Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial

Abstract

Importance: In PIONEER-HF, among stabilized patients with acute decompensated heart failure (ADHF), the in-hospital initiation of sacubitril/valsartan was well tolerated and led to improved outcomes compared with enalapril. However, there are limited data comparing the strategies of in-hospital vs postdischarge initiation of sacubitril/valsartan.

Objective: To describe changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients recently hospitalized for ADHF and switching from taking enalapril to taking sacubitril/valsartan after discharge and compare clinical outcomes for patients randomized to receive in-hospital initiation of sacubitril/valsartan vs in-hospital initiation of enalapril who later switched to taking sacubitril/valsartan during an open-label extension phase.

Interventions: Sacubitril/valsartan titrated to 97/103 mg twice daily.

Design, setting, and participants: The PIONEER-HF trial was a multicenter, randomized, double-blind, active-controlled trial conducted at 129 US sites between May 2016 and May 2018 that compared the in-hospital initiation of sacubitril/valsartan vs enalapril (titrated to target dose, 10 mg twice daily) for 8 weeks among patients admitted for ADHF with reduced ejection fraction and hemodynamic stability. All patients were to continue in a 4-week, open-label study of sacubitril/valsartan; of 881 patients enrolled in PIONEER-HF, 832 (94%) continued in the open-label study.

Main outcomes and measures: Changes in NT-proBNP levels from week 8 to 12 as well as the exploratory composite of heart failure rehospitalization or cardiovascular death from randomization through week 12.

Results: Of 881 participants, 226 (27.7%) were women, 487 (58.5%) were white, 297 (35.7%) were black, 15 (1.8%) were Asian, and 73 (8.8%) were of Hispanic ethnicity; the mean (SD) age was 61 (14) years. For patients who continued to take sacubitril/valsartan, NT-proBNP levels declined -17.2% (95% CI, -3.2 to -29.1) from week 8 to 12. The NT-proBNP levels declined to a greater extent for those switching from taking enalapril to sacubitril/valsartan after the week 8 visit (-37.4%; 95% CI, -28.1 to -45.6; P < .001; comparing changes in 2 groups). Over the entire 12 weeks of follow-up, patients that began taking sacubitril/valsartan in the hospital had a lower hazard for the composite outcome compared with patients that initiated enalapril in the hospital and then had a delayed initiation of sacubitril/valsartan 8 weeks later (hazard ratio, 0.69; 95% CI 0.49-0.97).

Conclusions and relevance: Switching patients' treatment from enalapril to sacubitril/valsartan at 8 weeks after randomization led to a further 37% reduction in NT-proBNP levels in patients with heart failure with reduced ejection fraction and a recent hospitalization for ADHF.

Trial registration: ClinicalTrials.gov identifier: NCT02554890.

Conflict of interest statement

Conflict of Interest Disclosures: Dr DeVore reported grants and consulting fees from Novartis Pharmaceuticals Corporation; grants from AstraZeneca, Amgen, the American Heart Association, Bayer, Luitpold Pharmaceuticals, Medtronic, the National Heart, Lung, and Blood Institute, and PCORI; and consulting fees from AstraZeneca, Bayer, LivaNova, Mardil Medical, and Procyrion. Dr Braunwald reported grants from Novartis, AstraZeneca, Daiichi Sankyo, and GlaxoSmithKline; grants and serving as a consultant for Merck and Novartis; personal fees from Cardurion, MyoKardia, Sanofi, Verve, and Medscape; and serving as a consultant for The Medicines Company. Dr Morrow reported grants and personal fees from Abbott Laboratories, AstraZeneca, Roche Diagnostics, and Bayer Pharma; grants from Novartis, BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Takeda, Pfizer, Quark, The Medicines Company, Merck, and Zora Diagnostics; personal fees from InCarda, Aralez, Peloton, and Verseon. He is a member of the TIMI Study Group, for which he has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Drs Duffy and Rocha reported being employees of Novartis Pharmaceuticals. Dr Ambrosy reported travel reimbursement from Novartis during the conduct of the study. Dr McCague reported being a former employee of Novartis Pharmaceuticals and owning stock. Dr Velazquez reported grants and personal fees from Novartis and Amgen; grants from Pfizer, the National Heart, Lung, and Blood Institute, and Alnylam; and personal fees from Philips. No other disclosures were reported.

Figures

Figure.. Changes in N-terminal Pro–b-Type (NT-proBNP) From Baseline Over 12 Weeks

This figure displays changes in NT-proBNP by randomized treatment arm during the double-blind period (weeks 0-8) and the open-label extension study (weeks 8-12; gray box). The vertical lines indicate 95% CIs and the dotted line represents patients switching from taking sacubitril/valsartan (S/V) after the week 8 visit.