Aims:
It is not known whether heart rate (HR) reduction with ivabradine provides similar effects across risk groups in heart failure (HF). We analyzed the treatment effect of HR reduction with ivabradine in patients with HF at high-risk indicated by left ventricular ejection fraction (LVEF) <= 25%, New York Heart Association (NYHA) Class III/IV, systolic blood pressure (SBP) < 110 mmHg, HR >= 75 bpm and its combinations. 

Methods and results:

From the 6505 patients who were randomized in SHIFT trial (LVEF <=35% and HR >=70 beats/min), 186 high-risk patients were compared to 6313 patients with (NYHA class II, LVEF >25%, SBP >= 110 mmHg and HR <75 bpm). All patients were randomized to ivabradine or placebo on a background of guideline-defined standard care. The effect of ivabradine was analysed for primary composite endpoint (cardiovascular death or HF hospitalization). Compared to placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint in patients with SBP <=110 vs. >110 mmHg (HR 0.89, 95 % CI 0.74–1.08 vs. HR 0.80, 95 % CI 0.72–0.89, P interaction=0.34), LVEF <=25% vs. >25% (HR 0., 85 % CI 0.72–1.01 vs. HR 0.80, 95 % CI 0.71–0.90, P interaction=0.53), NYHA II vs. III-IV  (HR 0, 82 % CI 0.70–0.95 vs. HR 0.83, 95 % CI 0.74–0.94, P interaction=0.43) and HR >=75 vs. HR <75 bpm (HR 0, 77 % CI 0.69–0.86 vs. HR 0.97, 95 % CI 0.81–0.1.16, P =0.25). Treatment with ivabradine in high-risk HF patients was associated with risk reductions comparable to low-risk patients for the primary end point (29% reduction), all-cause death (22%), cardiovascular death (21%), HF death (49%), and HF hospitalization (38%; all p values for interaction: 0.87). 

Conclusion:
In conclusion, our analysis shows that HR reduction with ivabradine in high-risk HF patients improves clinical outcomes across several risk conditions. In those, despite similar relative risk reductions the absolute risk reduction was higher, and the number needed to treat lower to prevent events.