Ivabradine is most appropriately used as a second-line treatment for systolic heart failure (HF) and chronic stable angina, according to a review published September 25 in the Journal of the American College of Cardiology.

Ivabradine selectively inhibits the pacemaker current in sinoatrial node tissue, decreasing the rate of diastolic depolarization. This action causes a dose-dependent reduction in heart rate without affecting cardiac inotropy or systemic vascular resistance. The most common cardiovascular side effect is bradycardia. Ivabradine is contraindicated in patients with sinus bradycardia or significant sick sinus syndrome and should be avoided in patients with arrhythmias. A meta-analysis reported a 15 percent increase in relative risk for atrial fibrillation (AFib).

Ivabradine has been evaluated as a treatment for coronary artery disease (CAD) and HF. In several early studies, it improved exercise tolerance and time to development of ischemia during exercise, and reduced angina severity. In the BEAUTIFUL trial, ivabradine reduced the mean heart rate in patients with CAD but did not improve the primary endpoint, a composite of cardiovascular death, admission for acute myocardial infarction (MI) or new or worsening HF. However, in patients with heart rates >=70 beats/min ivabradine reduced fatal and nonfatal MI admissions (hazard ratio [HR], 0.64; p = 0.001) and coronary revascularizations (HR, 0.70; p = 0.016). A post-hoc analysis in patients with activity-limiting angina had a 24 percent reduction in the primary endpoint, largely driven by a 42 percent reduction in hospitalization for MI.

In the SIGNIFY trial in patients with CAD and a heart rate >=70 beats/min, ivabradine reduced heart rate by 10 beats/min but did not affect the primary endpoint of cardiovascular death or nonfatal MI. The primary endpoint actually increased among patients with activity-limiting angina.

The SHIFT trial in patients with HF, left ventricular ejection fraction (LVEF) <=35 percent and heart rate >=70 beats/min reported the primary outcome of cardiovascular death or hospital admission for worsening HF was reduced by 18 percent with ivabradine vs. placebo (HR, 0.82; p < 0.00001), driven primarily by a 26 percent reduction in HF hospitalizations. There were also reductions in HF deaths (26 percent), all-cause hospitalizations (11 percent) and cardiovascular hospitalizations (15 percent).

Ivabradine significantly reduced heart rates, increased LVEF and lowered B-type natriuretic peptide in patients with acute HF, but had no effect on mortality or HF hospitalizations. In patients with HF with preserved ejection fraction, ivabradine failed to improve any of the co-primary endpoints. Results of a small study suggested short-term efficacy in patients with inappropriate sinus tachycardia (IST) but additional studies are needed.

Ivabradine is approved in the United States and Europe for HF and in Europe for angina. The authors wrote that "Its role in the treatment of IST and other electrophysiological disorders, although encouraging, lacks the support of large studies and currently remain unapproved indications."