAC score of zero for patients on the fence for statin treatment as a strong indicator for many people that they can safely defer treatment.
As a result of this new endorsement for selectively obtaining CAC scores, “I think the number of tests will increase, probably fairly substantially,” said Dr. Lloyd-Jones, professor and chair of preventive medicine at Northwestern University here. He also expressed hope that this acknowledgment of an evidenced-based role for selected CAC score imaging may prompt health insurers to start coving this expense, something they don’t now do. Patients generally pay out-of-pocket from $50 to $300 for CAC score imaging. “I hope they will start paying for this,” Dr. Lloyd-Jones said.
The guidelines also deal, at least in passing, with another financial issue that has loomed large for cholesterol treatment, the role of the notoriously expensive PCSK9 inhibitors, alirocumab (Praluent) and evolocumab (Repatha). For secondary prevention patients or for patients with familial hypercholesterolemia who do not reach their LDL cholesterol goal on statin treatment alone, the guideline recommended treatment first with generic ezetimibe. If the goal remains elusive, the next step is prescribing a PCSK9 inhibitor. The guideline also noted the poor cost-benefit ratio for the PCSK9 inhibitors at the U.S. list prices that existed in mid-2018, about $14,000 a year.
The guideline writers noted that this is one of the first times that cost considerations found their way into cardiology guidelines. Clinicians “need to be attuned to prescribing PCSK9 inhibitors only in those settings when it provides good value to patients,” explained Mark A. Hlatky, MD, a professor of medicine, cardiologist, and health policy specialist at Stanford (Calif.) University. The guideline “focuses on patient selection for PCSK9 inhibitors, limiting it to patients who get the most benefit,” said Dr. Hlatky, another member of the writing panel.
Although 10 medical groups joined the American College of Cardiology and American Heart Association in endorsing the guideline, conspicuously absent were the two largest U.S. societies representing primary care physicians, the American College of Physicians and American Academy of Family Practitioners. The guideline’s organizers invited both these societies to participate in the process and they declined, said Sidney C. Smith, Jr., MD, a member of the guideline committee.
Dr. Stone and Dr. Lloyd-Jones had no financial disclosures. The writing committee members’ disclosures can be found at jaccjacc.acc.org/Clinical_Document/Cholesterol_GL_Au_Comp_RWI.pdf.
*Correction, 11/13/18: An earlier version of this article misstated the name of Dr. Donald M. Lloyd-Jones.
SOURCE: AHA 2018 and Grundy S et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.11.003.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Vitamin D, fish oil circling the drain for primary prevention
CHICAGO – In what will surely come as a major disappointment to many millions of nutritional supplement enthusiasts, the daily use of vitamin D3 and/or omega-3 fatty acid capsules for a median of 5.3 years did not result in a lower incidence of invasive cancers or cardiovascular events than placebo in nearly 26,000 average-risk Americans who participated in the VITAL trial, JoAnn E. Manson, MD, reported at the American Heart Association scientific sessions.
VITAL (the Vitamin D and Omega-3 Trial) featured a 2x2 factorial design in which 25,871 subjects, including 5,016 black participants, were randomized in double-blind fashion to either vitamin D3, also known as cholecalciferol, at 2,000 IU/day and/or 1 g/day of omega-3 fatty acid, or placebo. The men had to be at least 50 years old, the women 55, and none had a baseline history of cardiovascular disease or invasive cancer. Their mean age was 67. Study pill adherence exceeded 83% over the course of 5.3 years.
This major study, funded by the National Institutes of Health, was designed to answer the question of whether two relatively inexpensive supplements with plausible mechanisms of potential benefit could be harnessed as effective agents for primary prevention of the two leading causes of death in the United States.
The simple answer turned out to be no. Invasive cancer of any type occurred in 793 patients in the vitamin D group and 824 placebo-treated controls, for a nonsignificant hazard ratio of 0.96. Major cardiovascular events – a composite of MI, stroke, or cardiovascular mortality – occurred in 396 and 409 patients, respectively, for a hazard ratio of 0.97.
Similarly, invasive cancer was diagnosed in 820 subjects in the omega-3 fatty acid group and 797 controls, while major cardiovascular events occurred in 386 patients taking fish oil and 419 on placebo. Again, the between-group differences were nonsignificant, noted Dr. Manson, chief of the division of preventive medicine and Brigham and Women’s Hospital and professor of medicine and women’s health at Harvard Medical School, Boston.
Buried within this vast data set were a few intriguing bright spots. For example, the prespecified secondary endpoint of total MIs was significantly reduced by 28% in patients using omega-3 fatty acid compared with placebo. In nonprespecified exploratory analyses, the risk of PCI was decreased by 22% in the omega-3 fatty acid group and total coronary heart disease events - a composite of MI, revascularization, or death due to coronary heart disease – was reduced by 17%. In black subjects, the use of omega-3 fatty acids reduced the risk of MIs by 77%.
Dietary fish consumption interacted with the effects of omega-3 supplementation. Subjects in the omega-3 group who ate less than the median 1.5 servings of fish per week had a statistically significant 19% relative risk reduction in major cardiovascular events and 40% fewer MIs than with placebo. In contrast, subjects who ate 1.5 or more fish servings derived no benefit from omega-3 supplements.
The most noteworthy finding in the vitamin D group was that, after excluding the first 2 years of follow-up, they had a 25% reduction in cancer mortality compared with controls.
However, Dr. Manson cautioned that these subgroup analyses should be interpreted with caution.
Discussant Jane Armitage, MD, went further, emphasizing that the primary study endpoints of invasive cancer and major cardiovascular events were negative for both vitamin D and fish oil.
“To drill down into the secondary endpoints is of some concern because I think there is often the risk of getting spurious results,” said Dr. Armitage, professor of clinical trials and epidemiology at the University of Oxford (England).
“I think the primary result that universal supplementation with vitamin D in a primary prevention population has not been shown to be beneficial is a robust result, and these other results need to be seen as hypothesis-generating,” according to Dr. Armitage.
She added that she thinks the VITAL trial is practice-changing.
“I think the general recommendation to take vitamin D is not supported by this paper,” she said.
The same holds true for omega-3 fatty acid supplementation based on the VITAL results, Dr. Armitage continued. She noted that the VITAL findings are consistent with a recent meta-analysis of 10 large trials of omega-3 which found no benefit in nearly 78,000 high-cardiovascular-risk subjects (JAMA Cardiol. 2018 Mar 1;3[3]:225-234).
VITAL vs. REDUCE-IT
The negative results in VITAL stood in sharp contrast to the findings of the REDUCE-IT trial, presented at the same late-breaker session by Deepak Bhatt, MD, of Harvard Medical School. In REDUCE-IT, icosapent ethyl, another fish-derived product, reduced major cardiovascular events by 25% in a study of more than 8,000 high-cardiovascular-risk patients with elevated triglycerides.
Why the difference in outcomes? Among the proposed explanations were that participants in VITAL got 1 g/day of omega-3 while those in REDUCE-IT got a much higher dose of 4 g/day of iscosapent ethyl, the REDUCE-IT population was at much higher cardiovascular risk, and icosapent ethyl has a mechanism of action that’s distinct from that of conventional fish oil products.
Dr. Manson said numerous ancillary studies from VITAL are underway and will begin appearing soon. These will look at the impact of vitamin D and fish oil supplementation on cognitive function, hypertension, atrial fibrillation, autoimmune disorders, bone health, depression, kidney disease, and other issues.
Simultaneously with her presentation at the AHA scientific sessions, the VITAL results were published online (N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa1809944 and 10.1056/NEJMoa1811403).
The study was sponsored by the National Institutes of Health. The presenter reported having no financial conflicts.
bjancin@mdedge.com
SOURCE: Manson JE. AHA Abstr. #19539
CHICAGO – In what will surely come as a major disappointment to many millions of nutritional supplement enthusiasts, the daily use of vitamin D3 and/or omega-3 fatty acid capsules for a median of 5.3 years did not result in a lower incidence of invasive cancers or cardiovascular events than placebo in nearly 26,000 average-risk Americans who participated in the VITAL trial, JoAnn E. Manson, MD, reported at the American Heart Association scientific sessions.
VITAL (the Vitamin D and Omega-3 Trial) featured a 2x2 factorial design in which 25,871 subjects, including 5,016 black participants, were randomized in double-blind fashion to either vitamin D3, also known as cholecalciferol, at 2,000 IU/day and/or 1 g/day of omega-3 fatty acid, or placebo. The men had to be at least 50 years old, the women 55, and none had a baseline history of cardiovascular disease or invasive cancer. Their mean age was 67. Study pill adherence exceeded 83% over the course of 5.3 years.
This major study, funded by the National Institutes of Health, was designed to answer the question of whether two relatively inexpensive supplements with plausible mechanisms of potential benefit could be harnessed as effective agents for primary prevention of the two leading causes of death in the United States.
The simple answer turned out to be no. Invasive cancer of any type occurred in 793 patients in the vitamin D group and 824 placebo-treated controls, for a nonsignificant hazard ratio of 0.96. Major cardiovascular events – a composite of MI, stroke, or cardiovascular mortality – occurred in 396 and 409 patients, respectively, for a hazard ratio of 0.97.
