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

Background and Aims: Patients 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. Methods: The 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. Results: Cilostazol 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). Conclusions: Amongst 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 Registration: ClinicalTrials.gov Identifier: NCT05126836.