Spironolactone in Patients With Heart Failure, Preserved Ejection Fraction, and Worsening Renal Function

Iris E. Beldhuis, Peder L. Myhre, Michael Bristow, Brian Claggett, Kevin Damman, James C. Fang, Jerome L. Fleg, Sonja McKinlay, Eldrin F. Lewis, Eileen O'Meara, Bertram Pitt, Sanjiv J. Shah, Orly Vardeny, Adriaan A. Voors, Marc A. Pfeffer, Scott D. Solomon, Akshay S. Desai

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood. Objectives: The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF. Methods: In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term. Results: WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF. Conclusions: Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF.

Original languageEnglish (US)
Pages (from-to)1211-1221
Number of pages11
JournalJournal of the American College of Cardiology
Volume77
Issue number9
DOIs
StatePublished - Mar 9 2021

Bibliographical note

Funding Information:
The TOPCAT study was supported by a contract from the National Heart, Lung, and Blood Institute, National Institutes of Health (HHSN268200425207C). Dr. Beldhuis has received a research grant from the Dutch Heart Foundation. Dr. Myhre has received speaker fees from Novartis. Dr. Lewis has received research grants from Novartis, Amgen, and Sanofi; and has served as a consultant for and serves on the advisory boards of Modest and Novartis. Dr. Pitt has served as a consultant for Pfizer, Bayer, Relypsa, AstraZeneca, and KBP Biosciences; holds a pending patent related to site-specific delivery of eplerenone to the myocardium; and holds stock options in Relypsa and KBP Biosciences. Dr. Shah has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GlaxoSmithKline, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr. Vardeny has received research support from AstraZeneca. Dr. Voors has received consultancy fees from Amgen, Bayer, Boehringer Ingelheim, Merck/Merck Sharp & Dohme, Novartis, Roche Diagnostics, Sanofi, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, and Vifor; has received research grants from Boehringer Ingelheim and Roche Diagnostics; and has received research support from Singulex, Sphingotec, and Vifor. Dr. Pfeffer has received research support from Novartis; has served as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, DalCor, Genzyme, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Novo Nordisk, Sanofi, Teva, and Thrasos; and has stock options in DalCor. Dr. Solomon has received research support from the National Heart, Lung, and Blood Institute; and has served as a consultant for Novartis and Bayer. Dr. Desai has received consulting fees from Abbott, Amgen, AstraZeneca, Alnylam, Biofourmis, Boston Scientific, Boehringer Ingelheim, Cytokinetics, Dalcor Pharma, Merck, Novartis, Relypsa, and Regeneron; and has received research grants from Novartis, Bayer, AstraZeneca, and Alnylam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The content of this paper is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Publisher Copyright:
© 2021 American College of Cardiology Foundation

Keywords

  • heart failure with preserved ejection fraction
  • spironolactone
  • worsening renal function

PubMed: MeSH publication types

  • Journal Article

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