Author + information
- Received October 3, 2016
- Revision received November 23, 2016
- Accepted November 28, 2016
- Published online March 27, 2017.
- Inder S. Anand, MD, DPhil (Oxon)a,∗ (, )
- Brian Claggett, PhDb,
- Jiankang Liu, PhDb,
- Amil M. Shah, MD, MPHb,
- Thomas S. Rector, PhDa,
- Sanjiv J. Shah, MDc,
- Akshay S. Desai, MD, MPHb,
- Eileen O’Meara, MDd,
- Jerome L. Fleg, MDe,
- Marc A. Pfeffer, MD, PhDb,
- Bertram Pitt, MDf and
- Scott D. Solomon, MDb
- aVA Medical Center and University of Minnesota, Minneapolis, Minnesota
- bCardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- cCardiology Division, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- dMontreal Heart Institute, Montreal, Quebec, Canada
- eNational Heart, Lung, and Blood Institute, Bethesda, Maryland
- fUniversity of Michigan School of Medicine, Ann Arbor, Michigan
- ↵∗Address for correspondence:
Dr. Inder S. Anand, Department of Cardiology, VA Medical Center, 5448 Caminito Bayo, La Jolla, California 92037.
Objectives The aims of this study were to explore the relationship of baseline levels of natriuretic peptides (NPs) with outcomes and to test for an interaction between baseline levels of NPs and the effects spironolactone.
Background Plasma NPs are considered to be helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF), and elevated levels are associated with adverse outcomes. Levels of NPs higher than certain cutoffs are often used as inclusion criteria in clinical trials of HFpEF to increase the likelihood that patients have HF and to select patients at higher risk for events. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear.
Methods The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) trial randomized patients with HFpEF and either prior hospitalization for HF or elevated natriuretic peptide levels (B-type NP [BNP] ≥100 pg/ml or N-terminal proBNP ≥360 pg/ml) to spironolactone or placebo. Baseline BNP (n = 430) or N-terminal proBNP (n = 257) levels were available in 687 patients enrolled from the Americas in the elevated-NP stratum of TOPCAT.
Results Higher levels of NPs were independently associated with an increased risk for TOPCAT’s primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for HF when analyzed either continuously or grouped by terciles, adjusting for region of enrollment, age, sex, atrial fibrillation, diabetes, renal function, body mass index, and heart rate. There was a significant interaction between the effect of spironolactone and baseline NP terciles for the primary outcome (p = 0.017), with greater benefit of the drug in the lower compared with higher NP terciles.
Conclusions Similar to the effects of irbesartan in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, a greater benefit of spironolactone was observed in the group with lower levels of NPs and overall risk in TOPCAT. Elevated NPs in HFpEF identify patients at higher risk for events but who may be less responsive to treatment. The mechanism of this apparent interaction between disease severity and response to therapy requires further exploration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302)
TOPCAT was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health (Contract No. HHSN268200425207C). The content of this paper does not necessarily represent the views of the sponsor or of the U.S. Department of Health and Human Services. Dr. A.M. Shah has received research support from Novartis, Gilead, and Action. Dr. S.J. Shah has received consulting fees from the American Board of Internal Medicine, AstraZeneca, DC Devices, Novartis, Bayer, and Alnilam; and speaking fees from the Pulmonary Hypertension Association and the American Society of Echocardiography. Dr. Desai has received consulting fees from Novartis, Boston Scientific, Reata, Cardiomems, 5 am Ventures, Intel, Coverys, and Relypsa; and research grants from AtCor Medical to support the Vascular Stiffness Ancillary Study to the TOPCAT trial, for which he is listed as principal investigator. Dr. O’Meara has received consulting fees from Pfizer, Novartis, and Servier; grants from Servier; and a research grant from the New England Research Institute via subcontract from the National Institutes of Health. Dr. Fleg is employed by the National Institutes of Health. Dr. Pfeffer has received research grants from Amgen, Celladon, Novartis, Sanofi, and Hamilton Health Sciences; and has consulted for Abbot Vascular, Amgen, Bristol-Myers Squibb, Cerenis, Concert, Fibrogen, Genzyme, GlaxoSmithKline, Medtronic, Merck, Novo Nordisk, Roche, Salix, Sanderling, Servier, and the University of Oxford. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in selected survivors of myocardial infarction with Novartis; Dr. Pfeffer is a coinventor, and his share of the licensing agreement is irrevocably transferred to charity. Dr. Pitt has served as a consultant for Pfizer, Bayer, Eli Lilly, Novartis, and DaVinci Biosciences; and has a patent pending for site-specific delivery of eplerenone to the myocardium. Dr. Solomon has received consulting fees from Novartis and Bayer; and research grants from the National Heart, Lung, and Blood Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 3, 2016.
- Revision received November 23, 2016.
- Accepted November 28, 2016.