Muthiah Vaduganathan1, Brian Claggett1, Milton Packer2, John J V McMurray3, Jean L Rouleau4, Michael R Zile5, Karl Swedberg6, Scott D Solomon7. 1. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. 2. Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas. 3. British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. 4. Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada. 5. Division of Cardiology, Department of Medicine, Medical University of South Carolina and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina. 6. Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 7. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: ssolomon@rics.bwh.harvard.edu.
Abstract
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.
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.
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