Vaduganathan, M., Claggett, B., Packer, M., McMurray, J. J.V. , Rouleau, J. L., Zile, M. R., Swedberg, K. and Solomon, S. D. (2018) Natriuretic peptides as biomarkers of treatment response in clinical trials of heart failure. JACC: Heart Failure, 6(7), pp. 564-569. (doi: 10.1016/j.jchf.2018.02.007) (PMID:29501807)
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Abstract
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.
| Item Type: | Articles |
|---|---|
| Keywords: | Biomarker, clinical trial methodology, heart failure, natriuretic peptides, surrogate endpoints. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | McMurray, Professor John |
| Authors: | Vaduganathan, M., Claggett, B., Packer, M., McMurray, J. J.V., Rouleau, J. L., Zile, M. R., Swedberg, K., and Solomon, S. D. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | JACC: Heart Failure |
| Publisher: | Elsevier |
| ISSN: | 2213-1779 |
| ISSN (Online): | 2213-1787 |
| Published Online: | 04 March 2018 |
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