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Introduction
Heart failure with preserved ejection fraction (HFpEF) is associated with poor quality
of life and increased mortality with exercise intolerance being the main symptom.
Hypothesis
The soluble guanylate cyclase (sGC) stimulator praliciguat (PRL) may help restore
deficient NO-sGC-cGMP signaling and improve exercise capacity.
Methods
CAPACITY HFpEF was a phase 2, multicenter, randomized, double-blind, placebo-controlled
trial to evaluate the safety and efficacy of PRL over 12 weeks in patients with HFpEF
and at least 2 of 4 conditions potentially associated with NO deficiency (diabetes,
hypertension, obesity, age >70 years). Patients were randomized to PRL or placebo.
The primary endpoints were change from baseline to week 12 in peak oxygen consumption
(pVO2) by cardiopulmonary exercise testing and treatment-emergent adverse events (TEAEs).
Secondary endpoints included the change in 6-minute walk distance (6MWD), ventilatory
efficiency (VE/VCO2 slope), and the proportion of pVO2 responders (change ≥1.5 mL/kg/min). Health status was assessed using the Kansas City
Cardiomyopathy Questionnaire (KCCQ).
Results
Among 196 patients randomized (mean age 70.3 years, 57% men), 169 completed. For the
evaluable population (completed 8 weeks of dosing with no dose reduction), mean baseline
pVO2 was 13.3 and 12.8 mL O2/kg/min in PRL 40 mg (N=65) and placebo (N=78) groups, respectively. Placebo-adjusted
least squares mean changes from baseline to week 12 [95% CI] were pVO2 (-0.30 mL O2/kg/min [-0.95, 0.35] p=0.37), 6MWD (-16.7 m [-47.4, 13.9]) and VE/VCO2 slope (-0.30 [-1.59, 1.00]). The odds ratio for pVO2 response [95% CI] was 0.91 [0.40, 2.1]. KCCQ overall and domain scores did not improve
in the PRL group versus the placebo group. PRL was generally well tolerated; headache,
dizziness, and hypotension TEAEs were reported more frequently in the PRL group. The
frequency of serious TEAEs was similar between groups.
Conclusion
In a population selected to enrich for the metabolic/NO-deficient profile of HFpEF,
PRL was well tolerated but did not affect pVO2, 6MWD, VE/VCO2 slope, proportion of pVO2 responders or KCCQ scores over 12 weeks compared to placebo.
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Copyright
© 2020 Published by Elsevier Inc.
