Beyond Beta-Blockers: Ivabradine for CHF
The American College of Cardiology, the American Heart Association, and the Heart Failure Society of America published a consensus statement in May, 2016 on the newest pharmacological recommendations in the management of Heart Failure (HF) based on the latest literature. Ivabradine is included in this update as a potential option to further lower heart rate in certain patients with stable, chronic, symptomatic (NYHA class II-III) HF who cannot achieve a heart rate <70 beats per minute despite being treated with maximumally tolerated beta blocker doses. This is a class IIa-BR recommendation, which is a moderate recommendation based on moderate quality of evidence from a randomized controlled trial (RCT).3
The Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (SHIFT) trial was the pivotal RCT that the FDA evaluated to approve this drug. The SHIFT trial set out to assess the effect of ivabradine on outcomes in HF patients. Over 6,500 patients were enrolled and given either ivabradine or placebo.
Investigators chose a primary endpoint of the composite of cardiovascular death or hospital admission for worsening HF. Results showed an 18% relative reduction in this composite endpoint with ivabradine (24.5%) vs placebo (28.7%)(HR: 0.82; 95% CI: 0.75–0.90; p<0.0001). Individual endpoints of hospitalization for worsening HF (16% vs 21%, HR: 0.74 95% CI: 0.66–0.83; p<0.001) and death from HF (3% vs 5%; HR: 0.74 0.58–0.94; p=0.014) were both also significantly decreased, but the drug failed to show a statistically significant benefit over placebo on all-cause or cardiovascular mortality.4
The starting dose of ivabradine is 5 mg twice daily with meals and can be titrated up to 7.5 mg twice daily after two weeks, as tolerated, to achieve a resting heart rate of 50-60 beats per minute. The lower dose of 2.5 mg twice daily should be utilized in patients 75 years of age or older, those with conduction defects, or those at high risk of hemodynamic instability due to bradycardia. No dosage adjustments are necessary in patients with mild or moderate liver dysfunction or in those with a creatinine clearance above 15 mL/min. Ivabradine is contraindicated in severe liver or renal impairment.1
Common side effects seen in the SHIFT trial included bradycardia, hypertension, atrial fibrillation, and phosphenes—transient visual changes often highlighted by brightness or blurriness. This effect is thought to be caused by the inhibition of hyperpolarization-activated current in the retinal channels.
Contraindications of note include acute decompensated HF, hypotension, bradycardia, sick sinus syndrome, and use of strong CYP3A4 inhibitors.1