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%; I²: 74%) with high heterogeneity across trials. Higher NYHA functional class (P < 0.001), lower systolic blood pressure (P < 0.001), diuretic use (P = 0.001), and diabetes (P < 0.001) were associated with stroke. No association of renin-angiotensin-aldosterone inhibitors, beta-blockers, 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.