Similarly, invasive cancer was diagnosed in 820 subjects in the omega-3 fatty acid group and 797 controls, while major cardiovascular events occurred in 386 patients taking fish oil and 419 on placebo. Again, the between-group differences were nonsignificant, noted Dr. Manson, chief of the division of preventive medicine and Brigham and Women’s Hospital and professor of medicine and women’s health at Harvard Medical School, Boston.
Buried within this vast data set were a few intriguing bright spots. For example, the prespecified secondary endpoint of total MIs was significantly reduced by 28% in patients using omega-3 fatty acid compared with placebo. In nonprespecified exploratory analyses, the risk of PCI was decreased by 22% in the omega-3 fatty acid group and total coronary heart disease events - a composite of MI, revascularization, or death due to coronary heart disease – was reduced by 17%. In black subjects, the use of omega-3 fatty acids reduced the risk of MIs by 77%.
Dietary fish consumption interacted with the effects of omega-3 supplementation. Subjects in the omega-3 group who ate less than the median 1.5 servings of fish per week had a statistically significant 19% relative risk reduction in major cardiovascular events and 40% fewer MIs than with placebo. In contrast, subjects who ate 1.5 or more fish servings derived no benefit from omega-3 supplements.
The most noteworthy finding in the vitamin D group was that, after excluding the first 2 years of follow-up, they had a 25% reduction in cancer mortality compared with controls.
However, Dr. Manson cautioned that these subgroup analyses should be interpreted with caution.
Discussant Jane Armitage, MD, went further, emphasizing that the primary study endpoints of invasive cancer and major cardiovascular events were negative for both vitamin D and fish oil.
“To drill down into the secondary endpoints is of some concern because I think there is often the risk of getting spurious results,” said Dr. Armitage, professor of clinical trials and epidemiology at the University of Oxford (England).
“I think the primary result that universal supplementation with vitamin D in a primary prevention population has not been shown to be beneficial is a robust result, and these other results need to be seen as hypothesis-generating,” according to Dr. Armitage.
She added that she thinks the VITAL trial is practice-changing.
“I think the general recommendation to take vitamin D is not supported by this paper,” she said.
The same holds true for omega-3 fatty acid supplementation based on the VITAL results, Dr. Armitage continued. She noted that the VITAL findings are consistent with a recent meta-analysis of 10 large trials of omega-3 which found no benefit in nearly 78,000 high-cardiovascular-risk subjects (JAMA Cardiol. 2018 Mar 1;3[3]:225-234).
VITAL vs. REDUCE-IT
The negative results in VITAL stood in sharp contrast to the findings of the REDUCE-IT trial, presented at the same late-breaker session by Deepak Bhatt, MD, of Harvard Medical School. In REDUCE-IT, icosapent ethyl, another fish-derived product, reduced major cardiovascular events by 25% in a study of more than 8,000 high-cardiovascular-risk patients with elevated triglycerides.
Why the difference in outcomes? Among the proposed explanations were that participants in VITAL got 1 g/day of omega-3 while those in REDUCE-IT got a much higher dose of 4 g/day of iscosapent ethyl, the REDUCE-IT population was at much higher cardiovascular risk, and icosapent ethyl has a mechanism of action that’s distinct from that of conventional fish oil products.
Dr. Manson said numerous ancillary studies from VITAL are underway and will begin appearing soon. These will look at the impact of vitamin D and fish oil supplementation on cognitive function, hypertension, atrial fibrillation, autoimmune disorders, bone health, depression, kidney disease, and other issues.
Simultaneously with her presentation at the AHA scientific sessions, the VITAL results were published online (N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa1809944 and 10.1056/NEJMoa1811403).
The study was sponsored by the National Institutes of Health. The presenter reported having no financial conflicts.
bjancin@mdedge.com
SOURCE: Manson JE. AHA Abstr. #19539
CHICAGO – In what will surely come as a major disappointment to many millions of nutritional supplement enthusiasts, the daily use of vitamin D3 and/or omega-3 fatty acid capsules for a median of 5.3 years did not result in a lower incidence of invasive cancers or cardiovascular events than placebo in nearly 26,000 average-risk Americans who participated in the VITAL trial, JoAnn E. Manson, MD, reported at the American Heart Association scientific sessions.
VITAL (the Vitamin D and Omega-3 Trial) featured a 2x2 factorial design in which 25,871 subjects, including 5,016 black participants, were randomized in double-blind fashion to either vitamin D3, also known as cholecalciferol, at 2,000 IU/day and/or 1 g/day of omega-3 fatty acid, or placebo. The men had to be at least 50 years old, the women 55, and none had a baseline history of cardiovascular disease or invasive cancer. Their mean age was 67. Study pill adherence exceeded 83% over the course of 5.3 years.
This major study, funded by the National Institutes of Health, was designed to answer the question of whether two relatively inexpensive supplements with plausible mechanisms of potential benefit could be harnessed as effective agents for primary prevention of the two leading causes of death in the United States.
The simple answer turned out to be no. Invasive cancer of any type occurred in 793 patients in the vitamin D group and 824 placebo-treated controls, for a nonsignificant hazard ratio of 0.96. Major cardiovascular events – a composite of MI, stroke, or cardiovascular mortality – occurred in 396 and 409 patients, respectively, for a hazard ratio of 0.97.
Similarly, invasive cancer was diagnosed in 820 subjects in the omega-3 fatty acid group and 797 controls, while major cardiovascular events occurred in 386 patients taking fish oil and 419 on placebo. Again, the between-group differences were nonsignificant, noted Dr. Manson, chief of the division of preventive medicine and Brigham and Women’s Hospital and professor of medicine and women’s health at Harvard Medical School, Boston.
Buried within this vast data set were a few intriguing bright spots. For example, the prespecified secondary endpoint of total MIs was significantly reduced by 28% in patients using omega-3 fatty acid compared with placebo. In nonprespecified exploratory analyses, the risk of PCI was decreased by 22% in the omega-3 fatty acid group and total coronary heart disease events - a composite of MI, revascularization, or death due to coronary heart disease – was reduced by 17%. In black subjects, the use of omega-3 fatty acids reduced the risk of MIs by 77%.
Dietary fish consumption interacted with the effects of omega-3 supplementation. Subjects in the omega-3 group who ate less than the median 1.5 servings of fish per week had a statistically significant 19% relative risk reduction in major cardiovascular events and 40% fewer MIs than with placebo. In contrast, subjects who ate 1.5 or more fish servings derived no benefit from omega-3 supplements.
The most noteworthy finding in the vitamin D group was that, after excluding the first 2 years of follow-up, they had a 25% reduction in cancer mortality compared with controls.
However, Dr. Manson cautioned that these subgroup analyses should be interpreted with caution.
Discussant Jane Armitage, MD, went further, emphasizing that the primary study endpoints of invasive cancer and major cardiovascular events were negative for both vitamin D and fish oil.
“To drill down into the secondary endpoints is of some concern because I think there is often the risk of getting spurious results,” said Dr. Armitage, professor of clinical trials and epidemiology at the University of Oxford (England).
“I think the primary result that universal supplementation with vitamin D in a primary prevention population has not been shown to be beneficial is a robust result, and these other results need to be seen as hypothesis-generating,” according to Dr. Armitage.
She added that she thinks the VITAL trial is practice-changing.
“I think the general recommendation to take vitamin D is not supported by this paper,” she said.
The same holds true for omega-3 fatty acid supplementation based on the VITAL results, Dr. Armitage continued. She noted that the VITAL findings are consistent with a recent meta-analysis of 10 large trials of omega-3 which found no benefit in nearly 78,000 high-cardiovascular-risk subjects (JAMA Cardiol. 2018 Mar 1;3[3]:225-234).
VITAL vs. REDUCE-IT
The negative results in VITAL stood in sharp contrast to the findings of the REDUCE-IT trial, presented at the same late-breaker session by Deepak Bhatt, MD, of Harvard Medical School. In REDUCE-IT, icosapent ethyl, another fish-derived product, reduced major cardiovascular events by 25% in a study of more than 8,000 high-cardiovascular-risk patients with elevated triglycerides.
Why the difference in outcomes? Among the proposed explanations were that participants in VITAL got 1 g/day of omega-3 while those in REDUCE-IT got a much higher dose of 4 g/day of iscosapent ethyl, the REDUCE-IT population was at much higher cardiovascular risk, and icosapent ethyl has a mechanism of action that’s distinct from that of conventional fish oil products.
Dr. Manson said numerous ancillary studies from VITAL are underway and will begin appearing soon. These will look at the impact of vitamin D and fish oil supplementation on cognitive function, hypertension, atrial fibrillation, autoimmune disorders, bone health, depression, kidney disease, and other issues.
Simultaneously with her presentation at the AHA scientific sessions, the VITAL results were published online (N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa1809944 and 10.1056/NEJMoa1811403).
The study was sponsored by the National Institutes of Health. The presenter reported having no financial conflicts.
bjancin@mdedge.com
SOURCE: Manson JE. AHA Abstr. #19539
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The primary cancer and cardiovascular outcomes were unaffected by either supplement in the VITAL study.
Study details: VITAL was a randomized, double-blind trial in which nearly 26,000 middle-age or older Americans at average cardiovascular risk were assigned to vitamin D3, omega-3 fatty acid, and placebo in a 2x2 factorial design and followed prospectively for a median of 5.3 years.
