Association between dosing and combination use of medications and outcomes in heart failure with reduced ejection fraction: data from the Swedish Heart Failure Registry

Aims: To assess the association between combination, dose and use of current guideline-recommended target doses (TD) of renin–angiotensin system inhibitors (RASi), angiotensin receptor–neprilysin inhibitors (ARNi) and β-blockers, and outcomes in a large and unselected contemporary cohort of patients with heart failure (HF) and reduced ejection fraction. Methods and results: Overall, 17 809 outpatients registered in the Swedish Heart Failure Registry (SwedeHF) from May 2000 to December 2018, with ejection fraction <40% and duration of HF ≥90 days were selected. Primary outcome was a composite of time to cardiovascular death and first HF hospitalization. Compared with no use of RASi or ARNi, the adjusted hazard ratio (HR) (95% confidence interval [CI]) was 0.83 (0.76–0.91) with <50% of TD, 0.78 (0.71–0.86) with 50%–99%, and 0.73 (0.67–0.80) with ≥100% of TD. Compared with no use of β-blockers, the adjusted HR (95% CI) was 0.86 (0.76–0.91), 0.81 (0.74–0.89) and 0.74 (0.68–0.82) with <50%, 50%–99% and ≥100% of TD, respectively. Patients receiving both an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB)/ARNi and a β-blocker at 50%–99% of TD had a lower adjusted risk of the primary outcome compared with patients only receiving one drug, i.e. ACEi/ARB/ARNi or β-blocker, even if this was at ≥100% of TD. Conclusion: Heart failure with reduced ejection fraction patients using higher doses of RASi or ARNi and β-blockers had lower risk of cardiovascular death or HF hospitalization. Use of two drug classes at 50%–99% of TD dose was associated with lower risk than one drug class at 100% of TD