Author + information
- Received February 14, 2018
- Revision received February 23, 2018
- Accepted February 23, 2018
- Published online June 25, 2018.
- Muthiah Vaduganathan, MD, MPHa,
- Brian Claggett, PhDa,
- Milton Packer, MDb,
- John J.V. McMurray, MDc,
- Jean L. Rouleau, MDd,
- Michael R. Zile, MDe,
- Karl Swedberg, MDf and
- Scott D. Solomon, MDa,∗ ()
- aCardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- bBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- cBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- dMontreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
- eDivision of Cardiology, Department of Medicine, Medical University of South Carolina and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina
- fSahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- ↵∗Address for correspondence:
Dr. Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Objectives This study sought to determine whether treatment-related changes in natriuretic peptides (NPs) predict longer-term therapeutic effects in clinical trials of heart failure (HF).
Background The lack of reliable predictors of efficacy of drugs and devices in HF has presented a major hurdle to the development and evaluation of novel therapies.
Methods The study conducted a trial-level analysis of 16 phase III chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. Weighted Pearson correlation coefficients were calculated between average control- or placebo-corrected changes in NPs and longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios).
Results Median follow-up for clinical endpoints was 28 (25th to 75th percentile range: 18 to 36) months. NPs were available in a median of 748 (25th to 75th percentile range: 270 to 1,868) patients and measured at a median of 4 (25th to 75th percentile range: 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r = 0.12; p = 0.63), but were correlated with HF hospitalization (r = 0.63; p = 0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r = 0.92; p = 0.0095), using N-terminal pro–B-type NP assays (r = 0.65; p = 0.06), and evaluating inhibitors of the renin-angiotensin-aldosterone system (r = 0.97; p = 0.0002).
Conclusions When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision making regarding phase III trials.
Dr. Vaduganathan is supported by a National Heart, Lung, and Blood Institute T32 postdoctoral training grant (T32HL007604). Dr. Packer has served as a consultant for Novartis, Pfizer, Sanofi, Cytokinetics, Cardiokinetix, Amgen, and Cardiorentis. Dr. McMurray’s employer, University of Glasgow, was paid by Novartis for Dr. McMurray’s time spent as co-chairman of the PARADIGM-HF trial. Dr. Rouleau has served as a consultant for Novartis, AstraZeneca, and Bayer. Dr. Zile has served as a consultant for and received grants from Novartis. Dr. Swedberg has received research support or honoraria from Amgen, AstraZeneca, Novartis, and Servier. Dr. Solomon has served as a consultant for and received grants from Novartis, Amgen, AstraZeneca, Alnylam, Bristol-Myers Squibb, Bayer, Ionis, Theracos, and GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 14, 2018.
- Revision received February 23, 2018.
- Accepted February 23, 2018.
- 2018 American College of Cardiology Foundation