Author + information
- Received August 3, 2018
- Revision received October 16, 2018
- Accepted October 23, 2018
- Published online December 31, 2018.
- Iris E. Beldhuis, BSca,b,
- Peder L. Myhre, MD, PhDa,
- Brian Claggett, PhDa,
- Kevin Damman, MD, PhDb,
- James C. Fang, MDc,
- Eldrin F. Lewis, MD, MPHa,
- Eileen O’Meara, MDd,
- Bertram Pitt, MDe,
- Sanjiv J. Shah, MDf,
- Adriaan A. Voors, MD, PhDb,
- Marc A. Pfeffer, MD, PhDa,
- Scott D. Solomon, MDa and
- Akshay S. Desai, MD, MPHa,∗ ()
- aCardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- bDepartment of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- cDivision of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City, Utah
- dDepartment of Medicine, Montreal Heart Institute, Montreal, Montreal, Canada
- eDepartment of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
- fDivision of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- ↵∗Address for correspondence:
Dr. Akshay S. Desai, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Objectives This study investigated the association between baseline renal function and the net benefit of spironolactone in patients with heart failure (HF) with a preserved ejection fraction (HFpEF).
Background Guidelines recommend consideration of spironolactone to reduce HF hospitalization in HFpEF. However, spironolactone may increase risk for hyperkalemia and worsening renal function, particularly in patients with chronic kidney disease.
Methods This investigation analyzed data from patients enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) Americas study (N = 1,767) to examine the association between the baseline estimated glomerular filtration rate (eGFR) and the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest, as well as safety outcomes, including hyperkalemia, worsening renal function, and permanent drug discontinuation for adverse events (AEs). Variations in the efficacy and safety of spironolactone according to eGFR were examined in Cox models using interaction terms.
Results The incidence of both the primary outcome and drug-related AEs increased with declining eGFR. Compared with placebo, across all eGFR categories, spironolactone was associated with lower relative risk for the primary efficacy outcome and for hypokalemia, but higher relative risk for hyperkalemia, worsening renal function, and drug discontinuation. During 4-year follow-up, the absolute risk for AEs that prompted drug discontinuation was amplified in the lower eGFR categories, which suggested heightened risk for drug intolerance with declining renal function.
Conclusions Although consistent efficacy of spironolactone was observed across the range of eGFR, the risk of AEs was amplified in the lower eGFR categories. These data supported use of spironolactone to treat HFpEF patients with advanced chronic kidney disease only when close laboratory surveillance is possible.
- chronic kidney disease
- heart failure with preserved ejection fraction
- renal function
Ms. Beldhuis is supported by a research grant from the Dutch Heart Association. The TOPCAT study was supported by a contract from the National Heart, Lung, and Blood Institute, National Institutes of Health (HHSN268200425207C). The content of this manuscript 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. Dr. Solomon has received research support from National Heart, Lung, and Blood Institute. Dr. Myhre has received speaker fees from Novartis. Dr. Fang is a member of the Steering Committees for Novartis and AstraZeneca. Dr. Lewis has received institutional research grants from Novartis, Amgen, and Sanofi in order to conduct clinical trials; and has received consulting fees from Novartis. Dr. Pitt has received consulting fees from Amorcyte, AstraZeneca, Aurasense, Bayer, BG Medicine, Gambro, Johnson & Johnson, Mesoblast, Novartis, Pfizer, Relypsa, and Takeda; research grant support from Forest Laboratories; holds stock in Aurasense, Relypsa, BG Medicine, and Aurasense; and has a pending patent related to site-specific delivery of eplerenone to the myocardium. Dr. Voors has received consultancy fees and/or research grants from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cytokinetics, GlaxoSmithKline, Novartis, Roche Diagnostics, and Servier. Dr. Pfeffer has received research support from Novartis; serves 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 been a consultant for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Corvia, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Pfizer, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions; and has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol-Myers Squibb, Celladon, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, Novartis, Sanofi Pasteur, and Theracos. Dr. Desai has received consulting fees from Novartis, AstraZeneca, Abbott, Relypsa, and DalCor Pharma; and research grants from Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received August 3, 2018.
- Revision received October 16, 2018.
- Accepted October 23, 2018.
- 2019 American College of Cardiology Foundation
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