Abstract
Background Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and beta-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and beta-blockers with all-cause mortality and its combination with hospitalization for HF. Methods and results A total of 6787 HFrEF patients (mean age 62.6 +/- 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 +/- 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF;n = 2100) and Asian (ASIAN-HF;n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and beta-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved >= 50% GRTD for both ACEi/ARB and beta-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and beta-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating beta-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07). Conclusion This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and beta-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating beta-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.