Τίτλος:
Effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients withworsening chronic heart failure and reduced ejection fraction the socrates-reduced randomized trial
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
IMPORTANCE Worsening chronic heart failure (HF) is a major public health problem. OBJECTIVE To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS Dose-finding phase 2 study that randomized 456 patients acrossEurope,North America,andAsiabetweenNovember2013andJanuary2015, with follow-up ending June 2015. Patientswere clinically stable with LVEF less than 45%within 4weeks of a worseningchronicHFevent, defined asworseningsignsandsymptomsofcongestionandelevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. INTERVENTIONS Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25mg [n = 91], 2.5mg [n = 91], 5mg [n = 91], 10mg [n = 91]) for 12 weeks. MAIN OUTCOMES AND MEASURES The primary end pointwas change from baseline toweek 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. RESULTS Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2%and 71.4% among the placebo and 10-mg vericiguat groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF. Copyright 2015 American Medical Association. All rights reserved.
Συγγραφείς:
Gheorghiade, M.
Greene, S.J.
Butler, J.
Filippatos, G.
Lam, C.S.P.
Maggioni, A.P.
Ponikowski, P.
Shah, S.J.
Solomon, S.D.
Kraigher-Krainer, E.
Samano, E.T.
Muller, K.
Roessig, L.
Pieske, B.
Περιοδικό:
JAMA - JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION - INTERNATIONAL EDITION
Εκδότης:
American Medical Association
Λέξεις-κλειδιά:
amino terminal pro brain natriuretic peptide; natriuretic factor; placebo; vericiguat; brain natriuretic peptide; fused heterocyclic rings; guanylate cyclase; peptide fragment; pro-brain natriuretic peptide (1-76); pyrimidine derivative; vericiguat, acute kidney failure; aged; Article; controlled study; dose response; double blind procedure; drug dose comparison; drug dose titration; drug effect; drug safety; drug tolerability; drug withdrawal; faintness; female; follow up; heart failure; heart left ventricle ejection fraction; human; hypotension; major clinical study; male; multicenter study; phase 2 clinical trial; priority journal; randomized controlled trial; treatment outcome; chronic disease; clinical trial; complication; drug effects; heart failure; heart left ventricle function; hospitalization; middle aged; very elderly, Aged; Aged, 80 and over; Chronic Disease; Female; Guanylate Cyclase; Heart Failure; Heterocyclic Compounds, 2-Ring; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pyrimidines; Treatment Outcome; Ventricular Dysfunction, Left
DOI:
10.1001/jama.2015.15734
