Effects on outcomes of heart rate reduction by Ivabradine in patients with congestive heart failure: Is there an influence of beta-blocker dose? Findings from the SHIFT (Systolic Heart Failure Treatment with I-f inhibitor ivabradine Trial) Study

Objectives: This study used the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) database to assess the impact of background beta-blocker dose on response to ivabradine. Background: In systolic heart failure, reduction in relatively high heart rates improves clinical outcomes when achieved with beta-blockers and even more so when the sinus node inhibitor ivabradine also is added. Methods: Among patients with systolic heart failure, sinus rhythm, and heart rate >= 70 beats/min on recommended background therapy, maximally tolerated beta-blocker doses were subgrouped as no beta-blocker, <25%, 25% to <50%, 50% to <100%, and 100% of European Society of Cardiology-suggested target doses. The impact of ivabradine on cardiovascular death or heart failure hospitalization (primary endpoint) was analyzed in each subgroup as time-to-first event using Cox models adjusted for heart rate. The statistical models assessed heterogeneity and trend of the treatment effect across subgroups, and an additional analysis was made adjusting for the interaction of randomized treatment with baseline heart rate. Results: The primary endpoint and heart failure hospitalizations were significantly reduced by ivabradine in all subgroups with <50% of target beta-blocker dose, including no beta-blocker (p = 0.012). Despite an apparent trend to reduction in treatment-effect magnitude with increasing beta-blocker dose, no variation in treatment effect was seen in general heterogeneity interaction tests (p = 0.35). Across beta-blocker subgroups, treatment effect was borderline nonsignificant only for the primary endpoint (p = 0.056), and significance was further lost after adjusting for interaction between baseline heart rate and ivabradine effect (p = 0.14). Conclusions: The magnitude of heart rate reduction by beta-blocker plus ivabradine, rather than background beta-blocker dose, primarily determines subsequent effect on outcomes