Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial

Abstract

Importance: Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency.

Objective: To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF.

Design, setting, and participants: CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019.

Interventions: Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90).

Main outcomes and measures: The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs).

Results: Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; 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 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group).

Conclusions and relevance: Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF.

Trial registration: ClinicalTrials.gov Identifier: NCT03254485.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Udelson reported receiving grants and personal fees from Cyclerion during the conduct of the study and grants from Bayer, Cardurion, Cytokinetics, scPharmaceutical, Edwards, and LivaNova and personal fees from Imbria outside the submitted work. Dr Lewis reported receiving grants and personal fees from Cyclerion during the conduct of the study and grants from Amgen, Cytokinetics, AstraZeneca, and Applied Therapeutics and personal fees from American Regeant, Boehringer-Ingelheim, and Pfizer outside the submitted work. Dr Shah reported receiving personal fees from Cyclerion during the conduct of the study and grants and personal fees from Actelion, AstraZeneca, Novartis, and Pfizer; grants from Corvia; and personal fees from Bayer, Amgen, Boehringer-Ingelheim, Cardiora, Cytokinetics, MyoKardia, Merck, Shifamed, Eisai, Ionis, Novo Nordisk, Sanofi, Tenax, and United Therapeutics outside the submitted work. Dr Zile reported serving as a consultant to Cyclerion Therapeutics and Ironwood Pharmaceuticals as a member of the executive steering committee for Capacity HFpEF during the conduct of the study. Dr Burnett reported receiving payment from Cyclerion for serving on a steering committee outside the submitted work. Dr Parker reported receiving grants from Mount Sinai Hospital during the conduct of the study and grants from Merck, Aventis, LivaNova, Luitpold Pharmaceuticals, and Theracos and personal fees from Boeringher Ingelheim, LivaNova, and Ironwood Pharmaceuticals outside the submitted work. Dr Seferovic reported being a full-time employee of and receiving personal fees and stock/stock options from Cyclerion Therapeutics during the conduct of the study. Dr Wilson reported being a full-time employee of and receiving personal fees and stock/stock options from Cyclerion Therapeutics during the conduct of the study. Dr Mittleman reported receiving personal fees from Ironwood Pharmaceuticals during the conduct of the study. Dr Profy reported receiving personal fees and stock/stock options from Cyclerion Therapeutics during the conduct of the study and being an inventor on a patent application (WO2019/055859) pending for the treatment of metabolic syndrome with a soluble guanylate cyclase stimulator (assigned to Cyclerion Therapeutics). Dr Konstam reported receiving grants and personal fees from Cyclerion during the conduct of the study and grants and personal fees from Livanova and scPharmaceuticals and personal fees from Amgen, Cytokinetics, Boehringer Ingelheim, Leopold, and Bristol Myers Squibb outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow of Participants in a Study of the Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction

aOther reasons for exclusion were primarily administrative (eg, informed consent form updates, outside of window, end of recruitment). bPatients were initially randomized in a 1:1:1:1 ratio to 1 of 3 praliciguat dose groups or a placebo group. The study protocol was revised on June 27, 2018, and patients were subsequently randomized in a 1:1 ratio to either the 40-mg praliciguat group or the placebo group. cData for these patients were not included in the efficacy data analysis. dPatients may have had more than 1 reason for exclusion.

Figure 2.. Subgroup Analysis of the Primary Efficacy End Point in a Study of the Effect of Praliciguat on Peak Rate of Oxygen Consumption (V̇o2) in Patients With Heart Failure With Preserved Ejection Fraction

The median peak V̇o2 was 12.6 mL/kg/min; mean age, 70.3 years; median left ventricular ejection fraction (LVEF), 61.5%; and median N-terminal fragment of brain natriuretic peptide (NT-proBNP), 232 ng/L. The analysis models were adjusted for the stratification factors and the baseline assessments.