|Systematic (IUPAC) name|
|Metabolism||Hepatic (first-pass) >50%, CYP3A4-mediated|
|Excretion||Renal and fecal|
|Mol. 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 Servier 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 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. 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 patients inadequately controlled by beta-blocker alone and whose heart rate exceeds 60 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, broad spectrum antibiotics etc.
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 cannot be used concomitantly with inhibitors of CYP3A4 such as azole antifungals (such as ketoconazole), macrolide antibiotics, nefazodone and antiretroviral drugs nelfinavir and ritonavir. Use of ivabradine with verapamil or diltiazem is now (December 2014) contra-indicated, following review by EMA.
14.5% of all 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, fully reversible and non-severe. In clinical studies about 1% of all patients had to discontinue the drug because of these sensations, which occurred on average 40 days after commencement of the drug.
Bradycardia (unusually slow heart rate) occurs at 2% and 5% for doses of 7.5 and 10 mg respectively (compared to 4.3% in 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, slowing the heart rate and allowing more time for blood to flow to the myocardium.
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).
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.
- Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K (2005). "Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina". Eur. Heart J. 26 (23): 2529–36. doi:10.1093/eurheartj/ehi586. PMID 16214830.
- Ruzyllo W, Tendera M, Ford I, Fox KM (2007). "Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial". Drugs 67 (3): 393–405. doi:10.2165/00003495-200767030-00005. PMID 17335297.
- Yusuf S, Camm AJ (2003). "Sinus tachyarrhythmias and the specific bradycardic agents: a marriage made in heaven?". J. Cardiovasc. Pharmacol. Ther. 8 (2): 89–105. doi:10.1177/107424840300800202. PMID 12808482.
- Journal of the American College of Cardiology. 2012;60:1323-9.
- Nair AS, Gopal T. Ivabradine in sepsis . J Anaesthesiol Clin Pharmacol [serial online] 2013 [cited 2014 Jun 17];29:570-1. Available from: http://www.joacp.org/text.asp?2013/29/4/570/119154
- Stiles, Steve. "SHIFT: Adding HR-slowing agent ivabradine to HF meds cuts mortality, hospitalization". TheHeart.org. Retrieved 1 April 2011.
- "European Medicine Agency, Procoralan Summary of Product Characteristics". Retrieved 2010-09-13.
- Anonymous (2006). "New medicines: Procoralan". Pharmaceutical Journal 276 (7386): 131.
- Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP (1994). "Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49". Br. J. Pharmacol. 112 (1): 37–42. doi:10.1111/j.1476-5381.1994.tb13025.x. PMC 1910295. PMID 8032660.
- Sulfi S, Timmis AD (2006). "Ivabradine – the first selective sinus node If channel inhibitor in the treatment of stable angina". Int. J. Clin. Pract. 60 (2): 222–8. doi:10.1111/j.1742-1241.2006.00817.x. PMC 1448693. PMID 16451297.
- Kim Fox, Ian Ford, P Gabriel Steg, Michal Tendera, Prof Roberto Ferrari (2008). "Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction: a randomised, double-blind, placebo-controlled trial". The Lancet 372 (9641): 807–816. doi:10.1016/S0140-6736(08)61170-8.
- Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; on behalf of the SHIFT Investigators (2010). "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study". The Lancet 376 (9744): 875–885. doi:10.1016/S0140-6736(10)61198-1. PMID 20801500.