Disclosures: The study was sponsored by the National Institutes of Health. The presenter reported having no financial conflicts.
Source: Manson JE. AHA 2018 Abst. #19539.
New cholesterol guidelines expand options for primary care
CHICAGO – New U.S. cholesterol guidelines spell out the role for ezetimibe and PCSK9 inhibitors, expand the scope of individualized risk assessment, and cite the potential value of a coronary artery calcium score as an additional risk determinant.
Neil J. Stone MD, vice chair of the of the 2018 Cholesterol Guidelines Committee, sat down for an interview and detailed the research behind the guidelines and how new features can help guide treatment decisions for patients at risk for a cardiovascular event.
mzoler@mdedge.com
CHICAGO – New U.S. cholesterol guidelines spell out the role for ezetimibe and PCSK9 inhibitors, expand the scope of individualized risk assessment, and cite the potential value of a coronary artery calcium score as an additional risk determinant.
Neil J. Stone MD, vice chair of the of the 2018 Cholesterol Guidelines Committee, sat down for an interview and detailed the research behind the guidelines and how new features can help guide treatment decisions for patients at risk for a cardiovascular event.
mzoler@mdedge.com
CHICAGO – New U.S. cholesterol guidelines spell out the role for ezetimibe and PCSK9 inhibitors, expand the scope of individualized risk assessment, and cite the potential value of a coronary artery calcium score as an additional risk determinant.
Neil J. Stone MD, vice chair of the of the 2018 Cholesterol Guidelines Committee, sat down for an interview and detailed the research behind the guidelines and how new features can help guide treatment decisions for patients at risk for a cardiovascular event.
mzoler@mdedge.com
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
DECLARE: Dapagliflozin improves some cardiovascular, renal outcomes
For patients with type 2 diabetes who have or are at risk for atherosclerotic cardiovascular disease, do, according to investigators.
A composite measure of major adverse cardiovascular events (MACE), including cardiovascular death, ischemic stroke, or myocardial infarction, was comparable between dapagliflozin and placebo; in contrast, diabetic ketoacidosis occurred more frequently with dapagliflozin, reported lead author Stephen D. Wiviott, MD at the American Heart Association scientific sessions.
“As a result of [the] intersection of diabetes, atherosclerotic cardiovascular disease, and heart failure, the importance of determining diabetes therapies that are not only safe but also effective in reducing cardiovascular risk is paramount,” Dr. Wiviott and colleagues wrote in an article published simultaneously in the New England Journal of Medicine.
“Dapagliflozin is a selective inhibitor of sodium–glucose cotransporter (SGLT2) that blocks glucose resorption in the proximal tubule of the kidney and promotes glucosuria,” the investigators wrote. “Other SGLT2 inhibitors have shown favorable cardiovascular effects, including a reduction in the risk of hospitalization for heart failure, predominantly in patients with type 2 diabetes and established cardiovascular disease; they have also been shown to delay the progression of kidney disease.”
The goal of the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial was to determine what impact, if any, dapagliflozin has on renal and cardiovascular outcomes in a diverse array of patients with or at risk for atherosclerotic cardiovascular disease. The phase III, double-blind, placebo-controlled, randomized study involved 17,160 adults with type 2 diabetes from 33 countries. Of these, nearly 7,000 patients had atherosclerotic cardiovascular disease and the remaining 10,000 or so patients had multiple risk factors for atherosclerotic cardiovascular disease. Patients were at least 40 years of age, had a creatinine clearance of at least 60 mL/minute, and a HbA1c level between 6.5% and 12.0%. They were randomly assigned to receive either dapagliflozin 10 mg daily or placebo. Every 6 months, patients had laboratory testing with in-person follow-up for safety, clinical response, and adherence; patients were contacted via telephone at the halfway point between appointments (3 months).
The primary safety outcome of the study was major adverse cardiovascular outcomes (MACE: ischemic stroke, myocardial infarction, or cardiovascular death). The trial began with MACE as the sole primary safety outcome, as guided by the Food and Drug Administration, but this changed before completion. “During the trial,” the investigators explained, “compelling external scientific information from the EMPA-REG OUTCOME trial, which evaluated another SGLT2 inhibitor, showed greater benefit with respect to cardiovascular death and hospitalization for heart failure than with respect to MACE.” Therefore, before data were known, the investigators added a second primary outcome: a composite of cardiovascular death or hospitalization for heart failure. The two secondary outcomes were a renal composite (new end-stage renal disease, estimated glomerular filtration rate decrease by at least 40% to less than 60 m/min per 1.73 m2 of body-surface area, or death from renal or cardiovascular disease), and death from any cause.
The primary safety outcome (MACE rate) showed that dapagliflozin was noninferior to placebo (upper boundary of the 95% confidence interval, less than 1.3; P less than .001 for noninferiority). Although the MACE rate was similar between treatment groups (8.8% for dapagliflozin vs 9.4% for placebo; P = .017), the composite rate of cardiovascular death or hospitalization for heart failure was 17% lower for patients receiving dapagliflozin, compared with those who received placebo (4.9% vs 5.8%); this latter finding was attributable mostly to a 27% lower risk of hospitalization, instead of the 2% reduction in cardiovascular death. Seven percent fewer deaths of any kind were observed in the dapagliflozin group (6.2%) than in the placebo group (6.6%). Renal events saw a bigger difference, of 23% (4.3% vs 5.6%).
Statistically significant adverse events seen in more dapagliflozin than placebo patients included diabetic ketoacidosis and genital infection. Dr. Wiviott noted that adverse events favoring hypoglycemia included major hypoglycemia and bladder cancer..
“We did not find that SGLT2 inhibition with dapagliflozin resulted in a lower rate of cardiovascular death or death from any cause than placebo, a finding that contrasts with that in the EMPA-REG OUTCOME trial,” the investigators noted. Apart from possible differences in drugs within the same class, the investigators pointed to more restrictive renal criteria in the DECLARE trial and possible inherent differences between patient populations, among other possible factors.
“…in a broad population of patients with type 2 diabetes [dapagliflozin] did result in a significantly lower rate of cardiovascular death or hospitalization for heart failure than placebo, with additional findings supporting a possible lower rate of adverse renal outcomes,” the investigators concluded.
The DECLARE-TIMI 58 trial was sponsored by AstraZeneca and Bristol-Myers Squibb. Authors reported various financial affiliations with Eisai, Medtronic, Sanofi Aventis, Abbott, Regeneron, and others.
SOURCE: Wiviott et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389
For patients with type 2 diabetes who have or are at risk for atherosclerotic cardiovascular disease, do, according to investigators.
A composite measure of major adverse cardiovascular events (MACE), including cardiovascular death, ischemic stroke, or myocardial infarction, was comparable between dapagliflozin and placebo; in contrast, diabetic ketoacidosis occurred more frequently with dapagliflozin, reported lead author Stephen D. Wiviott, MD at the American Heart Association scientific sessions.
“As a result of [the] intersection of diabetes, atherosclerotic cardiovascular disease, and heart failure, the importance of determining diabetes therapies that are not only safe but also effective in reducing cardiovascular risk is paramount,” Dr. Wiviott and colleagues wrote in an article published simultaneously in the New England Journal of Medicine.
“Dapagliflozin is a selective inhibitor of sodium–glucose cotransporter (SGLT2) that blocks glucose resorption in the proximal tubule of the kidney and promotes glucosuria,” the investigators wrote. “Other SGLT2 inhibitors have shown favorable cardiovascular effects, including a reduction in the risk of hospitalization for heart failure, predominantly in patients with type 2 diabetes and established cardiovascular disease; they have also been shown to delay the progression of kidney disease.”
The goal of the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial was to determine what impact, if any, dapagliflozin has on renal and cardiovascular outcomes in a diverse array of patients with or at risk for atherosclerotic cardiovascular disease. The phase III, double-blind, placebo-controlled, randomized study involved 17,160 adults with type 2 diabetes from 33 countries. Of these, nearly 7,000 patients had atherosclerotic cardiovascular disease and the remaining 10,000 or so patients had multiple risk factors for atherosclerotic cardiovascular disease. Patients were at least 40 years of age, had a creatinine clearance of at least 60 mL/minute, and a HbA1c level between 6.5% and 12.0%. They were randomly assigned to receive either dapagliflozin 10 mg daily or placebo. Every 6 months, patients had laboratory testing with in-person follow-up for safety, clinical response, and adherence; patients were contacted via telephone at the halfway point between appointments (3 months).
The primary safety outcome of the study was major adverse cardiovascular outcomes (MACE: ischemic stroke, myocardial infarction, or cardiovascular death). The trial began with MACE as the sole primary safety outcome, as guided by the Food and Drug Administration, but this changed before completion. “During the trial,” the investigators explained, “compelling external scientific information from the EMPA-REG OUTCOME trial, which evaluated another SGLT2 inhibitor, showed greater benefit with respect to cardiovascular death and hospitalization for heart failure than with respect to MACE.” Therefore, before data were known, the investigators added a second primary outcome: a composite of cardiovascular death or hospitalization for heart failure. The two secondary outcomes were a renal composite (new end-stage renal disease, estimated glomerular filtration rate decrease by at least 40% to less than 60 m/min per 1.73 m2 of body-surface area, or death from renal or cardiovascular disease), and death from any cause.
