Literature
Clinical Pearls & Morning Reports
Published May 13, 2020
Did vericiguat as compared with placebo lower the incidence of the primary outcome in the trial by Armstrong et al.?
The effect of vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received intravenous diuretic therapy is unclear. In a phase 3, randomized, double-blind, placebo-controlled trial, Armstrong et al. assessed the efficacy and safety of vericiguat in this population. Read the NEJM Original Article here.
Clinical Pearls
Q: Did vericiguat as compared with placebo lower the incidence of the primary outcome in the trial by Armstrong et al.?
A: In this trial involving patients with chronic heart failure and a reduced ejection fraction who had worsening symptoms for which hospitalization or urgent treatment was warranted, the incidence of the composite of death from cardiovascular causes or hospitalization for heart failure (the primary outcome) was lower with vericiguat than with placebo. The primary outcome occurred in 897 patients (35.5%) in the vericiguat group and in 972 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.02). The difference favoring vericiguat appeared after approximately 3 months of treatment and persisted throughout the trial.
Q: What were some of the secondary outcome results in the trial by Armstrong et al.?
A: There were 1223 total hospitalizations (first and recurrent events) for heart failure (38.3 events per 100 patient-years) in the vericiguat group and 1336 total hospitalizations (42.4 events per 100 patient-years) in the placebo group (hazard ratio, 0.91; 95% CI, 0.84 to 0.99; P=0.02). Death from any cause or first hospitalization for heart failure (a composite secondary outcome) occurred in 957 patients (37.9%) in the vericiguat group and in 1032 patients (40.9%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P=0.02). Death from any cause occurred in 512 patients (20.3%) in the vericiguat group and in 534 patients (21.2%) in the placebo group (hazard ratio, 0.95; 95% CI, 0.84 to 1.07; P=0.38).
Morning Report Questions
Q: Were symptomatic hypotension and syncope more common with vericiguat than with placebo in the trial by Armstrong et al.?
A: The prespecified adverse events of clinical interest were symptomatic hypotension and syncope. As expected, symptomatic hypotension and syncope were more common in the patients receiving vericiguat than in those receiving placebo. Symptomatic hypotension occurred in 9.1% of the patients in the vericiguat group and in 7.9% of the patients in the placebo group (P=0.12), and syncope occurred in 4.0% of patients in the vericiguat group and in 3.5% of patients in the placebo group (P=0.30). Anemia developed in more patients in the vericiguat group than in the placebo group (in 7.6% and 5.7%); of these cases, 1.6% (in the vericiguat group) and 0.9% (in the placebo group) were considered serious adverse events.
Q: What is the connection between vericiguat, the cyclic guanosine monophosphate pathway, and cardiovascular function?
A: Modulation of the nitric oxide–soluble guanylate cyclase pathway that generates cyclic guanosine monophosphate (GMP) is essential for normal cardiovascular function. In heart failure, endothelial dysfunction and reactive oxygen species reduce nitric oxide bioavailability, resulting in relative deficiency of soluble guanylate cyclase and reduced cyclic GMP generation. In contrast to the therapeutic approach of antagonizing counterregulatory neurohormonal pathways characteristic of many other therapies for heart failure, vericiguat enhances the cyclic GMP pathway by directly stimulating soluble guanylate cyclase through a binding site independent of nitric oxide and by sensitizing soluble guanylate cyclase to endogenous nitric oxide. This selectivity in cyclic GMP generation does not occur with nitrates or phosphodiesterase inhibitors.