Cilostazol in patients with heart failure and preserved ejection fraction—The CLIP‐HFpEF trial

Abstract

Background and AimsPatients with heart failure with preserved ejection fraction (HFpEF) tend to have low resting and exercise heart rates. Phosphodiesterase‐3 (PDE‐3) inhibitors improve heart rates, haemodynamics and symptoms in patients with HFpEF. Cilostazol is an oral PDE‐3 inhibitor used in peripheral artery disease. This study thought to evaluate the short‐term effects of cilostazol on health status, N‐terminal brain natriuretic peptide (NT‐proBNP) levels and mechanisms of action.MethodsThe effect of cilostazol was evaluated in 23 patients with HFpEF in a randomized placebo controlled multiple crossover trial (CLIP‐HFpEF). Participants received placebo or cilostazol for 1 week followed by three crossovers to the alternate assignment at weeks 2, 3 and 4. The primary endpoint was the Kansas City Cardiomyopathy Questionnaire (KCCQ‐12) overall summary score obtained at the end of each treatment period. NT‐proBNP was the secondary endpoint. In an exploratory mechanistic analysis, pulmonary artery (PA) pressures and heart rates were followed amongst the five participants with implanted pressure monitors.ResultsCilostazol improved the KCCQ score by 4.8 points (95% confidence interval, 2.0–7.7, P = 0.003). NT‐proBNP levels were 448 (154–1056) pg/mL on placebo and 375 (68–974) pg/mL on cilostazol (P = 0.006). In patients with PA pressure monitors, diastolic pressure was 20.5 (18.7–23.0) mmHg on placebo and 18.0 (17.0–20.0) mmHg on cilostazol, an effect linked to higher heart rates (P < 0.001).ConclusionsAmongst patients with HFpEF, short‐term treatment with cilostazol leads to improvements in health status and NT‐proBNP when compared with placebo. These effects are likely conveyed by a heart rate‐dependent reduction in cardiac filling pressures.Trial RegistrationClinicalTrials.gov Identifier: NCT05126836.