Stroke in Heart Failure With Reduced Ejection Fraction Systematic Review and Meta-Analysis of Randomized Trials

BACKGROUND Patients with heart failure with reduced ejection fraction (HFrEF) have a heightened stroke risk. However, stroke as an endpoint in heart failure trials remains under-reported. OBJECTIVES The authors sought to define the incidence, characteristics, predictors, modifier treatments, and prognostic impact of stroke in patients with HFrEF who were enrolled in randomized controlled trials (RCTs). METHODS The authors systematically reviewed MEDLINE for RCTs of pharmacologic and nonpharmacologic treatments in HFrEF. The annualized stroke incidence was the primary outcome. Subgroup analyses and meta-regressions were performed to determine the baseline modulating characteristics and to assess the association of stroke with other clinical outcomes. RESULTS Of 7,104 records, 188 RCTs fulfilled inclusion criteria for the systematic review. Of these, 158 studies (84.0%) did not report stroke outcomes and were excluded from the meta-analysis, leading to a final cohort of 30 studies, with 61 arms and 75,327 patients. Stroke incidence was 1.1% (95% CI: 0.9%-1.3%; I-2: 74%) with high heterogeneity across trials. Higher NYHA functional class (P < 0.001), lower systolic blood pressure (P < 0.001), diuretic use (P 1/4 0.001), and diabetes (P < 0.001) were associated with stroke. No association of renin-angiotensin-aldosterone inhibitors, betablockers, mineralocorticoid receptor antagonists, and transcatheter mitral valve replacement with stroke was observed. Stroke was associated with higher risk of all-cause and cardiovascular mortality, heart failure hospitalization and acute coronary syndromes (P < 0.001 for all). CONCLUSIONS Stroke was reported in a vast minority of HFrEF RCTs with heterogeneous definitions and no reference to underlying mechanisms. Despite under-reporting, stroke incidence is non-negligible. Stroke is associated with HFrEF specific characteristics and outcomes, whereas it is not impacted by current HFrEF treatments. There is a need for dedicated research into preventive strategies and effective treatments to address this debilitating and deadly comorbidity. (Stroke Events in Heart Failure With Reduced Ejection Fraction-A Systematic Review and Meta-Analysis of Pharmacologic Randomized Trial; CRD42023418422) (JACC Heart Fail. 2025;13:102389) (c) 2025 by the American College of Cardiology Foundation.