Enhancing cyclic guanosine monophosphate reduced heart failure hospitalization in patients with worsening disease
An investigational stimulator of guanylate cyclase, vericiguat, reduced the incidence of either cardiovascular (CV) death or heart failure hospitalization in a large randomized international phase III study of patients with worsening heart failure (HF) with reduced ejection fraction who were already receiving optimal standard of care.
In the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, conducted in 600 centers across 42 countries, patients randomized to vericiguat plus standard of care experienced a 10% reduction in the primary endpoint of CV death plus HF hospitalization after a median follow-up of 10.8 months compared with patients randomized to placebo plus standard of care (hazard ratio [HR], 0.90; P = 0.019), reported Paul W. Armstrong, MD, from the Canadian VIGOUR Centre, University of Alberta.
Vericiguat enhances the production of cyclic guanosine monophosphate (GMP), which is a pathway that is critical for normal cardiac and vascular function not currently targeted by existing heart failure drugs. Vericiguat also restores nitric oxide sensitivity; nitric oxide exerts a favorable effect on vascular homeostasis through upregulation of cyclic GMP.
“VICTORIA enrolled a very high-risk HF population with significant unmet needs not well addressed by prior HF studies,” said Dr. Armstrong, who indicated that the findings from VICTORIA would apply to approximately the one fourth of patients with chronic HF who fit the inclusion criteria for the study.
VICTORIA enrolled 5,050 patients with New York Heart Association (NYHA) class II to IV chronic HF with an ejection fraction (EF) less than 45% (on guideline-based heart failure therapies) after a worsening event, defined as hospitalization for HF within the past 6 months or the need for intravenous diuretics within 3 months. Patients were randomized in a 1:1 ratio to vericiguat, titrated stepwise from 2.5 mg to a target of 10 mg once daily, or placebo in addition to standard HF treatments. Patients could be randomized as an inpatient or outpatient but must have met criteria for clinical stability.
Baseline characteristics were comparable between the 2 arms. Patients’ mean age was approximately 67, about one fourth were female, and about 40% had NYHA class III–IV HF. Mean EF at baseline was about 29%, and approximately 60% of patients were receiving triple guideline-directed drug therapy. About one third of patients enrolled had either an implantable cardioverter-defibrillator, biventricular pacemaker, or both devices.
The favorable effect of vericiguat on the primary endpoint appeared after approximately 3 months of treatment and persisted for the duration of the study. The absolute event reduction in the vericiguat arm relative to placebo was 4.2 per 100 patient years. The number needed to treat to prevent one primary outcome was 24.
The rate of CV mortality favored vericiguat but did not achieve statistical significance (HR, 0.93; P = 0.269). The rate of first hospitalization for HF was reduced significantly in the vericiguat arm versus placebo (HR, 0.90; P = 0.048). There was no significant difference between arms in all-cause mortality (HR, 0.95; P = 0.377).
Vericiguat was generally well-tolerated. Patients taking vericiguat had a numerically increased incidence of symptomatic hypotension (9.1% vs 7.9%; P = 0.121) and syncope (4% vs 3.5%; P = 0.303) compared with placebo. The rates of anemia were 7.6% in the vericiguat arm and 5.7% in the placebo arm. No adverse effects of vericiguat on either electrolytes or renal function was observed.
“Because vericiguat is a once daily medicine, easy to titrate, generally safe and well tolerated, without the need for monitoring renal function or electrolytes, it may play a useful role in patients with recent worsening HF,” Dr. Armstrong concluded. A separate study is underway to investigate whether vericiguat offers benefits for patients with HF with preserved ejection fraction.
Results of the study were published simultaneously online in The New England Journal of Medicine.
Clyde Yancy, MD, from Northwestern University Feinberg School of Medicine in Chicago, who was not involved in the study, noted that hospitalization for HF represents a major inflection point in the natural history HF, with a marked change in the risk for rehospitalization and death. “Until now, no therapies have attenuated this risk, except for more intensive process of care improvement strategies,” he said. “Now we have a therapy that may be the first one to change that natural history after a person with HF has had a worsening event.”
The risk of death, however, after HF hospitalization appears recalcitrant to any of the current medical therapies, and “that is still an issue that we have to address,” said Dr. Yancy.
Black patients constituted less than 5% of the study population, he pointed out, despite prevailing concerns that this unique patient population may exhibit diminished NO bioavailability.
Lynne Stevenson, MD, from Harvard Medical School, Boston, remarked that vericiguat is “not only a therapy for a new physiologic target but it’s also for a new population. Patients with recent HF hospitalization and decompensation have been actively excluded from all the trials that have shown benefit. VICTORIA finally addresses this population of decompensated patients.”
The VICTORIA trial was supported by Merck Sharp & Dohme, a subsidiary of Merck and Co., Inc.; and Bayer AG. Paul W. Armstrong, MD reported nothing to disclose; Clyde W. Yancy, MD reported Other: Abbott Laboratories.