Heart failure pharmacological treatments and outcomes in heart failure with mildly reduced ejection fraction

Background: Guideline recommendations for the treatment of heart failure with mildly reduced ejection fraction (HFmrEF) derive from small subgroups in post-hoc analyses of randomized trials. Objectives: We investigated predictors of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI) and beta-blockers use, and the associations between these medications and mortality/morbidity in a large real-world cohort with HFmrEF. Methods: Patients with HFmrEF (EF 40-49%) from the Swedish HF Registry were included. The associations between medications and cardiovascular (CV) mortality/HF hospitalization (HFH) and all-cause mortality were assessed through Cox regressions in a 1:1 propensity score-matched cohort. A positive control analysis was performed in patients with EF < 40%, while a negative control outcome analysis had cancer-related hospitalization as endpoint. Results: Of 12 421 patients with HFmrEF, 84% received RASI/ARNI and 88% beta-blockers. Shared independent predictors of RASI/ARNI and beta-blockers use were younger age, being an outpatient, follow-up in specialty care, hypertension. In the matched cohorts, use of both RASI/ARNI and beta-blocker use was separately associated with lower risk of CV mortality/HFH (HR = 0.90, 95%CI:0.83-0.98 and HR = 0.82, 95%CI:0.74-0.90, respectively) and of all-cause mortality (HR = 0.75, 95%CI:0.69-0.81 and HR = 0.79, 95%CI:0.72-0.87, respectively). Results were consistent at the positive control analysis, and there were no associations between treatment use and the negative control outcome. Conclusions: RASI/ARNI and beta-blockers were extensively used in this large real-world cohort with HFmrEF. Their use was safe since associated with lower mortality and morbidity. Our findings confirm in the real world evidence from previous post-hoc analyses of trials, and represent a further call for implementing guideline recommendations.