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SOCRATES-REDUCED: Vericiguat effect on NT-proBNP in patients with worsening HF may depend on dose
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ORLANDO, Fla. — Vericiguat, a novel soluble guanylate cyclase stimulator, did not significantly influence changes in N-terminal pro-B-type natriuretic peptide in patients with worsening HF, according to findings presented at the American Heart Association Scientific Sessions.
However, a dose-response relationship between the drug and reduction in NT-proBNP may be present, according to the researchers.
The researchers conducted a dose-finding phase 2 study of vericiguat (Bayer/Merck) to determine the tolerability of the drug and its impact on NT-proBNP. They presented their findings here; they were also published in JAMA.
Mihai Gheorghiade, MD, and colleagues randomized 456 patients with HF with reduced ejection fraction (< 45%) who had experienced a worsening chronic HF event within the past 4 weeks to receive placebo or one of four doses of oral vericiguat: 1.25 mg/day, 2.5 mg/day, 5 mg/day or 10 mg/day. Those in the 5-mg and 10-mg groups were started at 2.5 mg/day and uptitrated, he said.
The primary endpoint was change in log-transformed NT-proBNP levels at 12 weeks. In the primary analysis, researchers compared the pooled results of the three highest vericiguat doses vs. placebo. In the secondary analysis, they investigated the dose-response relationship between vericiguat and the primary endpoint.
Among those randomized, 77% completed the 12-week study with valid NT-proBNP levels and no major deviations from the protocol, Gheorghiade, from the Center for Cardiovascular Innovation at Northwestern University Feinberg School of Medicine, said at a press conference.
In the primary analysis, he said, there was no significant difference in the primary endpoint between the pooled vericiguat group and the placebo group (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 secondary analysis determined that there may be a dose-response relationship between vericiguat and reduction in NT-proBNP, Gheorghiade said. The higher the dose of vericiguat, the greater reduction in NT-proBNP (P < .02), he said.
The rate of CV death or HF hospitalization at 12 weeks was 19.6% in the placebo group, 18.7% in the 1.25-mg group, 19.8% on the 2.5-mg group, 12.1% in the 5-mg group and 11% in the 10-mg group, with none of the groups differing from each other significantly, according to the researchers.
The 10-mg group had a “small but significant increase in [left ventricular] ejection fraction” compared with the placebo group, (P < .05), Gheorghiade said.
The rate of any adverse event was 71.4% in the 10-mg vericiguat group compared with 77.2% in the placebo group, researchers found.
“We were able to find a dose response and we saw benefits in clinical outcome and BNP,” Gheorghiade said. “There were no changes in renal function, and importantly, an improvement in LVEF with the highest dose.” by Erik Swain
References:
Gheorghiade M, et al. LBCT 1: Failure Is Not an Option: New Drugs and Systems of Care. Presented at: American Heart Association Scientific Sessions; Nov. 7-11, 2015; Orlando, Fla.
Gheorghiade M, et al. JAMA. 2015;doi:10.1001/jama.2015.15734.
Disclosures: The study was funded by affiliates of Bayer and Merck. Gheorghiade reports financial ties with numerous pharmaceutical and biotechnology companies. See the full study for a list of the other researchers’ relevant financial disclosures.
Perspective
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Clyde W. Yancy, MD, MSc
The SOCRATES-REDUCED study addressed a very provocative hypothesis addressing the benefit of up-regulating nitric oxide in heart failure. Many of us believe that this may be a new target in the treatment of HF. SOCRATES was recently launched and fairly broad, with almost 500 patients and many different countries represented. There is a signal that emerges but it isn't very strong. If we can redesign a study where we can capture that group at the higher dose that showed the drop in BNP and the increase in LVEF, then we may have found a path forward, but my enthusiasm is tempered based on the current data. But it’s definitely a question we needed to pursue and answer.
The results point out just how complicated HF is. For something such as nitric oxide upregulation that was so tantalizing — I have a fair amount of experience with that clinically and as an investigator, and there are patient populations where it works well — this experience is sobering. It tells us that even when you have a great hypothesis that ought to work, the resulting signal may be weak or even nonexistent. Remember, the primary endpoint for SOCRATES-REDUCED was negative. We have to take this information as another moment of pause to recognize that HF is a complex environment. There are a lot of things happening at one time. We have to figure out what is the causative factor and what are the tagalongs.
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