Ivabradine

Medical uses

It is used for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who cannot take beta blockers. It is also being used off-label in the treatment of inappropriate sinus tachycardia.

Chest pain

It may be as effective as the beta blocker atenolol and comparable with amlodipine in the management of chronic stable angina.

Heart failure

It is used in combination with beta blockers in people with heart failure with LVEF lower than 35 percent inadequately controlled by beta blockers alone and whose heart rate exceeds 70 beats per minute. In people not sufficiently managed with beta blockers for their heart failure adding ivabradine decreases the risk of hospitalization for heart failure.

Contraindications

Ivabradine is contraindicated in sick sinus syndrome, and should not be used concomitantly with potent inhibitors of CYP3A4, including azole antifungals (such as ketoconazole), macrolide antibiotics, nefazodone and the antiretroviral drugs nelfinavir and ritonavir.

Use of ivabradine with verapamil or diltiazem is contraindicated.

Adverse effects

Overall, 14.5% of patients taking ivabradine experience luminous phenomena (by patients described as sensations of enhanced brightness in a fully maintained visual field). This is probably due to blockage of I_h ion channels in the retina, which are very similar to cardiac I_f. These symptoms are mild, transient, and fully reversible. In clinical studies, about 1% of all patients had to discontinue the drug because of these sensations, which occurred on average 40 days after the drug was started.

In a large clinical trial, bradycardia (unusually slow heart rate) occurred in 2% and 5% of patients taking ivabradine at doses of 7.5 and 10 mg respectively (compared to 4.3% in those taking atenolol). 2.6–4.8% reported headaches. Other common adverse drug reactions (1–10% of patients) include first-degree AV block, ventricular extrasystoles, dizziness and/or blurred vision.

Mechanism of action

Ivabradine acts on the I_f (f is for "funny", so called because it had unusual properties compared with other current systems known at the time of its discovery) ion current, which is highly expressed in the sinoatrial node. I_f is a mixed Na⁺–K⁺ inward current activated by hyperpolarization and modulated by the autonomic nervous system. It is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. Ivabradine selectively inhibits the pacemaker I_f current in a dose-dependent manner. Blocking this channel reduces cardiac pacemaker activity, selectively slowing the heart rate and allowing more time for blood to flow to the myocardium. This is in contrast to other commonly used rate-reducing medications, such as beta-blockers and calcium channel blockers, which not only reduce heart rate, but also the cardiac contractility. Given the selective decrease in rate without loss of contractility, ivabradine may prove efficacious for treatment of congestive heart failure with reduced ejection fraction.

Coronary artery disease

The BEAUTIFUL study randomised over 10917 patients having stable coronary artery disease and left ventricle dysfunction (ejection fraction < 40%). Ivabradine did not show a significant reduction in the primary composite endpoint of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. However, in a prespecified subgroup of patients with a heart rate of more than 70 bpm, ivabradine significantly reduced the following secondary endpoints:

The SIGNIFY trial randomized 19,102 patients with coronary artery disease and a heart rate greater than 70, but without clinical heart failure to ivabradine or placebo in addition to standard therapy. Ivabradine did not improve outcomes in this patient group.

Chronic heart failure

In the SHIFT study, ivabradine significantly reduced the risk of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death by 18% (P<0.0001) compared with placebo on top of optimal therapy. These benefits were observed after 3 months of treatment. SHIFT also showed that administration of ivabradine to heart failure patients significantly reduced the risk of death from heart failure by 26% (P=0.014) and hospitalization for heart failure by 26% (P<0.0001). The improvements in outcomes were observed throughout all prespecified subgroups: female and male, with or without beta-blockers at randomization, patients below and over 65 years of age, with heart failure of ischemic or non-ischemic etiology, NYHA class II or class III, IV, with or without diabetes, and with or without hypertension.

Approval

Ivabradine was approved by the European Medicines Agency in 2005 and by the United States Food and Drug Administration in 2015.

Names

It is marketed by Amgen under the trade name Corlanor in the United States, and by Servier in the rest of the world under the trade names Procoralan (worldwide), Coralan (in Hong Kong, Singapore, Australia and some other countries), Corlentor (in Armenia, Spain, Italy and Romania) and Coraxan (in Russia and Serbia). It is also marketed in India under the brand names Ivabid and Bradia. During its development, ivabradine was known as S-16257.