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

Abstract

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 and results: 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. 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, and hypertension. In the matched cohorts, use of both RASI/ARNI and beta-blocker use was separately associated with lower risk of CV mortality/HFH [hazard ratio (HR) = 0.90, 95% confidence interval (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 the real-world evidence from previous post-hoc analyses of trials, and represent a further call for implementing guideline recommendations.

Keywords: Beta-blockers; Heart failure; Mildly reduced ejection fraction; Registry; Renin–angiotensin system inhibitors; SwedeHF.

Graphical Abstract

The overall study cohort counted on 12 421 patients with mildly reduced ejection fraction heart failure (HFmrEF). Two sensitivity outcome analyses were adopted, the first conducted on the same population with cancer hospitalization as an outcome (falsification analysis), and the second on 26 143 patients with reduced ejection fraction heart failure (HFrEF). In the upper right panel: use of RASI/ARNI and beta-blockers and percentage of target dose achievement in the overall study population with HFmrEF (n = 12 421). In the bottom panels: Kaplan–Meier curves for the association between RASI/ARNI use (left panel) and the composite outcome (cardiovascular mortality or heart failure hospitalization) and between beta-blockers use (right panel) and the composite outcome. CI, confidence interval; HR, hazard ratio; RASI/ARNI, renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitor; TD, target dose.

Figure 1

Predictors of treatment with RASI/ARNI and beta-blockers in the overall HFmrEF cohort. BMI, body mass index; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, heart rate; ICD, implantable cardioverter defibrillator; MAP, mean arterial pressure; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; NT-proBNP, N-terminal pro-brain natriuretic peptide; RASI/ARNI, renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitor; TIA, transient ischaemic attack.

Figure 2

Kaplan–Meier curves for the association between RASI/ARNI use (left panel) and the composite outcome (cardiovascular mortality or heart failure hospitalization) and between beta-blockers use (right panel) and the composite outcome. CI, confidence interval; HR, hazard ratio; RASI/ARNI, renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitor.