The effect of heart rate reduction with ivabradine on renal function in patients with chronic heart failure: an analysis from SHIFT

Aims We studied the relationship between heart rate and renal function and the effects of heart rate reduction with ivabradine in heart failure patients with and without renal dysfunction. Methods and results From the 6505 patients who were randomized in SHIFT, baseline creatinine and at least one follow-up measurement were available in 6160 patients. Median follow-up was 22.9 months. Worsening renal function (WRF) was defined as a creatinine increase of >= 0.3 mg/dL and >= 25% from the baseline value. WRF developed in 1029 (17%) patients and was directly related to baseline heart rate, with an incremental risk of 5% for every 5 b.p.m. heart rate increment (P = 0.003). WRF was associated with an increased risk of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death [hazard ratio (HR) 1.38, P < 0.001] and of all-cause mortality (HR 1.42, P < 0.001). Ivabradine use was associated with a reduction of the primary composite endpoint in patients both with (HR 0.82, P = 0.023) and without renal dysfunction (HR 0.81, P < 0.001) at baseline (P for interaction=0.89), and tolerability of ivabradine was comparable in the two groups. No differences were found in changes in renal function over time between ivabradine-and placebo-treated patients. Conclusion In chronic stable systolic heart failure patients, heart rate is directly and independently associated with the risk of WRF, but reduction in heart rate by ivabradine had a neutral effect on renal function during 2 years of follow-up. The beneficial cardiovascular effects and safety of ivabradine were similar in patients with and without renal dysfunction.