Abstract and Introduction
Objective To quantify any risk of atrial fibrillation (AF) associated with ivabradine treatment by meta-analysis of clinical trial data.
Methods Medline, Embase, Web of Knowledge and the Cochrane central register of controlled trials were searched for double-blinded randomised controlled trials of ivabradine with a minimum follow-up period of 4 weeks. For studies where AF data were unpublished, safety data were obtained from the European Medicines Agency (EMeA) website and personal communications. Studies were appraised for risk of bias using components recommended by the Cochrane Collaboration. Meta-analyses were performed of relative risk of AF and absolute risk difference of AF per year of treatment. The main outcome measure was incident AF during the follow-up period.
Results AF data were available from 11 studies: one from the published report, six from the EMeA and four from personal communications. Ivabradine treatment was associated with a relative risk of AF of 1.15 (95% CI 1.07 to 1.24, p=0.0027) among 21 571 patients in the meta-analysis. From this we estimated that the number needed to harm for ivabradine would be 208 (95% CI 122 to 667) per year of treatment.
Conclusions AF is a substantially more common side effect of ivabradine treatment than one patient in 10 000, the risk presently reported in the product literature. The incidence of AF has not routinely been reported in clinical trials of ivabradine.
Ivabradine (Procoralan, Servier) is a heart rate lowering drug which acts by specifically inhibiting the pacemaker If current, which causes spontaneous depolarisation in the sino-atrial node that regulates the heart rate. Ivabradine was approved for use by the European Medicines Agency (EMeA) in 2005 for use in the treatment of stable angina pectoris in patients with normal sinus rhythm who are not able to tolerate β-blocker therapy. In 2010, the indication was extended to include treatment in patients with uncontrolled angina symptoms and a heart rate in excess of 60 bpm despite β-blocker therapy, following the results of the BEAUTIFUL trial. A new indication was approved in 2012, following the results of the SHIFT trial, for treatment of chronic heart failure (New York Heart Association class II–IV) with systolic dysfunction, in patients in sinus rhythm and whose heart rate is greater than 75 bpm, in combination with standard therapy, including β-blocker therapy, or when β-blockers are contraindicated or not tolerated. Use of ivabradine is yet to be approved by the US Food and Drug Administration.
Genome-wide association studies have identified associations between genetic variants in the region of the gene HCN4, which codes for the main ion channel responsible for the If current, and both heart rate and atrial fibrillation (AF). The pulmonary venous myocardium, which is an important source of AF initiation and maintenance, demonstrates an If current which is affected by ivabradine. This raises the possibility that ivabradine treatment may affect AF risk. AF is common in patients with coronary artery disease and cardiac failure and so incident AF in the target population for ivabradine treatment would not necessarily be attributed to the drug. It has been shown that genome-wide association study hits can identify therapeutic targets and provide insight into drug side effects. For example, a single nucleotide plymorphism (SNP) in the tumour necrosis factor receptor 1 gene which is associated with multiple sclerosis (MS) risk has been shown to explain the mechanism whereby antitumour necrosis factor therapies typically exacerbate MS. We therefore examined whether there was a significant increase in AF risk associated with ivabradine treatment by meta-analysis, and quantified that risk in terms of number needed to harm (NNH) per year.