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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.