Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure

• 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. (C) 2018 by the American College of Cardiology Foundation.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Nyckelord

biomarker

clinical trial methodology

heart failure

natriuretic peptides

surrogate endpoints

cardiac resynchronization therapy

preserved ejection fraction

beta-blocker

base-line

mortality

morbidity

norepinephrine

flosequinan

heft

drug

Cardiovascular System & Cardiology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)