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.
Gheorghiade, M., Greene, S., Butler, J., Filippatos, G., Lam, C., Maggioni, A., et al. (2015). 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. JAMA, 314(21), 2251-2262.
|Citazione:||Gheorghiade, M., Greene, S., Butler, J., Filippatos, G., Lam, C., Maggioni, A., et al. (2015). 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. JAMA, 314(21), 2251-2262.|
|Tipo:||Articolo in rivista - Articolo scientifico|
|Carattere della pubblicazione:||Scientifica|
|Presenza di un coautore afferente ad Istituzioni straniere:||Si|
|Titolo:||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|
|Autori:||Gheorghiade, M; Greene, S; Butler, J; Filippatos, G; Lam, C; Maggioni, A; Ponikowski, P; Shah, S; Solomon, S; Kraigher Krainer, E; Samano, E; Muller, K; Roessig, L; Pieske, B; PARATI, G|
PARATI, GIANFRANCO [Membro del Collaboration Group]
|Data di pubblicazione:||2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1001/jama.2015.15734|
|Appare nelle tipologie:||01 - Articolo su rivista|