Natriuretic peptide-based inclusion criteria in a heart failure clinical trial: insights from COMMANDER HF

Cunningham, J. W. et al. (2020) Natriuretic peptide-based inclusion criteria in a heart failure clinical trial: insights from COMMANDER HF. JACC: Heart Failure, 8(5), pp. 359-368. (doi: 10.1016/j.jchf.2019.12.009) (PMID:32171760) (PMCID:PMC7151428)

Abstract

Objectives: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial. Background: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide greater than or equal to 200 ng/l or N-terminal pro–B-type natriuretic peptide greater than or equal to 800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria. Methods: We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death. Results: A total of 5,022 patients with left ventricular ejection fraction less than or equal to 40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints. Conclusions: In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915)

• Item Type: Articles
• Additional Information: Funding: The COMMANDER HF trial was sponsored by Janssen Research and Development.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cleland, Professor John
• Authors: Cunningham, J. W., Ferreira, J. P., Deng, H., Anker, S. D., Byra, W. M., Cleland, J. G.F., Gheorghiade, M., Lam, C. S.P., La Police, D., Mehra, M. R., Neaton, J. D., Spiro, T. E., van Veldhuisen, D. J., Greenberg, B., and Zannad, F.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: JACC: Heart Failure
• Publisher: Elsevier
• ISSN: 2213-1779
• ISSN (Online): 2213-1787
• Published Online: 11 March 2020
• Copyright Holders: Copyright © 2020 by the American College of Cardiology Foundation
• First Published: First published in JACC: Heart Failure 8(5):359-368
• Publisher Policy: Reproduced in accordance with the publisher copyright policy