The Risk of Atrial Fibrillation With Ivabradine Treatment: A Meta‐analysis With Trial Sequential Analysis of More Than 40000 Patients

Recent trials reported that risk of atrial fibrillation (AF) is increased in patients using ivabradine compared with controls. We performed this meta-analysis to investigate the risk of AF association with ivabradine treatment on the basis of data obtained from randomized controlled trials (RCTs). We searched PubMed, EMBASE, Scopus, and the Cochrane Library for RCTs that comprised >100 patients. The incidence of AF was assessed. We obtained data from European Medicines Agency (EMA) scientific reports for the RCTs in which the incidence of AF was not reported. We used trial sequential analysis (TSA) to provide information on when we had reached firm evidence of new AF based on a 15% relative risk increase (RRI) in ivabradine treatment. Three RCTs and 1 EMA overall oral safety set (OOSS) pooled analysis (included 5 RCTs) were included in the meta-analysis (N = 40 437). The incidence of AF was 5.34% in patients using ivabradine and 4.56% in placebo. There was significantly higher incidence of AF (24% RRI) in the ivabradine group when compared with placebo before (RR: 1.24, 95% confidence interval: 1.08-1.42, P = 0.003, I 1980 = 53%) and after excluding OOSS (RR: 1.24, 95% confidence interval: 1.06-1.44, P = 0.008). In the TSA, the cumulative z-curve crossed both the traditional boundary (P = 0.05) and the trial sequential monitoring boundary, indicating firm evidence for ≥15% increase in ivabradine treatment when compared with placebo. Study results indicate that AF is more common in the ivabradine group (24% RRI) than in controls.