Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study

We analysed the effect of ivabradine on outcomes in heart failure (HF) patients on recommended background therapies with heart rates >= 75 bpm and < 75 bpm in the SHIFT trial. A cut-off value of >= 75 bpm was chosen by the EMEA for approval for the use of ivabradine in chronic heart failure. The SHIFT population was divided by baseline heart rate >= 75 or < 75 bpm. The effect of ivabradine was analysed for primary composite endpoint (cardiovascular death or HF hospitalization) and other endpoints. In the >= 75 bpm group, ivabradine reduced primary endpoint (HR 0.76, 95 % CI 0.68-0.85, P < 0.0001), all-cause mortality (HR 0.83, 95 % CI, 0.72-0.96, P = 0.0109), cardiovascular mortality (HR 0.83, 95 % CI, (0.71-0.97, P = 0.0166), HF death (HR 0.61, 95 % CI, 0.46-0.81, P < 0.0006), and HF hospitalization (HR 0.70, 95 % CI, 0.61-0.80, P < 0.0001). Risk reduction depended on heart rate after 28 days, with the best protection for heart rates < 60 bpm or reductions > 10 bpm. None of the endpoints was significantly reduced in the < 75 bpm group, though there were trends for risk reductions in HF death and hospitalization for heart rate < 60 bpm and reductions > 10 bpm. Ivabradine was tolerated similarly in both groups. The effect of ivabradine on outcomes is greater in patients with heart rate >= 75 bpm with heart rates achieved < 60 bpm or heart rate reductions > 10 bpm predicting best risk reduction. Our findings emphasize the importance of identification of high-risk HF patients by high heart rates and their treatment with heart rate-lowering drugs such as ivabradine.