Abstract
INTRODUCTION: Heart failure (HF), a leading cause of morbidity and mortality worldwide, continues to pose a therapeutic challenge. Nitroxyl (HNO) donors, such as Cimlanod (BMS-986231 or CXL-1427), are emerging as promising agents owing to their unique vasodilatory, inotropic, and lusitropic properties. PURPOSE: This meta-analysis assesses the safety, tolerability, and hemodynamic effects of Cimlanod, in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: This study consists of four studies, including 459 patients (278 receiving Cimlanod and 181 receiving placebo). The mean age was 63.9 years, 85% were male, and common comorbidities included hypertension (77%) and diabetes (45.7%). Outcomes were evaluated using risk ratios (RR) for binary end points and mean differences (MD) for continuous variables, with 95% confidence intervals (CI) and I(2) for heterogeneity. Study quality followed Cochrane methods. Primary outcomes included cardiovascular mortality, hemodynamic measures, and severe adverse events. The protocol was prospectively registered in PROSPERO (CRD420250652675; Feb 2025). RESULTS: Cimlanod did not significantly reduce all-cause mortality (RR = 0.96; 95% CI 0.88-1.04; p = 0.15), cardiac death (RR = 0.75; 95% CI 0.37-1.54; p = 0.43), adverse events (RR = 1.51; 95% CI 0.94-2.44; p = 0.073), or serious adverse events (RR = 0.83; 95% CI 0.46-1.48; p = 0.429), when compared with placebo. Although a significantly increased risk of symptomatic hypotension was observed with the use of Cimlanod (RR = 2.22; 95% CI 1.56-3.15; p < 0.01) but no significant effect on systolic or diastolic blood pressure or heart rate was observed in the pooled analyses, whereas significant drop in systolic blood pressure (SBP) (MD - 10.41, 95% CI - 19.89 to - 0.93) was observed with highest dose of Cimlanod i.e. 12 μcg/kg/min. CONCLUSIONS: Cimlanod did not improve mortality, major hemodynamic end points, or biomarkers and increased the risk of symptomatic hypotension. Although a modest improvement in cardiac index was observed, evidence does not currently support routine clinical use, and further studies are required to identify whether any specific subgroup may benefit. REGISTRATION: PROSPERO identifier number CRD420250652675.