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

Abstract

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.

Keywords: Heart failure; Implementation; Pharmacotherapy; Up-titration.

Figure 1

Flow chart describing cohort selection. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; EF, ejection fraction; HF, heart failure. *Cilazapril, fosinopril, kinapril, perindopril. ^†Eprosartan, irbesartan, telmisartan. ^‡Atenolol, betaxolol, labetalol, pindolol, propranolol, sotalol, timolol.

Figure 2

Kaplan–Meier curves for the risk of cardiovascular death or heart failure hospitalization and of all‐cause death according to the percentage of target dose achieved per class of drug and their combination. Categories of monotherapy <100% of target dose not shown because of the very low number of observations, but included in the long‐rank test. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; CV, cardiovascular; HF, heart failure; TD, target dose.

Figure 3

Independent associations of the percentages of target dose achieved per class of drug with the composite outcome of cardiovascular death or heart failure hospitalization and with all‐cause death. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; CV, cardiovascular; HF, heart failure; HR, hazard ratio; TD, target dose.

Figure 4

Independent associations of the different combinations of target dose achievement for renin–angiotensin system inhibitors/angiotensin receptor–neprilysin inhibitor and β‐blocker with the composite outcome of cardiovascular death or heart failure hospitalization. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; CV, cardiovascular; HF, heart failure; HR, hazard ratio; TD, target dose.