Author + information
- Received February 14, 2018
- Revision received February 23, 2018
- Accepted February 23, 2018
- Published online March 11, 2018.
- Muthiah Vaduganathan, MD MPH1,
- Brian Claggett, PhD1,
- Milton Packer, MD2,
- John J.V. McMurray, MD3,
- Jean L. Rouleau, MD4,
- Michael R. Zile, MD5,
- Karl Swedberg, MD6 and
- Scott D. Solomon, MD1,∗ ()
- 1Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA
- 2Baylor University Medical Center, Dallas, TX, USA
- 3University of Glasgow, Glasgow, UK
- 4Montreal Heart Institute and University of Montreal, Montreal, QC, Canada
- 5Medical University of South Carolina and Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC, USA
- 6University of Gothenburg, Gothenburg, Sweden
- ↵∗Address for Correspondence:
Dr. Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115.
Background The lack of reliable predictors of the efficacy of drugs and devices in heart failure (HF) has presented a major hurdle to the development and evaluation of novel therapies.
Objectives To determine whether treatment-related changes in natriuretic peptides (NP) predict longer-term therapeutic effects in clinical trials of HF.
Methods We conducted a trial-level analysis of 16 phase-3 chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. We calculated weighted Pearson correlation coefficients between average control- or placebo-corrected changes in NPs and the longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios).
Results Median follow-up for clinical endpoints was 28 (interquartile range: 18 to 36) months. NPs were available in a median of 748 (interquartile range: 270 to 1868) patients and measured at a median of 4 (interquartile 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), employing NT-proBNP 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.
Funding: The PARADIGM-HF trial was funded by Novartis AG.
Disclosures: Dr. Vaduganathan is supported by the NHLBI T32 postdoctoral training grant (T32HL007604). Dr. Packer has consulted for Novartis, Pfizer, Sanofi, Cytokinetics, Cardiokinetix, Amgen, and Cardiorentis. Prof McMurray’s employer, University of Glasgow, was paid by Novartis for Prof McMurray’s time spent as co-chairman of the PARADIGM-HF trial. Dr. Swedberg has received honoraria from Novartis for sponsored lectures. Dr. Zile is a consultant for and has received grants from Novartis. Dr. Solomon is a consultant for and has received grants from Novartis. All other authors report no other 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