Effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction

Gheorghiade, M. et al. (2015) Effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction. JAMA: Journal of the American Medical Association, 314(21), pp. 2251-2262. (doi: 10.1001/jama.2015.15734) (PMID:26547357)

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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 across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. Interventions: Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks. Main Outcomes and Measures: The primary end point was change from baseline to week 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. Trial Registration: clinicaltrials.gov Identifier: NCT01951625

Item Type:Articles
Additional Information:Data and Safety Monitoring Committee: John J. V. McMurray (chair, replaced Paul W. Armstrong during the trial), Christopher Granger, Wilhelm Haverkamp. Clinical Event Committee: Gerasimos Filippatos (chair), Aldo P. Maggioni, Piotr Ponikowski.
Glasgow Author(s) Enlighten ID:McMurray, Professor John
Authors: 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., Müller, K., Roessig, L., Pieske, B., McMurray, J., and for the SOCRATES-REDUCED Investigators and Coordinators, .
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:JAMA: Journal of the American Medical Association
ISSN (Online):1538-3598

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