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.