Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM-HF trial

Ankeet S. Bhatt, Muthiah Vaduganathan, Brian L. Claggett, Jiankang Liu, Milton Packer, Akshay S. Desai, Martin P. Lefkowitz, Jean L. Rouleau, Victor C. Shi, Michael R. Zile, Karl Swedberg, Orly Vardeny, John J.V. McMurray, Scott D. Solomon

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on β-blocker and mineralocorticoid receptor antagonist (MRA) use and dosing in a large randomized clinical trial. Methods and results: Patients with full data on medication use were included. We examined β-blocker and MRA use in patients randomized to sacubitril/valsartan vs. enalapril through 12-month follow-up. New initiations and discontinuations of β-blocker and MRA were compared between treatment groups. Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of β-blocker and MRA at any dose was 87% and 56%, respectively. Mean doses of β-blocker and MRA were similar between treatment groups at baseline and at 6-month and 12-month follow-up. New initiations through 12-month follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for β-blockers [37 (9.0%) vs. 42 (10.2%), P = 0.56] and MRA [127 (7.6%) vs. 143 (9.2%), P = 0.10]. Among patients on MRA therapy at baseline, there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12 months [125 (6.2%) vs. 187 (9.0%), P = 0.001]. Discontinuations of β-blockers were not significantly different between groups in follow-up (2.2% vs. 2.6%, P = 0.26). Conclusions: Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose down-titration of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.

Original languageEnglish (US)
Pages (from-to)1518-1524
Number of pages7
JournalEuropean Journal of Heart Failure
Volume23
Issue number9
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
The PARADIGM-HF trial was funded by Novartis AG. Conflict of interest: A.S.B. has received consulting/speaking fees from Sanofi Pasteur, Verve Therapeutics, and Clarivate and is supported by the National Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant T32HL094301. M.V. has received research grants from and/or serves on advisory boards for American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, Relypsa, and Roche Diagnostics, has participated in speaking engagements supported by Roche Diagnostics and Novartis, and participates in clinical endpoint committees for studies sponsored by Galmed and Novartis. B.L.C. received consultancy fees from Boehringer Ingelheim, Gilead, AOBiome, Novartis, Myokardia, and Corvia. M.P. has received personal fees from Akcea Therapeutics, AstraZeneca, Amgen, Actavis, AbbVie, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. A.S.D. has received grants from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and has been a consultant for Abbott, Alnylam, Amgen, AstraZeneca, Boehringer Ingelheim, Biofourmis, Boston Scientific, Cytokinetics, DalCor Pharmaceuticals, Merck, Novartis, Regeneron, and Relypsa. J.L.R. has received personal fees from Novartis, Abbott, Bayer, Myokardia Aventis and AstraZeneca. V.C.S. and M.P.L. are employees of Novartis. M.R.Z. has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and MyoKardia V Wave. K.S. has served on advisory boards for AstraZeneca, Novartis, and Pfizer. Dr. Anand has been a consultant for AstraZeneca, ARCA, Amgen, Boston Scientific, Boehringer Ingelheim, Novartis, LivaNova, and Zensun. O.V. reports grants and non-financial support from Sanofi-Pasteur, personal fees from Novartis, and grants from AstraZeneca and Bayer. J.J.V.M. has received consulting payments through Glasgow University from Bayer, Cardiorentis, Amgen, Theracos, AbbVie, DalCor Pharmaceuticals, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Vifor-Fresenius, Kidney Research UK, Novartis, and Theraco. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta.

Funding Information:
K.S. has served on advisory boards for AstraZeneca, Novartis, and Pfizer. Dr. Anand has been a consultant for AstraZeneca, ARCA, Amgen, Boston Scientific, Boehringer Ingelheim, Novartis, LivaNova, and Zensun. O.V. reports grants and non‐financial support from Sanofi‐Pasteur, personal fees from Novartis, and grants from AstraZeneca and Bayer. J.J.V.M. has received consulting payments through Glasgow University from Bayer, Cardiorentis, Amgen, Theracos, AbbVie, DalCor Pharmaceuticals, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Bristol‐Myers Squibb, Vifor‐Fresenius, Kidney Research UK, Novartis, and Theraco. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer‐Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi‐Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi‐Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta.

Funding Information:
: A.S.B. has received consulting/speaking fees from Sanofi Pasteur, Verve Therapeutics, and Clarivate and is supported by the National Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant T32HL094301. M.V. has received research grants from and/or serves on advisory boards for American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, Relypsa, and Roche Diagnostics, has participated in speaking engagements supported by Roche Diagnostics and Novartis, and participates in clinical endpoint committees for studies sponsored by Galmed and Novartis. B.L.C. received consultancy fees from Boehringer Ingelheim, Gilead, AOBiome, Novartis, Myokardia, and Corvia. M.P. has received personal fees from Akcea Therapeutics, AstraZeneca, Amgen, Actavis, AbbVie, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. A.S.D. has received grants from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and has been a consultant for Abbott, Alnylam, Amgen, AstraZeneca, Boehringer Ingelheim, Biofourmis, Boston Scientific, Cytokinetics, DalCor Pharmaceuticals, Merck, Novartis, Regeneron, and Relypsa. J.L.R. has received personal fees from Novartis, Abbott, Bayer, Myokardia Aventis and AstraZeneca. V.C.S. and M.P.L. are employees of Novartis. M.R.Z. has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and MyoKardia V Wave. Conflict of interest

Publisher Copyright:
© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Keywords

  • Guideline-directed medical therapy
  • Heart failure with reduced ejection fraction
  • Mineralocorticoid receptor antagonists
  • Sacubitril/valsartan
  • β-blockers

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