Efficacy and Safety of Ivabradine in Combination with Beta-Blockers in Patients with Stable Angina Pectoris: A Systematic Review and Meta-analysis

INTRODUCTION: Beta-blockers are recommended by the European Society of Cardiology as first-line antianginal therapy for reducing heart rate (HR) and symptoms in patients with chronic coronary syndrome, despite a lack of data showing superiority to other antianginal agents. Most patients with angina pectoris require combination therapy to manage symptoms, with a second-line agent chosen to manage the predominant cardiovascular problem. Ivabradine, a selective sinus node I(f) channel inhibitor shown to reduce HR and protect against anginal symptoms, has previously demonstrated noninferior anti-ischaemic and antianginal efficacy to beta-blockers. METHODS: This systematic review and meta-analysis assessed the efficacy and safety of ivabradine in patients with stable angina pectoris who remained symptomatic despite receiving beta-blockers. Keyword searches of PubMed, The Cochrane Central Library Register, ClinicalTrials.gov, The World Health Organization International Clinical Trials Registry Platform (ICTRP) and Google Scholar identified studies comparing ivabradine plus beta-blockers with placebo or other first- or second-line antianginal agents in patients with stable angina pectoris. No date limits or language restrictions were applied. Outcomes were evaluated after 1 and 4 months of treatment, including changes in HR, angina attacks, use of short-acting nitrates, quality of life and safety. Risk of bias was evaluated on the basis of recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Seven relevant studies were identified (N = 6821). Ivabradine plus a beta-blocker consistently reduced HR, anginal symptoms and short-acting nitrate consumption within 1 month of initiating therapy, with continued reductions for up to 4 months. Furthermore, ivabradine plus beta-blocker therapy was well tolerated, with bradycardia rarely reported (0.1% of patients overall). This study is limited by the inclusion of only two randomised studies, which may lead to result interpretation bias. CONCLUSIONS: Ivabradine may be valuable for tailoring early antianginal treatment when used in combination with beta-blockers for chronic stable angina inadequately controlled by beta-blockers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12325-022-02222-1.