Author + information
- Received November 19, 2019
- Revision received December 19, 2019
- Accepted December 20, 2019
- Published online March 11, 2020.
- Jonathan W. Cunningham, MDa,∗,
- João Pedro Ferreira, MD, PhDb,∗,
- Hsiaowei Deng, MSc,
- Stefan D. Anker, MD, PhDd,
- William M. Byra, MDc,
- John G.F. Cleland, MDe,f,
- Mihai Gheorghiade, MDg,†,
- Carolyn S.P. Lam, MD, PhDh,i,j,
- David La Policec,
- Mandeep R. Mehra, MDa,
- James D. Neaton, PhDk,
- Theodore E. Spiro, MDl,
- Dirk J. van Veldhuisen, MD, PhDm,
- Barry Greenberg, MDn and
- Faiez Zannad, MD, PhDb,∗ ()
- aBrigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- bCentre d'Investigations Cliniques-Plurithématique 1433, and INSERM U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
- cJanssen Research & Development, Raritan, New Jersey
- dDepartment of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
- eRobertson Centre for Biostatistics & Clinical Trials, University of Glasgow, Imperial College London, United Kingdom
- fNational Heart & Lung Institute, Imperial College London, United Kingdom
- gNorthwestern University, Chicago, Illinois
- hNational Heart Centre Singapore and Duke–National University of Singapore, Singapore
- iDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- jThe George Institute for Global Health, Newtown, New South Wales, Australia
- kDivision of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
- lBayer HealthCare Pharmaceuticals, Whippany, New Jersey
- mDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- nDepartment of Medicine, Cardiology Division, University of California, San Diego, California
- ↵∗Address for correspondence:
Dr. Faiez Zannad, CIC Inserm, Institut Lorrain du Coeur et des Vaisseaux, CHU de Nancy, 5 Rue du Morvan, 54500 Vandoeuvre lès Nancy, France.
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)
↵∗ Drs. Cunningham and Ferreira contributed equally to this work and are joint first authors.
The COMMANDER HF trial was sponsored by Janssen Research and Development. Dr. Cunningham is supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant (T32HL094301-10). Mrs. Deng has received support from Janssen Research & Development LLC during the conduct of the study and outside the submitted work; and is employed by and is a shareholder of Johnson & Johnson. Dr. Anker has received grants from Abbott Vascular and Vifor; and personal fees from Vifor, Janssen, Servier, Bayer, Boehringer Ingelheim, Respicardia, Impulse Dynamics, and Novartis. Dr. Cleland has received personal fees from Janssen Research & Development LLC as a member of the steering committee of the COMMANDER HF trial; and has received grants and honoraria for speaking, committees, and advisory boards from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Medtronic, MyoKardia, Novartis, Philips Healthcare, Pharmacosmos, Pharma Nord, Sanofi, Laboratoires Servier, Stealth BioTherapeutics, Torrent Pharmaceuticals, and Vifor Pharma. Dr. Byra has received support from Janssen Research & Development LLC during the conduct of the study and outside the submitted work; and is employed by and a shareholder of Johnson & Johnson. Dr. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; and has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, WebMD Global LLC, Radcliffe Group Ltd, and Corpus; and is cofounder and non-executive director of eKo.ai. Mr. La Police has received support from Janssen Research & Development LLC during the conduct of the study and outside the submitted work; and is employed by and a shareholder of Johnson & Johnson. Dr. Mehra has received travel support and consulting fees, paid to Brigham and Women’s Hospital, from Abbott; personal fees from Medtronic, Janssen (Johnson & Johnson), Mesoblast, Portola, Bayer, Xogenex, NuPulseCV, Leviticus, FineHeart, Baim Institue for Clinical Research, and Triple Gene. Dr. Neaton has received personal fees from Johnson & Johnson during the conduct of the study; fees from Janssen Research & Development LLC for serving as a member of the steering committee of the COMMANDER HF trial; and fees from Bristol-Myers Squibb and EBR Systems for serving on data and safety monitoring boards for heart failure trials. Dr. Spiro is an employee of Bayer US LLC and a shareholder. Dr. van Veldhuisen has received fees and Board Membership from Johnson & Johnson during the conduct of this study. Dr. Greenberg has received personal fees from Novartis, Janssen, Sanofi, Mesoblast, Zensun, Cellular Dynamics, MyoKardia, Bayer, Actelion, Viking, Amgen, Akcea, EBR System, IONIS and Tenaya; and was co-chair of the COMMANDER-HF steering committee. Dr. Zannad has received personal fees from Janssen, during the conduct of the study; personal fees from Novartis; and fees from Bayer, Boston Scientific, Amgen, CVRx, Boehringer, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmacuetical, Applied Therapeutics, Merck, CVCT, and Cardiorenal. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received November 19, 2019.
- Revision received December 19, 2019.
- Accepted December 20, 2019.
- 2020 American College of Cardiology Foundation
This article requires a subscription or purchase to view the full text. If you are a subscriber or member, click Login or the Subscribe link (top menu above) to access this article.