The primary safety outcome (MACE rate) showed that dapagliflozin was noninferior to placebo (upper boundary of the 95% confidence interval, less than 1.3; P less than .001 for noninferiority). Although the MACE rate was similar between treatment groups (8.8% for dapagliflozin vs 9.4% for placebo; P = .017), the composite rate of cardiovascular death or hospitalization for heart failure was 17% lower for patients receiving dapagliflozin, compared with those who received placebo (4.9% vs 5.8%); this latter finding was attributable mostly to a 27% lower risk of hospitalization, instead of the 2% reduction in cardiovascular death. Seven percent fewer deaths of any kind were observed in the dapagliflozin group (6.2%) than in the placebo group (6.6%). Renal events saw a bigger difference, of 23% (4.3% vs 5.6%).
Statistically significant adverse events seen in more dapagliflozin than placebo patients included diabetic ketoacidosis and genital infection. Dr. Wiviott noted that adverse events favoring hypoglycemia included major hypoglycemia and bladder cancer..
“We did not find that SGLT2 inhibition with dapagliflozin resulted in a lower rate of cardiovascular death or death from any cause than placebo, a finding that contrasts with that in the EMPA-REG OUTCOME trial,” the investigators noted. Apart from possible differences in drugs within the same class, the investigators pointed to more restrictive renal criteria in the DECLARE trial and possible inherent differences between patient populations, among other possible factors.
“…in a broad population of patients with type 2 diabetes [dapagliflozin] did result in a significantly lower rate of cardiovascular death or hospitalization for heart failure than placebo, with additional findings supporting a possible lower rate of adverse renal outcomes,” the investigators concluded.
The DECLARE-TIMI 58 trial was sponsored by AstraZeneca and Bristol-Myers Squibb. Authors reported various financial affiliations with Eisai, Medtronic, Sanofi Aventis, Abbott, Regeneron, and others.
SOURCE: Wiviott et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389
For patients with type 2 diabetes who have or are at risk for atherosclerotic cardiovascular disease, do, according to investigators.
A composite measure of major adverse cardiovascular events (MACE), including cardiovascular death, ischemic stroke, or myocardial infarction, was comparable between dapagliflozin and placebo; in contrast, diabetic ketoacidosis occurred more frequently with dapagliflozin, reported lead author Stephen D. Wiviott, MD at the American Heart Association scientific sessions.
“As a result of [the] intersection of diabetes, atherosclerotic cardiovascular disease, and heart failure, the importance of determining diabetes therapies that are not only safe but also effective in reducing cardiovascular risk is paramount,” Dr. Wiviott and colleagues wrote in an article published simultaneously in the New England Journal of Medicine.
“Dapagliflozin is a selective inhibitor of sodium–glucose cotransporter (SGLT2) that blocks glucose resorption in the proximal tubule of the kidney and promotes glucosuria,” the investigators wrote. “Other SGLT2 inhibitors have shown favorable cardiovascular effects, including a reduction in the risk of hospitalization for heart failure, predominantly in patients with type 2 diabetes and established cardiovascular disease; they have also been shown to delay the progression of kidney disease.”
The goal of the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial was to determine what impact, if any, dapagliflozin has on renal and cardiovascular outcomes in a diverse array of patients with or at risk for atherosclerotic cardiovascular disease. The phase III, double-blind, placebo-controlled, randomized study involved 17,160 adults with type 2 diabetes from 33 countries. Of these, nearly 7,000 patients had atherosclerotic cardiovascular disease and the remaining 10,000 or so patients had multiple risk factors for atherosclerotic cardiovascular disease. Patients were at least 40 years of age, had a creatinine clearance of at least 60 mL/minute, and a HbA1c level between 6.5% and 12.0%. They were randomly assigned to receive either dapagliflozin 10 mg daily or placebo. Every 6 months, patients had laboratory testing with in-person follow-up for safety, clinical response, and adherence; patients were contacted via telephone at the halfway point between appointments (3 months).
The primary safety outcome of the study was major adverse cardiovascular outcomes (MACE: ischemic stroke, myocardial infarction, or cardiovascular death). The trial began with MACE as the sole primary safety outcome, as guided by the Food and Drug Administration, but this changed before completion. “During the trial,” the investigators explained, “compelling external scientific information from the EMPA-REG OUTCOME trial, which evaluated another SGLT2 inhibitor, showed greater benefit with respect to cardiovascular death and hospitalization for heart failure than with respect to MACE.” Therefore, before data were known, the investigators added a second primary outcome: a composite of cardiovascular death or hospitalization for heart failure. The two secondary outcomes were a renal composite (new end-stage renal disease, estimated glomerular filtration rate decrease by at least 40% to less than 60 m/min per 1.73 m2 of body-surface area, or death from renal or cardiovascular disease), and death from any cause.
The primary safety outcome (MACE rate) showed that dapagliflozin was noninferior to placebo (upper boundary of the 95% confidence interval, less than 1.3; P less than .001 for noninferiority). Although the MACE rate was similar between treatment groups (8.8% for dapagliflozin vs 9.4% for placebo; P = .017), the composite rate of cardiovascular death or hospitalization for heart failure was 17% lower for patients receiving dapagliflozin, compared with those who received placebo (4.9% vs 5.8%); this latter finding was attributable mostly to a 27% lower risk of hospitalization, instead of the 2% reduction in cardiovascular death. Seven percent fewer deaths of any kind were observed in the dapagliflozin group (6.2%) than in the placebo group (6.6%). Renal events saw a bigger difference, of 23% (4.3% vs 5.6%).
Statistically significant adverse events seen in more dapagliflozin than placebo patients included diabetic ketoacidosis and genital infection. Dr. Wiviott noted that adverse events favoring hypoglycemia included major hypoglycemia and bladder cancer..
“We did not find that SGLT2 inhibition with dapagliflozin resulted in a lower rate of cardiovascular death or death from any cause than placebo, a finding that contrasts with that in the EMPA-REG OUTCOME trial,” the investigators noted. Apart from possible differences in drugs within the same class, the investigators pointed to more restrictive renal criteria in the DECLARE trial and possible inherent differences between patient populations, among other possible factors.
“…in a broad population of patients with type 2 diabetes [dapagliflozin] did result in a significantly lower rate of cardiovascular death or hospitalization for heart failure than placebo, with additional findings supporting a possible lower rate of adverse renal outcomes,” the investigators concluded.
The DECLARE-TIMI 58 trial was sponsored by AstraZeneca and Bristol-Myers Squibb. Authors reported various financial affiliations with Eisai, Medtronic, Sanofi Aventis, Abbott, Regeneron, and others.
SOURCE: Wiviott et al. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1812389
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: For patients with type 2 diabetes who have or are at risk for atherosclerotic cardiovascular disease, dapagliflozin is associated with a lower composite rate of cardiovascular death or hospitalization for heart failure, compared with placebo.
Major finding: Of patients taking dapagliflozin, 4.9% died of cardiovascular disease or were hospitalized for heart failure, compared with 5.8% of patients receiving placebo (P = .005).
Study details: The phase III DECLARE–TIMI 58 trial was a double-blind, placebo-controlled, randomized study that involved 17,160 patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease.
Disclosures: DECLARE–TIMI 58 was sponsored by AstraZeneca and Bristol-Myers Squibb. Authors reported various financial affiliations with Eisai, Medtronic, Sanofi Aventis, Abbott, Regeneron, and others.
Source: Wiviott et al. N Engl J Med. 2018 Nov 10. doi: ___________
REDUCE-IT: Fish-derived agent cut CV events 25%
CHICAGO – Detailed results of the REDUCE-IT trial have confirmed earlier-reported top line results that showed a 25% reduction in the risk of cardiovascular death or nonfatal cardiovascular event with the fish-derived, triglyceride-reducing agent icosapent acid in combination with statin.
But they should not be interpreted as validation of the cardiovascular benefits of fish-oil supplements, according to Deepak L. Bhatt, MD, principal investigator and steering committee chair for REDUCE-IT, who presented the results at the American Heart Association scientific sessions.
He reported the results from 8,179 patients followed for a median of 4.9 years. The treatment group received 4 g/day of icosapent ethyl (Vascepa, Amarin), a single-molecule agent consisting of the omega-3 acid known as eicosapentaeonoic acid (EPA) in ethyl-ester form, which Dr. Bhatt called “a highly purified” formulation. Vascepa is derived from fish but it is not fish oil, a company press release states. Amarin, sponsor of the study, released top line results in September.
To qualify for the trial, patients had to have a diagnosis of cardiovascular disease or diabetes and other risk factors, had been on statin therapy and had above normal triglyceride (135-499 mg/dL) and optimal LDL (41-100 mg/dL) levels. Patients were randomly assigned to receive 4 g/day of icosapent ethyl or placebo.
Dr. Bhatt stressed that the REDUCE-IT results do not necessarily validate the use of fish oil to lower cardiovascular risk. “It would be mistake if patients and physicians” to interpret the results that way, and that classifying the purified formulation of icosapent ethyl used in REDUCE-IT as fish oil is a “misnomer.” He added, “Really, what we’re talking about is prescription therapy icosapent ethyl vs. over-the-counter supplements.” Icosapent ethyl is approved in the United States for patients with triglyceride levels of more than 500 mg/dL.
