Meta-analysis of Ivabradine in Patients With Stable Coronary Artery Disease With and Without Left Ventricular Dysfunction

Abstract

Purpose: Ivabradine is a novel If-channel antagonist that controls heart rate and may be helpful in treating patients with left ventricular dysfunction (LVD) who are unable to tolerate β-blockers or achieve a heart rate of 70 beats/min with standard therapy. Three landmark trials were used for the approval of ivabradine in the United States. These trials tested ivabradine in addition to a standard of care (including β-blockers) in patients with stable coronary artery disease (CAD) and found modest benefit in those with established LVD unable to tolerate β-blockers. The goal of this review was to pool data from ivabradine studies in all patients with stable CAD to compare cardiovascular and safety-related outcomes.

Methods: Three randomized, double-blind, placebo-controlled trials of ivabradine added to standard treatment (including β-blockers) in patients with stable CAD with and without LVD were reviewed for effects on mortality, cardiovascular outcomes, and adverse events. Data were independently abstracted by 2 reviewers; the Oxford quality scoring system was used to evaluate randomization, blinding, withdrawals, and dropouts; and a Mantel-Haenszel random effects pairwise meta-analysis was used to combine data into odds ratios.

Findings: The initial search identified 116 trials; 3 of these trials, representing 36,524 patients with stable CAD, met inclusion criteria. According to the pooled results, ivabradine did not consistently reduce all-cause mortality (odds ratio [OR], 1.00 [95% CI, 0.91-1.11]; P = 0.98], cardiovascular death (OR, 1.02 [95% CI, 0.91-1.15]; P = 0.74), or hospitalization for worsening or new onset heart-failure in patients with stable CAD (OR, 0.94 [95% CI, 0.71-1.25]; P = 0.69). Ivabradine did not increase serious adverse drug reactions (OR, 0.99 [95% CI, 0.88-1.13]; P = 0.93) or cardiac disorders (OR, 1.03 [95% CI, 0.87-1.22]; P = 0.74). However, it was associated with drug-specific effects, including new-onset atrial fibrillation (OR, 1.35 [95% CI, 1.19-1.53]; P < 0.001], bradycardia (OR, 6.54 [95% CI, 3.30-12.9]; P < 0.001), phosphenes (OR, 7.77 [95% CI, 4.12-14.63]; P < 0.001), and blurry vision (OR, 3.07 [95% CI, 2.18-4.32]; P < 0.001).

Implications: Unselective use of ivabradine in patients with stable CAD is not supported by evidence and can be associated with new-onset atrial fibrillation, bradycardia, and drug-related nuisance adverse events.

Keywords: ivabradine; left ventricular dysfunction; outcomes; stable coronary artery disease.