Vericiguat Did Not Significantly Affect NT-proBNP Level in Chronic Heart Failure With Reduced LVEF

NT-proBNP levels were not significantly affected by vericiguat, a soluble guanylate cyclase stimulator, in patients with chronic heart failure and reduced LVEF.

Orlando, Fla. – In patients with worsening chronic heart failure (HF) and reduced left ventricular ejection fraction (LVEF), vericiguat—a soluble guanylate cyclase stimulator—did not have a statistically significant effect on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, but was well tolerated, according to research presented at the American Heart Association Scientific Sessions.

The results of the SOCRATES-REDUCED (The Soluable Guanylate Cyclase Stimulator in Heart Failure Patients With Reduced EF) study were also simultaneously published in the Journal of the American Medical Association.

The study was a multicenter, randomized, double-blind, placebo-controlled, dose-finding trial that enrolled patients with LVEF less than 45% and a recent episode of worsening chronic HF defined by the following: 1) worsening HF symptoms requiring hospitalization or outpatient administration of IV diuretics, 2) signs of congestion, and 3) elevated NT-proBNP level.

Participants were randomly assigned to 1 of 5 equally sized groups—placebo or vericiguat (Merck & Co., Kenilworth, NJ) 1.25 mg, 2.5 mg, 5 mg, and 10 mg. All treatment groups started at 2.5 mg once daily, except the 1.25 mg group, with up-titration at weeks 2 and 4 after randomization.

The primary end point was change in log-transformed NT-proBNP level from baseline to 12 weeks. A total of 456 patients were randomized. Of these, 351 (77%) completed treatment with vericiguat, 77.9% met worsening chronic HF criteria by being hospitalized, and 22.1% required outpatient IV diuretic use. Mean age was 68 years, and the majority of patients were white.

The change in log-transformed NT-proBNP level from baseline to 12 weeks was not significantly different between the pooled vericiguat treatment groups and the placebo groups (ratio of geometric means on original scale, 0.885; 90% CI, 0.73-1.08; P=.15).

In a secondary analysis, a dose-response relationship was seen, with the researchers observing an association between higher doses of vericiguat and greater reductions in NT-proBNP (P<.02).

“[While] we did not achieve the primary end point, as an exploratory analysis [by] randomizing to 10 mg, we got an idea that increasing the dose, we saw a further reduction in the NT-proBNP,” said Dr Mihai Gheorghiade, professor of medicine-cardiology and surgery-organ transplantation at Northwestern University in Chicago, Illinois, who presented the findings at a press conference. “We were pleasantly surprised that we saw no change in systolic pressure, heart rate, and no increase or decrease in troponin.”

It is also notable that all doses of vericiguat appeared to be well tolerated compared with placebo, and rates of mortality and hospitalization were also generally numerically lower among patients who received treatment, especially among those randomized to the 2 highest doses, according to the researchers. Hospitalization in the 2 highest-dose groups was 9.9% compared with 17.4% in the placebo group and 17.6% in the lower-dose groups. 

Patients who received either placebo or the 2.5-mg dose of vericiguat did experience higher rates of severe adverse events and any adverse event compared with the other treatment groups.

In the published findings, the researchers noted, “In the current trial, although only exploratory in nature, the collective signal toward potential benefit in natriuretic peptide trajectory, clinical events, and LVEF at 12 weeks of treatment with the higher vericiguat dosing schedule, while maintaining safety, suggests that titration to the 5-mg or 10-mg once daily dose may be reasonable for further testing in a phase 3 study.”

Disclosures: Funding for this study was provided by Bayer and Merck Sharp & Dohme (Kenilworth, NJ). Dr Mihai Gheorghiade reported relationships with Merck and Bayer Schering Pharma. For a full list of disclosures please see the published study.


  1. Gheorghiade M, Greene SJ, Butler J, et al; for the SOCRATES-REDUCED Investigators and Coordinators. Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial. JAMA. 2015;doi:10.1001/jama.2015.15734.
  2. Gheorghiade M. LBCT.0I—Failure Is Not an Option: New Drugs and Systems of Care. Oral sGC Stimulator Vericiguat in Patients with Worsening Chronic Heart Failure and Reduced Ejection Fraction—The SOCRATES-REDUCED Study. Presented at the American Heart Association Scientific Sessions; November 7-11, 2015; Orlando, FL.