Dr. Bhatt and the study coauthors acknowledged that the results of REDUCE-IT deviate from other trials of triglyceride-lowering agents, including other n-3 fatty acids. They noted two potential explanations: a high dose; or higher ratios of EPA to docosahexaenoic acid in the REDUCE-IT formulation vs. agents used in the other studies. For example, the ASCEND study, presented at the European Society of Cardiology in September, reported no cardiovascular benefit from a 1-g/day dose of omega-3 fatty acids and low-dose aspirin in patients with diabetes.
The primary endpoint of REDUCE-IT was a composite of cardiovascular death, nonfatal MI or stroke, coronary revascularization or unstable angina, which occurred in 17.2% of the patients taking icosapent ethyl, compared with 22% of the controls, for a risk reduction of 25% (P less than .001). The key secondary endpoint was composite of cardiovascular death and nonfatal MI or stroke, which occurred in 11.2% and 14.8% of the treated and placebo groups, respectively, for a risk reduction of 26% (P less than .001).
The study investigators also zeroed in on specific ischemic endpoints. Cardiovascular death rates were 20% lower in the treated patients (4.2% vs. 5.2%, P less than .03).
The study also evaluated lipid levels. The median change in triglyceride levels after a year of treatment was a decrease of 18.3%, or 39 mg/dL, in the treatment group while triglyceride levels rose 2.2% in the placebo patients (P less than .001). LDL levels increased in the treated patients by 3.1%, or 2 mg/dL (median) vs. 10.2%, or 7 mg/dL, in controls (P less than .001).
The trial also reported a 33% greater risk of hospitalization for atrial fibrillation or flutter and about a 30% heightened risk of serious bleeding among patients taking icosapent ethyl. Dr. Bhatt pointed out that, while the high rate of atrial fibrillation among treated patients was statistically significant, “the most feared complication of atrial fibrillation is stroke, but in this study we saw a 28% reduction in stroke.”
Likewise the nonsignificantly higher rate of bleeding in the treatment group was inconsequential. “When we looked at specific types of serious bleeding – GI or stomach bleeding, CNS or bleeding into the brain or fatal bleeding – there were no significant differences,” he said.
Discussant Carl Orringer, MD, of the University of Miami, said, “My perspective of this is that the likelihood of atrial fibrillation, although statistically higher, is something that should not prevent physicians from prescribing the drug because of the tremendous benefit that we’ve seen in those appropriate patients on high intensity statin.” However, he said, it does merit further investigation. He also pointed out that one limitation of the study was that the population was 90% white. “Thus the potential benefits of icosapent ethyl in patients of other ethnicities remains unclear,” he said.
The results were published simultaneously online in the New England Journal of Medicine.
Dr. Bhatt receives funding from Amarin, which sponsored the REDUCE-IT trial.
SOURCE: Bhatt DL, et al. N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa181279.
CHICAGO – Detailed results of the REDUCE-IT trial have confirmed earlier-reported top line results that showed a 25% reduction in the risk of cardiovascular death or nonfatal cardiovascular event with the fish-derived, triglyceride-reducing agent icosapent acid in combination with statin.
But they should not be interpreted as validation of the cardiovascular benefits of fish-oil supplements, according to Deepak L. Bhatt, MD, principal investigator and steering committee chair for REDUCE-IT, who presented the results at the American Heart Association scientific sessions.
He reported the results from 8,179 patients followed for a median of 4.9 years. The treatment group received 4 g/day of icosapent ethyl (Vascepa, Amarin), a single-molecule agent consisting of the omega-3 acid known as eicosapentaeonoic acid (EPA) in ethyl-ester form, which Dr. Bhatt called “a highly purified” formulation. Vascepa is derived from fish but it is not fish oil, a company press release states. Amarin, sponsor of the study, released top line results in September.
To qualify for the trial, patients had to have a diagnosis of cardiovascular disease or diabetes and other risk factors, had been on statin therapy and had above normal triglyceride (135-499 mg/dL) and optimal LDL (41-100 mg/dL) levels. Patients were randomly assigned to receive 4 g/day of icosapent ethyl or placebo.
Dr. Bhatt stressed that the REDUCE-IT results do not necessarily validate the use of fish oil to lower cardiovascular risk. “It would be mistake if patients and physicians” to interpret the results that way, and that classifying the purified formulation of icosapent ethyl used in REDUCE-IT as fish oil is a “misnomer.” He added, “Really, what we’re talking about is prescription therapy icosapent ethyl vs. over-the-counter supplements.” Icosapent ethyl is approved in the United States for patients with triglyceride levels of more than 500 mg/dL.
Dr. Bhatt and the study coauthors acknowledged that the results of REDUCE-IT deviate from other trials of triglyceride-lowering agents, including other n-3 fatty acids. They noted two potential explanations: a high dose; or higher ratios of EPA to docosahexaenoic acid in the REDUCE-IT formulation vs. agents used in the other studies. For example, the ASCEND study, presented at the European Society of Cardiology in September, reported no cardiovascular benefit from a 1-g/day dose of omega-3 fatty acids and low-dose aspirin in patients with diabetes.
The primary endpoint of REDUCE-IT was a composite of cardiovascular death, nonfatal MI or stroke, coronary revascularization or unstable angina, which occurred in 17.2% of the patients taking icosapent ethyl, compared with 22% of the controls, for a risk reduction of 25% (P less than .001). The key secondary endpoint was composite of cardiovascular death and nonfatal MI or stroke, which occurred in 11.2% and 14.8% of the treated and placebo groups, respectively, for a risk reduction of 26% (P less than .001).
The study investigators also zeroed in on specific ischemic endpoints. Cardiovascular death rates were 20% lower in the treated patients (4.2% vs. 5.2%, P less than .03).
The study also evaluated lipid levels. The median change in triglyceride levels after a year of treatment was a decrease of 18.3%, or 39 mg/dL, in the treatment group while triglyceride levels rose 2.2% in the placebo patients (P less than .001). LDL levels increased in the treated patients by 3.1%, or 2 mg/dL (median) vs. 10.2%, or 7 mg/dL, in controls (P less than .001).
The trial also reported a 33% greater risk of hospitalization for atrial fibrillation or flutter and about a 30% heightened risk of serious bleeding among patients taking icosapent ethyl. Dr. Bhatt pointed out that, while the high rate of atrial fibrillation among treated patients was statistically significant, “the most feared complication of atrial fibrillation is stroke, but in this study we saw a 28% reduction in stroke.”
Likewise the nonsignificantly higher rate of bleeding in the treatment group was inconsequential. “When we looked at specific types of serious bleeding – GI or stomach bleeding, CNS or bleeding into the brain or fatal bleeding – there were no significant differences,” he said.
Discussant Carl Orringer, MD, of the University of Miami, said, “My perspective of this is that the likelihood of atrial fibrillation, although statistically higher, is something that should not prevent physicians from prescribing the drug because of the tremendous benefit that we’ve seen in those appropriate patients on high intensity statin.” However, he said, it does merit further investigation. He also pointed out that one limitation of the study was that the population was 90% white. “Thus the potential benefits of icosapent ethyl in patients of other ethnicities remains unclear,” he said.
The results were published simultaneously online in the New England Journal of Medicine.
Dr. Bhatt receives funding from Amarin, which sponsored the REDUCE-IT trial.
SOURCE: Bhatt DL, et al. N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa181279.
CHICAGO – Detailed results of the REDUCE-IT trial have confirmed earlier-reported top line results that showed a 25% reduction in the risk of cardiovascular death or nonfatal cardiovascular event with the fish-derived, triglyceride-reducing agent icosapent acid in combination with statin.
But they should not be interpreted as validation of the cardiovascular benefits of fish-oil supplements, according to Deepak L. Bhatt, MD, principal investigator and steering committee chair for REDUCE-IT, who presented the results at the American Heart Association scientific sessions.
He reported the results from 8,179 patients followed for a median of 4.9 years. The treatment group received 4 g/day of icosapent ethyl (Vascepa, Amarin), a single-molecule agent consisting of the omega-3 acid known as eicosapentaeonoic acid (EPA) in ethyl-ester form, which Dr. Bhatt called “a highly purified” formulation. Vascepa is derived from fish but it is not fish oil, a company press release states. Amarin, sponsor of the study, released top line results in September.
To qualify for the trial, patients had to have a diagnosis of cardiovascular disease or diabetes and other risk factors, had been on statin therapy and had above normal triglyceride (135-499 mg/dL) and optimal LDL (41-100 mg/dL) levels. Patients were randomly assigned to receive 4 g/day of icosapent ethyl or placebo.
Dr. Bhatt stressed that the REDUCE-IT results do not necessarily validate the use of fish oil to lower cardiovascular risk. “It would be mistake if patients and physicians” to interpret the results that way, and that classifying the purified formulation of icosapent ethyl used in REDUCE-IT as fish oil is a “misnomer.” He added, “Really, what we’re talking about is prescription therapy icosapent ethyl vs. over-the-counter supplements.” Icosapent ethyl is approved in the United States for patients with triglyceride levels of more than 500 mg/dL.
