|Systematic (IUPAC) name|
|Metabolism||Hepatic (first-pass) >50%, CYP3A4-mediated|
|Biological half-life||2 hours|
|Excretion||Renal and fecal|
|Molar mass||468.585 g/mol|
|(what is this?)|
Ivabradine (INN) // is a novel medication used for the symptomatic management of stable angina pectoris. 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.
Ivabradine acts by reducing the heart rate via specific inhibition of the funny channel, a mechanism different from that of beta blockers and calcium channel blockers, two commonly prescribed antianginal drugs. Ivabradine is a cardiotonic agent.
Ivabradine was approved by the European Medicines Agency in 2005 and by the United States Food and Drug Administration in 2015. It is indicated for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who cannot take beta blockers. It is also indicated in combination with beta blockers in heart failure patients with LVEF lowers than 35 percent inadequately controlled by beta blockers alone and whose heart rate exceeds 70 beats per minute.
Apart from angina, it is also being used off-label in the treatment of inappropriate sinus tachycardia. An Italian clinical study showed significant improvement of symptoms with ivabradine compared to placebo in individuals with inappropriate sinus tachycardia. Ivabradine can possibly be used in reducing the heart rate in patients with sepsis or septic shock, along with supportive care like fluids, vasopressors, and broad spectrum antibiotics.
Adding ivabradine to heart failure medication decreases both cardiovascular death rate and risk of hospitalization for heart failure. In some countries, ivabradine was approved for the treatment of chronic heart failure with systolic dysfunction in patients with sinus rhythm and whose heart rate is ≥70 bpm.
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.
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 Ih ion channels in the retina, which are very similar to cardiac If. 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 If (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. If 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 If 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 without decreases in 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:
- Coronary events by 22% (P=0.023)
- Fatal and nonfatal myocardial infarction by 36% (P=0.001)
- Coronary revascularization by 30% (P=0.016).
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.
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