Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction

医学 耐受性 射血分数 心力衰竭 临床终点 随机对照试验 利尿剂 利钠肽 内科学 心脏病学 不利影响 安慰剂 病理 替代医学
作者
Mihai Gheorghiade,Stephen J. Greene,Javed Butler,Gerasimos Filippatos,Carolyn S.P. Lam,Aldo P. Maggioni,Piotr Ponikowski,Sanjiv J. Shah,Scott D. Solomon,Elisabeth Kraigher‐Krainer,Eliana T. Samano,Katharina Müller,Lothar Roessig,Burkert Pieske
出处
期刊:JAMA [American Medical Association]
卷期号:314 (21): 2251-2251 被引量:319
标识
DOI:10.1001/jama.2015.15734
摘要

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
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