Dr. Bhatt and the study coauthors acknowledged that the results of REDUCE-IT deviate from other trials of triglyceride-lowering agents, including other n-3 fatty acids. They noted two potential explanations: a high dose; or higher ratios of EPA to docosahexaenoic acid in the REDUCE-IT formulation vs. agents used in the other studies. For example, the ASCEND study, presented at the European Society of Cardiology in September, reported no cardiovascular benefit from a 1-g/day dose of omega-3 fatty acids and low-dose aspirin in patients with diabetes.
The primary endpoint of REDUCE-IT was a composite of cardiovascular death, nonfatal MI or stroke, coronary revascularization or unstable angina, which occurred in 17.2% of the patients taking icosapent ethyl, compared with 22% of the controls, for a risk reduction of 25% (P less than .001). The key secondary endpoint was composite of cardiovascular death and nonfatal MI or stroke, which occurred in 11.2% and 14.8% of the treated and placebo groups, respectively, for a risk reduction of 26% (P less than .001).
The study investigators also zeroed in on specific ischemic endpoints. Cardiovascular death rates were 20% lower in the treated patients (4.2% vs. 5.2%, P less than .03).
The study also evaluated lipid levels. The median change in triglyceride levels after a year of treatment was a decrease of 18.3%, or 39 mg/dL, in the treatment group while triglyceride levels rose 2.2% in the placebo patients (P less than .001). LDL levels increased in the treated patients by 3.1%, or 2 mg/dL (median) vs. 10.2%, or 7 mg/dL, in controls (P less than .001).
The trial also reported a 33% greater risk of hospitalization for atrial fibrillation or flutter and about a 30% heightened risk of serious bleeding among patients taking icosapent ethyl. Dr. Bhatt pointed out that, while the high rate of atrial fibrillation among treated patients was statistically significant, “the most feared complication of atrial fibrillation is stroke, but in this study we saw a 28% reduction in stroke.”
Likewise the nonsignificantly higher rate of bleeding in the treatment group was inconsequential. “When we looked at specific types of serious bleeding – GI or stomach bleeding, CNS or bleeding into the brain or fatal bleeding – there were no significant differences,” he said.
Discussant Carl Orringer, MD, of the University of Miami, said, “My perspective of this is that the likelihood of atrial fibrillation, although statistically higher, is something that should not prevent physicians from prescribing the drug because of the tremendous benefit that we’ve seen in those appropriate patients on high intensity statin.” However, he said, it does merit further investigation. He also pointed out that one limitation of the study was that the population was 90% white. “Thus the potential benefits of icosapent ethyl in patients of other ethnicities remains unclear,” he said.
The results were published simultaneously online in the New England Journal of Medicine.
Dr. Bhatt receives funding from Amarin, which sponsored the REDUCE-IT trial.
SOURCE: Bhatt DL, et al. N Engl J Med. 2018 Nov 10; doi: 10.1056/NEJMoa181279.
REPORTING FROM AMERICAN HEART ASSOCIATION SCIENTIFIC SESSIONS 2018
Key Clinical point: .
Major finding: Cardiovascular death or nonfatal cardiovascular event occurred in 17.7% of treated patients vs. 22% of controls.
Study details: Multicenter, randomized, double-blind, placebo-controlled clinical trial of 8,179 patients with established cardiovascular disease or diabetes and other risk factors.
Disclosures: Dr. Bhatt disclosed having a significant research relationship with Amarin Corp., which funded the trial.
Source: N Engl J Med. 2018; doi: 10.1056/NEJMoa181279.
Quality tool tied to improved adherence
CHICAGO – A multifaceted quality initiative that consists of staff education, patient reminders and a feedback loop may help to improve therapy adherence and encourage lifestyle changes of at-risk cardiovascular patients in settings with limited resources, according to results of a clinical trial from Brazil presented at the American Heart Association scientific sessions 2018.
“In patients at high cardiovascular risk – in this case patients with established cardiovascular disease – a multifaceted quality-improvement intervention resulted in significant improvement in the use of evidence-based therapies,” said Otavio Berwanger, MD, PhD, of the Heart Hospital in Sao Paolo. He reported results of the BRIDGE Cardiovascular Prevention Cluster Randomized Trial. “The tools used in our trial can become the basis for developing quality-improvement programs to maximize the use of evidence-based therapies for the management of these high-risk patients with, especially in limited-resource settings.”
BRIDGE-CV included 1,619 patients from 40 care settings. Institutions that adopted the multifaceted intervention adhered to 73.5% of the evidence-based therapies (antiplatelet agents, statins and ACE inhibitors) while those in the control group adhered to 58.7% of the performance measures, Dr. Berwanger said. That represents a gain of 25%. The study employed an “all-or-none” model. That is, participating sites were required to adopt all components of the quality-improvement initiative or none.
He noted that although the evidence supporting the use of platelet therapies, statins, and ACE inhibitors is strong, “translation of these findings in practice is clearly suboptimal.” He added, “It seems to be an even larger problem in settings like mine in Brazil, so quality-improvement interventions, especially in lower-resource settings such as low- and middle-income countries, are definitely needed.”
The quality-improvement model the trial evaluated involved two levels of intervention. The first level comprised three steps: a case manager evaluating the patient’s treatment needs with the aid of a checklist; then an evaluation by the physician; and then providing physicians with what Dr. Berwanger described as “a physician support tool” – a one-page summary of major guideline recommendations. The second level comprised monthly audit and feedback reports to the providers and patient education about lifestyle modification. Staff education and training was also provided to sites that adopted the model. “Our intervention was sort of based on behavioral marketing,” Dr. Berwanger said.
The trial also identified a number of trends among secondary endpoints, although the populations were too small to reach statistical significance. For example, Dr. Berwanger noted that intervention sites had higher use of high-dose statins and more than double the rate of smoking cessation. He also noted a 24% relative risk reduction in major cardiovascular events in the intervention group vs. controls. Among the intervention sites, teaching institutions seems to have a notable improvement in adherence outcomes than other settings, Dr. Berwanger said, but the study did not fully analyze that trend.
“We see this study not as the final word but as the first step,” he said. “More studies are needed.”
Dr. Berwanger reported receiving research support and/or honoraria from Astra Zeneca, Amgen, Bayer, Eurofarma, Servier, Novartis and NovoNordisk. Amgen sponsored the investigator-initiated trial.
SOURCE: Berwanger O, et al. AHA 2018 Abstr.19360.
CHICAGO – A multifaceted quality initiative that consists of staff education, patient reminders and a feedback loop may help to improve therapy adherence and encourage lifestyle changes of at-risk cardiovascular patients in settings with limited resources, according to results of a clinical trial from Brazil presented at the American Heart Association scientific sessions 2018.
“In patients at high cardiovascular risk – in this case patients with established cardiovascular disease – a multifaceted quality-improvement intervention resulted in significant improvement in the use of evidence-based therapies,” said Otavio Berwanger, MD, PhD, of the Heart Hospital in Sao Paolo. He reported results of the BRIDGE Cardiovascular Prevention Cluster Randomized Trial. “The tools used in our trial can become the basis for developing quality-improvement programs to maximize the use of evidence-based therapies for the management of these high-risk patients with, especially in limited-resource settings.”
BRIDGE-CV included 1,619 patients from 40 care settings. Institutions that adopted the multifaceted intervention adhered to 73.5% of the evidence-based therapies (antiplatelet agents, statins and ACE inhibitors) while those in the control group adhered to 58.7% of the performance measures, Dr. Berwanger said. That represents a gain of 25%. The study employed an “all-or-none” model. That is, participating sites were required to adopt all components of the quality-improvement initiative or none.
He noted that although the evidence supporting the use of platelet therapies, statins, and ACE inhibitors is strong, “translation of these findings in practice is clearly suboptimal.” He added, “It seems to be an even larger problem in settings like mine in Brazil, so quality-improvement interventions, especially in lower-resource settings such as low- and middle-income countries, are definitely needed.”
The quality-improvement model the trial evaluated involved two levels of intervention. The first level comprised three steps: a case manager evaluating the patient’s treatment needs with the aid of a checklist; then an evaluation by the physician; and then providing physicians with what Dr. Berwanger described as “a physician support tool” – a one-page summary of major guideline recommendations. The second level comprised monthly audit and feedback reports to the providers and patient education about lifestyle modification. Staff education and training was also provided to sites that adopted the model. “Our intervention was sort of based on behavioral marketing,” Dr. Berwanger said.
The trial also identified a number of trends among secondary endpoints, although the populations were too small to reach statistical significance. For example, Dr. Berwanger noted that intervention sites had higher use of high-dose statins and more than double the rate of smoking cessation. He also noted a 24% relative risk reduction in major cardiovascular events in the intervention group vs. controls. Among the intervention sites, teaching institutions seems to have a notable improvement in adherence outcomes than other settings, Dr. Berwanger said, but the study did not fully analyze that trend.
“We see this study not as the final word but as the first step,” he said. “More studies are needed.”
Dr. Berwanger reported receiving research support and/or honoraria from Astra Zeneca, Amgen, Bayer, Eurofarma, Servier, Novartis and NovoNordisk. Amgen sponsored the investigator-initiated trial.
SOURCE: Berwanger O, et al. AHA 2018 Abstr.19360.
