Nitric oxide insufficiency is a common symptom of heart failure with preserved ejection fraction (HFpEF). In patients with HFpEF, the efficacy and side effects of praliciguat, an oral soluble guanylate cyclase activator, were assessed for a study. CAPACITY HFpEF was a phase 2 experiment that was randomized, double-blind, and placebo-controlled. One-hundred-ninety-six patients with heart failure, an ejection fraction of at least 40%, and impaired peak rate of oxygen consumption (peak VO2), and at least two conditions linked with nitric oxide deficit were included from 49 sites (diabetes, hypertension, obesity, or advanced age). Patients were randomized to 1 of 3 praliciguat dose groups or a placebo group in the trial, but it was refocused early on to compare the 40-mg praliciguat dose to placebo. From November 15, 2017, until April 30, 2019, participants were enrolled, with the final follow-up on August 19, 2019. Patients were randomly assigned to receive either 40 mg praliciguat daily (n=91) or a placebo (n=90) for 12 weeks. The change in peak VO2 from baseline in participants who completed at least 8 weeks of the assigned dose was the primary efficacy end goal. Changes in 6-minute walk test distance and ventilatory efficiency (ventilation/carbon dioxide production slope) were used as secondary end objectives. The incidence of treatment-emergent adverse events was the primary adverse event endpoint (TEAEs). The experiment was completed by 155 (86%) of the 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women). Changes in peak VO2 were 0.04 mL/kg/min (95% confidence interval, –0.49 to 0.56) and -0.26 mL/kg/min (95% Confidence interval, -0.83 to 0.31), respectively, in the placebo (n=78) and praliciguat (n=65) groups; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min (95% CI −0.95 to 0.35]; P=.37). None of the three secondary endpoints that were chosen were statistically significant. Changes in 6-minute walk test distance were 58.1 m (95% Confidence interval, 26.1-90.1) and 41.4 m (95% Confidence interval, 8.2-74.5) in the placebo and praliciguat groups, respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was –16.7 m (95% Confidence interval, 47.4 to 13.9) in the placebo group. The placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% confidence interval, -1.6 to 1.0) in the placebo and praliciguat groups. When compared to placebo, praliciguat caused higher dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs. Between the groups, the frequency of serious TEAEs was similar that is 10% in the praliciguat group and 11% in the placebo group. The soluble guanylate cyclase stimulator praliciguat did not significantly improve peak VO2 in individuals with HFpEF from baseline to week 12 when compared to placebo. The use of praliciguat in patients with HFpEF is not supported by the data.
Link:jamanetwork.com/journals/jama/fullarticle/2771902?resultClick=1
