American Heart Association

American Heart Association

November 11, 2018
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PIONEER-HF: Sacubitril/valsartan superior to enalapril in acute decompensated HF

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CHICAGO — Patients with acute decompensated HF had greater reduction in N-terminal pro-B-type natriuretic peptide when assigned sacubitril/valsartan than treatment with enalapril, according to the results of the PIONEER-HF trial presented at the American Heart Association Scientific Sessions.

Sacubitril/valsartan (Entresto, Novartis) was also superior to enalapril for a secondary serious composite clinical endpoint of death, HF rehospitalization, left ventricular assist device implantation or transplant listing at 8 weeks. The two treatments did not differ in the safety endpoints of worsening renal function, hyperkalemia, symptomatic hypotension and angioedema, Eric J. Velazquez, MD, Robert W. Berliner Professor of Cardiology and chief of the section of cardiovascular medicine in the department of internal medicine at Yale University School of Medicine, chief of cardiovascular medicine at Yale New Haven Hospital and physician-in-chief of the Heart and Vascular Center for the Yale-New Haven Health System, said during a press conference.

The PARADIGM-HF trial, the pivotal study for sacubitril/valsartan, excluded patients with acute decompensated HF, so the effect of the drug on those patients was not confirmed and a trial in that population was needed, Velazquez told Cardiology Today.

“The outlook for patients in first 30 days following HF hospitalization is poor, with up to one in five readmitted during this vulnerable period and up to 10% likely to die,” he said. “We conducted PIONEER-HF to give the medical community greater insight into the safety of sacubitril/valsartan versus a standard HF medicine in this vulnerable time period. Additionally, we ensured that PIONEER-HF included populations typically underrepresented in HF studies.”

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Patients with acute decompensated HF had greater reduction in N-terminal pro-B-type natriuretic peptide when assigned sacubitril/valsartan than treatment with enalapril, according to the results of the PIONEER-HF trial presented at the American Heart Association Scientific Sessions.
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Prior to PIONEER-HF, data were unavailable or limited for in-hospital initiation in certain populations, including stabilized patients hospitalized for acute decompensated HF, those with de novo HF, and those not already known to tolerate high doses of guideline-directed HF medications or not received conventional renin-angiotensin system inhibitors, he told Cardiology Today.

Moreover, 36% of patients in this study were black, which Velazquez noted is “a group for whom evidence for use of sacubitril/valsartan from prior clinical studies was also limited and underrepresentative of heart failure patients in the real world.”

Biomarker changes

The trial enrolled 881 patients with acute decompensated HF with ejection fraction 40% who had been hemodynamically stabilized. Patients were randomly assigned to treatment with sacubitril 97 mg/valsartan 103 mg twice daily (median age, 61 years; 27% women) or enalapril 10 mg twice daily (median age, 63 years; 30% women).

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The primary endpoint was proportional change in NT-proBNP from baseline to the mean of weeks 4 and 8. The ratio of mean values of NT-proBNP at weeks 4 and 8 to the value at baseline was 0.53 in the sacubitril/valsartan group compared with 0.75 in the enalapril group (percent change, –46.7% vs. –25.3%; ratio of change between groups, 0.71; 95% CI, 0.63-0.81; P < .001; difference in reduction, 29%; 95% CI, 19-37; P < .0001), according to data presented here.

The groups had similar worsening renal function (RR = 0.93; 95% CI, 0.67-1.28), hyperkalemia (RR = 1.25; 95% CI, 0.84-1.84), symptomatic hypotension (RR = 1.18; 95% CI, 0.85-1.64) and angioedema (RR = 0.17; 95% CI, 0.02-1.38).

At 8 weeks, the serious composite clinical endpoint of death, HF rehospitalization, left ventricular assist device implantation or transplant listing was lower in the sacubitril/valsartan group (9.3% vs. 16.8%; HR = 0.54; 95% CI, 0.37-0.79; number needed to treat to prevent one event = 13). Velazquez said the difference was driven by HF rehospitalization (8% vs. 13.8%; HR = 0.56; P = .005) and was consistent across subgroups.

An expanded composite clinical endpoint, defined as the serious composite endpoint plus unplanned IV diuretics, addition of HF medications and an increase in diuretic dose of more than 50%, was not significantly different between the groups (HR = 0.93; P = .369).

“The findings of PIONEER-HF build on the results from the landmark PARADIGM-HF trial,” Velazquez told Cardiology Today. “We believe that the PIONEER-HF data, together with the prior data from PARADIGM-HF, support the initiation of sacubitril/valsartan in hospital in acute decompensated heart failure and continued long-term, supporting its use as foundation therapy for heart failure with reduced ejection fraction (HFrEF). There is now consistent evidence in the in- and outpatient settings supporting the use of sacubitril/valsartan as a new foundation therapy for patients with HFrEF.”

Simpler algorithm

During a discussion of the trial, Larry A. Allen, MD, MHS, medical director of advanced HF and professor of medicine at University of Colorado Anschutz Medical Campus, Aurora, said use of sacubitril/valsartan is low — less than 15% of patients in the CHAMP registry who are eligible for it are taking it — despite having a class I recommendation in the guidelines.

“Why is this the case? Perhaps people don’t trust a single trial,” Allen said during a press conference. “Switching from an ACE inhibitor to sacubitril/valsartan is complicated and requires a 36-hour delay. The background therapy is complicated. There are some concerns about cost. But I think a major issue is clinical inertia. So, PIONEER-HF comes in to this setting as a major success.”

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While the primary endpoint was a surrogate, “the NT-pro BNP changes correlated impressively with secondary endpoints, and these findings are consistent with what we saw in the outpatient setting in PARADIGM-HF,” Allen said. “The post-PIONEER-HF world is exciting. This is a simpler algorithm for inpatient and post-inpatient management of patients with heart failure with reduced ejection fraction.”

The results were simultaneously published in The New England Journal of Medicine. – by Erik Swain

References:

Velazquez EJ, et al. LBS.05 – Late Breaking Clinical Trial: Hot News in HF. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Velazquez EJ, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812851.

Disclosures: The study was funded by Novartis. Velazquez reports he received grants and personal fees from Amgen and Novartis, personal fees from Pfizer and grants from Philips. Please see the study for a list of the other authors’ relevant financial disclosures. Allen reports he consults or serves on an advisory board for Abbott, ACI Clinical, Boston Scientific and Janssen.