CHICAGO – A multifaceted quality initiative that consists of staff education, patient reminders and a feedback loop may help to improve therapy adherence and encourage lifestyle changes of at-risk cardiovascular patients in settings with limited resources, according to results of a clinical trial from Brazil presented at the American Heart Association scientific sessions 2018.
“In patients at high cardiovascular risk – in this case patients with established cardiovascular disease – a multifaceted quality-improvement intervention resulted in significant improvement in the use of evidence-based therapies,” said Otavio Berwanger, MD, PhD, of the Heart Hospital in Sao Paolo. He reported results of the BRIDGE Cardiovascular Prevention Cluster Randomized Trial. “The tools used in our trial can become the basis for developing quality-improvement programs to maximize the use of evidence-based therapies for the management of these high-risk patients with, especially in limited-resource settings.”
BRIDGE-CV included 1,619 patients from 40 care settings. Institutions that adopted the multifaceted intervention adhered to 73.5% of the evidence-based therapies (antiplatelet agents, statins and ACE inhibitors) while those in the control group adhered to 58.7% of the performance measures, Dr. Berwanger said. That represents a gain of 25%. The study employed an “all-or-none” model. That is, participating sites were required to adopt all components of the quality-improvement initiative or none.
He noted that although the evidence supporting the use of platelet therapies, statins, and ACE inhibitors is strong, “translation of these findings in practice is clearly suboptimal.” He added, “It seems to be an even larger problem in settings like mine in Brazil, so quality-improvement interventions, especially in lower-resource settings such as low- and middle-income countries, are definitely needed.”
The quality-improvement model the trial evaluated involved two levels of intervention. The first level comprised three steps: a case manager evaluating the patient’s treatment needs with the aid of a checklist; then an evaluation by the physician; and then providing physicians with what Dr. Berwanger described as “a physician support tool” – a one-page summary of major guideline recommendations. The second level comprised monthly audit and feedback reports to the providers and patient education about lifestyle modification. Staff education and training was also provided to sites that adopted the model. “Our intervention was sort of based on behavioral marketing,” Dr. Berwanger said.
The trial also identified a number of trends among secondary endpoints, although the populations were too small to reach statistical significance. For example, Dr. Berwanger noted that intervention sites had higher use of high-dose statins and more than double the rate of smoking cessation. He also noted a 24% relative risk reduction in major cardiovascular events in the intervention group vs. controls. Among the intervention sites, teaching institutions seems to have a notable improvement in adherence outcomes than other settings, Dr. Berwanger said, but the study did not fully analyze that trend.
“We see this study not as the final word but as the first step,” he said. “More studies are needed.”
Dr. Berwanger reported receiving research support and/or honoraria from Astra Zeneca, Amgen, Bayer, Eurofarma, Servier, Novartis and NovoNordisk. Amgen sponsored the investigator-initiated trial.
SOURCE: Berwanger O, et al. AHA 2018 Abstr.19360.
REPORTING FROM AMERICAN HEART ASSOCIATION SCIENTIFIC SESSIONS 2018
Key clinical point: A multifaceted quality-improvement initiative led to improved adherence to evidence-based therapies.
Major finding: Sites that adopted the intervention had adherence rates 25% higher than control sites.
Study details: Two-arm, cluster-randomized, controlled trial of 1,619 high-risk, stable patients with established CVD from 40 sites.
Disclosures: Dr. Berwanger disclosed receiving research support and/or honoraria from AstraZeneca, Amgen, Bayer, Eurofarma, Servier, Novartis and NovoNordisk. Amgen sponsored the investigator-initiated trial.
Source: Berwanger O, et al. 2018-LBCT-19360-AHA.
AHA promises practice-changing late breakers
Of the trials chosen for the six Late-Breaking Clinical Trial sessions, all being presented in the first 2 days of the American Heart Association scientific sessions in Chicago Nov. 10-12. Here are some of the most potentially practice-changing studies to look out for.
Saturday
- REDUCE-IT: Relative to placebo, the fish oil derivative AMR101 (icosapent-ethyl) evaluated in the REDUCE-IT trial was associated with a 25% reduction in a primary composite endpoint of major adverse cardiovascular events (MACE), according top-line data released in September. A highly purified ethyl ester of eicosapentaenoic acid (EPA), AMR101 (Vascepa, Amarin) was studied on top of statin therapy in both primary and secondary prevention cohorts among the 8,000 patients randomized. Relative efficacy for primary and secondary prevention was not described in the initial release of data and will be of particular when the full results are released on Saturday, Nov. 10 at 2:00 p.m.
- DECLARE TIMI58: In top line results from DECLARE TIMI58, which randomized more than 17,000 participants with type 2 diabetes an experimental arm or placebo, the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) was linked to a reduction in the composite endpoint of hospitalization for heart failure or cardiovascular death. In the early release of results, no mention was made of the effect of this agent on a composite of cardiovascular death, MI, or ischemic stroke, which was a secondary co-primary endpoint. This and the impact of dapagliflozin on an array of secondary endpoints will be revealed when the full results are made available in the Saturday late-breaker session at 2:00 p.m.
- VITAL: The relative effect of vitamin D, fish oil, or both on body composition was compared in the VITAL study, which randomized more than 20,000 patients. Fish oil plus vitamin D, fish oil plus placebo, vitamin D plus placebo, and two placebos were compared in a 2 x 2 factorial design. The primary outcome includes total body fat and lean mass as well as these components in the abdomen and other anatomic sites. Body mass index, waist circumference, and waist-to-hip ratio are among secondary outcomes. In addition, the relative effects of these treatments on lipids, blood glucose, and other aspects of metabolism were followed over the 2 years of the study, to presented at 2 p.m. on Saturday.
- CIRT: Responding to the evidence that inflammation is a crucial contributor to atherothrombosis, the CIRT trial tested whether the anti-inflammatory agent methotrexate reduces rates of MI, stroke, and cardiovascular death relative to placebo in patients with stable coronary artery disease and either type 2 diabetes or metabolic syndrome. The study enrolled about 7,000 patients and will have follow-up of nearly 6 years. Secondary endpoints, such as the impact of methotrexate on rates of coronary revascularization, peripheral artery disease, venous thromboembolism, and aortic stenosis, may provide insight about the ways in which control of inflammation affects vascular pathology. The presentation is at 2 p.m. on Saturday.
- Also on Saturday, diverse trial hypotheses are being tested. For example, the cost effectiveness of a PCSK9 inhibitor will be the focus of the ODYSSEY OUTCOMES economics study, presented at the 2:00 session. The results of YOGA-CaRe, a multicenter trial of a yoga-based cardiac rehabilitation program, will be presented in a subsequent Saturday late-breaking session. Of highlights of the third Saturday late-breaking session, ALERT-AF will determine whether a computerized decision protocol affected anticoagulation management in hospitalized patients with atrial fibrillation.
Sunday
- PIONEER-HF: It has been previously shown that sacubitril/valsartan improves outcome in stable heart failure patients with a reduced ejection fraction (HRrEF), but PIONEER-HF will test the tolerability of this strategy when this treatment is initiated prior to hospital discharge. Patients with a left ventricular ejection fraction of 40% or less and elevated N-terminal pro hormone BNP (NT-proBNP) will be randomized to sacubitril/valsartan (Entresto, Novartis) or the ACE inhibitor enalapril. The primary outcome of the trial, which enrolled more than 700 patients, is the time-averaged percentage change in NT-proBNP from baseline. Secondary outcome measures included the proportion of patients with symptomatic hypotension, hyperkalemia, and angioedema. Presentation will be at the Sunday 10:45 a.m. session.
- TICAB: The hypothesis that ticagrelor is superior to aspirin for preventing a composite MACE endpoint of CV death, myocardial infarction, target vessel revascularization, and stroke in patients undergoing coronary artery bypass grafting is the basis for the TICAB trial. The nearly 1,900 patients were randomized to 90 mg of ticagrelor twice daily or 100 mg of aspirin twice daily. Major bleeding events, CV death, and all cause death are key secondary outcomes. Relative benefit in context of safety, particularly bleeding risk, will be of interest when the final results are revealed at 5:30 p.m. on Sunday.
All-in-all, the Sunday late-breaking sessions are no less crowded with potentially practice-changing studies, including T-TIME, an evaluation of low-dose alteplase during primary percutaneous intervention at 9:00 a.m., TRED-HF, a study of withdrawal of heart failure therapy in patients who have recovered from dilated cardiomyopathy at 10:45 a.m., and ISAR TEST 4, which will provide 10-year outcomes after coronary stents with biodegradable versus permanent polymer coated devices, at 5:30 p.m.
Of the trials chosen for the six Late-Breaking Clinical Trial sessions, all being presented in the first 2 days of the American Heart Association scientific sessions in Chicago Nov. 10-12. Here are some of the most potentially practice-changing studies to look out for.
Saturday
- REDUCE-IT: Relative to placebo, the fish oil derivative AMR101 (icosapent-ethyl) evaluated in the REDUCE-IT trial was associated with a 25% reduction in a primary composite endpoint of major adverse cardiovascular events (MACE), according top-line data released in September. A highly purified ethyl ester of eicosapentaenoic acid (EPA), AMR101 (Vascepa, Amarin) was studied on top of statin therapy in both primary and secondary prevention cohorts among the 8,000 patients randomized. Relative efficacy for primary and secondary prevention was not described in the initial release of data and will be of particular when the full results are released on Saturday, Nov. 10 at 2:00 p.m.
