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Study Summary

The VICTORIA trial assessed the clinical efficacy of vericiguat, an oral soluble guanylate cyclase stimulator, versus placebo in 5,050 patients with chronic heart failure (NYHA classes II-IV) and reduced ejection fraction (<45%; HFrEF) who had recently been hospitalized or had received intravenous diuretic therapy. All patients were on maximally tolerated guideline-directed medical therapy (GDMT). Over the study period of 10.8 months, the primary outcome — death from cardiovascular causes or first hospitalization for heart failure — occurred in 35.5% of the vericiguat group compared to 38.5% of the placebo group (HR 0.90; 95% CI 0.82-0.98; P = 0.02; see accompanying Hurst's Central Illustration). A secondary composite outcome of all-cause death or hospitalization for heart failure occurred in 37.9% and 40.9% of the vericiguat and placebo groups, respectively (HR 0.90; 95% CI 0.83-0.98; P = 0.02). Of note, symptomatic hypotension (9.1% versus 7.9%; P = 0.12) and syncope (4.0% versus 3.5%; P = 0.30) did not significantly differ between the patients assigned vericiguat and those assigned placebo, and death from any cause was not significantly different between the two groups. Among patients with high-risk HFrEF, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower with vericiguat than with placebo.

VICTORIA: Vericiguat Lower Incidence of Cardiovascular Death.

Commentary

Study Strengths: The study was multinational, randomized, double-blind, and placebo-controlled. The study population was clearly defined and included a large range of patients with symptomatic HFrEF, and the mean ejection fraction was 29. All patients were optimized on GDMT, which allowed the study to assess whether vericiguat conferred incremental benefit.

Study Limitations: Only 15% of the study population were on an angiotensin—neprilysin inhibitor, which has recently been shown to confer NT-proBNP reduction as well as improvement in clinical benefit in HFrEF patients hospitalized for acute heart failure. This may potentially limit the incremental value of the addition of vericiguat in a modern HFrEF population. Further, only a small number of patients in this trial received sodium–glucose cotransporter 2 inhibitors, and therefore it is unknown if this medication is synergistic with vericiguat. Patients in the vericiguat group had non-statistically-significant increased occurrences of hypotension and syncope when compared to the placebo arm; however, generally the medication was well tolerated.

Next Steps/Clinical Perspective: Overall, this trial illustrates a small but significant benefit of a novel inodilator in the treatment of patients with HFrEF and recent decompensation. The study population in VICTORIA was higher risk (higher percentage of NYHA class III or IV heart failure and higher initial NT-proBNP values [median NT-proBNP level 2,816 pg/ml]) than two recent seminal trials in HF (PARADIGM and DAPA-HF). The relative risk reduction observed in this trial was less than in PARADIGM and DAPA-HF; however, the absolute risk reduction for the primary end point was similar. While the advent of new therapies must continue to improve outcomes for this high-risk population, increased focus should be placed on the optimization of therapies with known benefit. The CHAMP registry demonstrated the continued lack of GDMT use and highlights the opportunity to maximize medical therapy. Future research is needed on how to individualize the care of patients with HFrEF to harness the maximal benefit from these medications without causing harm.

Trial Reference

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Armstrong  PW, Pieske  B, Anstrom  KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. doi:10.1056/NEJMoa1915928.

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