Meta-analysis finds Cimlanod does not reduce mortality in HFrEF, increases hypotension risk

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 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.