Maximum tolerated medication dose and other predictors of mortality in heart failure with reduced ejection fraction: retrospective cohort study

BACKGROUND: In real-world patients with Heart Failure with reduced Ejection Fraction (HFrEF), it is unclear whether up-titration of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) and beta-blockers to maximal tolerated dose is beneficial. OBJECTIVE: To assess whether achievement of maximal tolerated heart failure therapies confers increased prognostic benefits, as compared with use of submaximal doses. DESIGN: Retrospective cohort study. PARTICIPANTS: Ambulatory HFrEF patients from two outpatient clinics in Adelaide, South Australia. MAIN MEASURES: Percentage of target dose of ACEi/ARB and beta-blocker, all-cause mortality. KEY RESULTS: Of 489 patients, with a mean age of 71 ± 14 years, 67% male, 304 (62%) died over a mean 4.0 years of follow-up. Increasing ACEi/ARB dose from 50 to 100% target dose was independently associated with improved survival (adjusted HR 0.74 [95% CI 0.63-0.87]). Similar improvement in mortality was seen with up-titration of beta-blockers (adjusted HR 0.79 [0.65-0.93]). Significant predictors associated with improved survival included younger age, systolic blood pressure in the range 100-120 mmHg, absence of comorbidities including chronic renal failure and peripheral vascular disease, and care by a multidisciplinary specialist clinic. CONCLUSIONS: This study, whilst predating angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitor use, confirms the importance of achieving maximal tolerated doses of ACEi/ARB and beta-blocker therapy, to maximise associated prognostic benefits in a real-world population. Our findings also highlight the need for continued focus on up-titration of these therapies in the ambulatory setting, and the benefits of a multidisciplinary approach.