- DECLARE TIMI58: In top line results from DECLARE TIMI58, which randomized more than 17,000 participants with type 2 diabetes an experimental arm or placebo, the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) was linked to a reduction in the composite endpoint of hospitalization for heart failure or cardiovascular death. In the early release of results, no mention was made of the effect of this agent on a composite of cardiovascular death, MI, or ischemic stroke, which was a secondary co-primary endpoint. This and the impact of dapagliflozin on an array of secondary endpoints will be revealed when the full results are made available in the Saturday late-breaker session at 2:00 p.m.
- VITAL: The relative effect of vitamin D, fish oil, or both on body composition was compared in the VITAL study, which randomized more than 20,000 patients. Fish oil plus vitamin D, fish oil plus placebo, vitamin D plus placebo, and two placebos were compared in a 2 x 2 factorial design. The primary outcome includes total body fat and lean mass as well as these components in the abdomen and other anatomic sites. Body mass index, waist circumference, and waist-to-hip ratio are among secondary outcomes. In addition, the relative effects of these treatments on lipids, blood glucose, and other aspects of metabolism were followed over the 2 years of the study, to presented at 2 p.m. on Saturday.
- CIRT: Responding to the evidence that inflammation is a crucial contributor to atherothrombosis, the CIRT trial tested whether the anti-inflammatory agent methotrexate reduces rates of MI, stroke, and cardiovascular death relative to placebo in patients with stable coronary artery disease and either type 2 diabetes or metabolic syndrome. The study enrolled about 7,000 patients and will have follow-up of nearly 6 years. Secondary endpoints, such as the impact of methotrexate on rates of coronary revascularization, peripheral artery disease, venous thromboembolism, and aortic stenosis, may provide insight about the ways in which control of inflammation affects vascular pathology. The presentation is at 2 p.m. on Saturday.
- Also on Saturday, diverse trial hypotheses are being tested. For example, the cost effectiveness of a PCSK9 inhibitor will be the focus of the ODYSSEY OUTCOMES economics study, presented at the 2:00 session. The results of YOGA-CaRe, a multicenter trial of a yoga-based cardiac rehabilitation program, will be presented in a subsequent Saturday late-breaking session. Of highlights of the third Saturday late-breaking session, ALERT-AF will determine whether a computerized decision protocol affected anticoagulation management in hospitalized patients with atrial fibrillation.
Sunday
- PIONEER-HF: It has been previously shown that sacubitril/valsartan improves outcome in stable heart failure patients with a reduced ejection fraction (HRrEF), but PIONEER-HF will test the tolerability of this strategy when this treatment is initiated prior to hospital discharge. Patients with a left ventricular ejection fraction of 40% or less and elevated N-terminal pro hormone BNP (NT-proBNP) will be randomized to sacubitril/valsartan (Entresto, Novartis) or the ACE inhibitor enalapril. The primary outcome of the trial, which enrolled more than 700 patients, is the time-averaged percentage change in NT-proBNP from baseline. Secondary outcome measures included the proportion of patients with symptomatic hypotension, hyperkalemia, and angioedema. Presentation will be at the Sunday 10:45 a.m. session.
- TICAB: The hypothesis that ticagrelor is superior to aspirin for preventing a composite MACE endpoint of CV death, myocardial infarction, target vessel revascularization, and stroke in patients undergoing coronary artery bypass grafting is the basis for the TICAB trial. The nearly 1,900 patients were randomized to 90 mg of ticagrelor twice daily or 100 mg of aspirin twice daily. Major bleeding events, CV death, and all cause death are key secondary outcomes. Relative benefit in context of safety, particularly bleeding risk, will be of interest when the final results are revealed at 5:30 p.m. on Sunday.
All-in-all, the Sunday late-breaking sessions are no less crowded with potentially practice-changing studies, including T-TIME, an evaluation of low-dose alteplase during primary percutaneous intervention at 9:00 a.m., TRED-HF, a study of withdrawal of heart failure therapy in patients who have recovered from dilated cardiomyopathy at 10:45 a.m., and ISAR TEST 4, which will provide 10-year outcomes after coronary stents with biodegradable versus permanent polymer coated devices, at 5:30 p.m.
Of the trials chosen for the six Late-Breaking Clinical Trial sessions, all being presented in the first 2 days of the American Heart Association scientific sessions in Chicago Nov. 10-12. Here are some of the most potentially practice-changing studies to look out for.
Saturday
- REDUCE-IT: Relative to placebo, the fish oil derivative AMR101 (icosapent-ethyl) evaluated in the REDUCE-IT trial was associated with a 25% reduction in a primary composite endpoint of major adverse cardiovascular events (MACE), according top-line data released in September. A highly purified ethyl ester of eicosapentaenoic acid (EPA), AMR101 (Vascepa, Amarin) was studied on top of statin therapy in both primary and secondary prevention cohorts among the 8,000 patients randomized. Relative efficacy for primary and secondary prevention was not described in the initial release of data and will be of particular when the full results are released on Saturday, Nov. 10 at 2:00 p.m.
- DECLARE TIMI58: In top line results from DECLARE TIMI58, which randomized more than 17,000 participants with type 2 diabetes an experimental arm or placebo, the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) was linked to a reduction in the composite endpoint of hospitalization for heart failure or cardiovascular death. In the early release of results, no mention was made of the effect of this agent on a composite of cardiovascular death, MI, or ischemic stroke, which was a secondary co-primary endpoint. This and the impact of dapagliflozin on an array of secondary endpoints will be revealed when the full results are made available in the Saturday late-breaker session at 2:00 p.m.
- VITAL: The relative effect of vitamin D, fish oil, or both on body composition was compared in the VITAL study, which randomized more than 20,000 patients. Fish oil plus vitamin D, fish oil plus placebo, vitamin D plus placebo, and two placebos were compared in a 2 x 2 factorial design. The primary outcome includes total body fat and lean mass as well as these components in the abdomen and other anatomic sites. Body mass index, waist circumference, and waist-to-hip ratio are among secondary outcomes. In addition, the relative effects of these treatments on lipids, blood glucose, and other aspects of metabolism were followed over the 2 years of the study, to presented at 2 p.m. on Saturday.
- CIRT: Responding to the evidence that inflammation is a crucial contributor to atherothrombosis, the CIRT trial tested whether the anti-inflammatory agent methotrexate reduces rates of MI, stroke, and cardiovascular death relative to placebo in patients with stable coronary artery disease and either type 2 diabetes or metabolic syndrome. The study enrolled about 7,000 patients and will have follow-up of nearly 6 years. Secondary endpoints, such as the impact of methotrexate on rates of coronary revascularization, peripheral artery disease, venous thromboembolism, and aortic stenosis, may provide insight about the ways in which control of inflammation affects vascular pathology. The presentation is at 2 p.m. on Saturday.
- Also on Saturday, diverse trial hypotheses are being tested. For example, the cost effectiveness of a PCSK9 inhibitor will be the focus of the ODYSSEY OUTCOMES economics study, presented at the 2:00 session. The results of YOGA-CaRe, a multicenter trial of a yoga-based cardiac rehabilitation program, will be presented in a subsequent Saturday late-breaking session. Of highlights of the third Saturday late-breaking session, ALERT-AF will determine whether a computerized decision protocol affected anticoagulation management in hospitalized patients with atrial fibrillation.
Sunday
- PIONEER-HF: It has been previously shown that sacubitril/valsartan improves outcome in stable heart failure patients with a reduced ejection fraction (HRrEF), but PIONEER-HF will test the tolerability of this strategy when this treatment is initiated prior to hospital discharge. Patients with a left ventricular ejection fraction of 40% or less and elevated N-terminal pro hormone BNP (NT-proBNP) will be randomized to sacubitril/valsartan (Entresto, Novartis) or the ACE inhibitor enalapril. The primary outcome of the trial, which enrolled more than 700 patients, is the time-averaged percentage change in NT-proBNP from baseline. Secondary outcome measures included the proportion of patients with symptomatic hypotension, hyperkalemia, and angioedema. Presentation will be at the Sunday 10:45 a.m. session.
- TICAB: The hypothesis that ticagrelor is superior to aspirin for preventing a composite MACE endpoint of CV death, myocardial infarction, target vessel revascularization, and stroke in patients undergoing coronary artery bypass grafting is the basis for the TICAB trial. The nearly 1,900 patients were randomized to 90 mg of ticagrelor twice daily or 100 mg of aspirin twice daily. Major bleeding events, CV death, and all cause death are key secondary outcomes. Relative benefit in context of safety, particularly bleeding risk, will be of interest when the final results are revealed at 5:30 p.m. on Sunday.
All-in-all, the Sunday late-breaking sessions are no less crowded with potentially practice-changing studies, including T-TIME, an evaluation of low-dose alteplase during primary percutaneous intervention at 9:00 a.m., TRED-HF, a study of withdrawal of heart failure therapy in patients who have recovered from dilated cardiomyopathy at 10:45 a.m., and ISAR TEST 4, which will provide 10-year outcomes after coronary stents with biodegradable versus permanent polymer coated devices, at 5:30 p.m.