Clinical data | |
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Pronunciation | /ɪˈvæbrədiːn/ |
Trade names | Corlanor, Procoralan, others |
Other names | S-16257 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a615027 |
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Routes of administration | By mouth |
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Pharmacokinetic data | |
Bioavailability | 40% |
Protein binding | 70% |
Metabolism | Liver (first-pass) >50%, CYP3A4-mediated |
Elimination half-life | 6 hours |
Excretion | Kidney and fecal |
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Chemical and physical data | |
Formula | C27H36N2O5 |
Molar mass | 468.594 g·mol−1 |
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Ivabradine, sold under the brand name Procoralan among others, is a medication, which is a pacemaker current (If) inhibitor, used for the symptomatic management of heart-related chest pain and heart failure. Patients who qualify for use of ivabradine for coronary heart failure are patients who have symptomatic heart failure, with reduced ejection volume, and heart rate at least 70 bpm, and the condition not able to be fully managed by beta blockers. [3]
Ivabradine acts by allowing negative chronotropy in the sinoatrial structure, thus reducing the heart rate via specific inhibition of the pacemaker current. It operates by a mechanism different from that of beta blockers and calcium channel blockers, which are two commonly prescribed antianginal classes of cardiac drugs. Ivabradine has no apparent inotropic properties and may be a cardiotonic agent.
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 (IST). [4] Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST. [5]
Ivabradine is as effective as the beta blocker atenolol and comparable with amlodipine in the management of chronic stable angina, as demonstrated by improvements in total exercise duration in non-inferiority trials, hence it can be an alternative therapy for those who cannot tolerate conventional therapies. [6] [7] In people not sufficiently managed with beta blockers for their angina, adding ivabradine can further reduce heart rate and improve total exercise duration. [8]
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. [9] In people not sufficiently managed with beta blockers for their heart failure adding ivabradine decreases the risk of hospitalization for heart failure. [3]
The clinical use of ivabradine is predicated on its mechanism of action on sinoatrial nodal tissue where it selectively inhibits the funny current (If) and results in a decrease in heart rate. [10]
Ivabradine’s most frequent application in electrophysiology is for the treatment of inappropriate sinus tachycardia. Its use for inappropriate sinus tachycardia is not a European Medicines Agency or Food and Drug Administration approved indication for ivabradine. [10]
It has been used experimentally for the treatment of postural orthostatic tachycardia syndrome in patients with long COVID. [11] It was used for POTS prior to this too. Many cardiologists have found success with this in their POTS patients.
Ivabradine is contraindicated in sick sinus syndrome. It should also 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. [12]
Use of ivabradine with verapamil or diltiazem is contraindicated. [13]
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. [6]
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). [6] Headaches were reported in 2.6 to 4.8 percent of cases. [6] Other common adverse drug reactions (1–10% of patients) include first-degree AV block, ventricular extrasystoles, dizziness and/or blurred vision. [14]
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. [15] [16] By inhibiting the If channel, ivabradine reduces the heart rate and workload on the heart. This is relevant in the usage of the medication to treat angina as well as congestive heart failure. 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.
Ivabradine binds to HCN4 receptors (potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4), utilizing Y506, F509 and I510 residues. [17]
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 baseline heart rate of more than 70 bpm, ivabradine significantly reduced the following secondary endpoints: [18]
These results were seen in combination therapy with beta blockers, and were found to be safe and effective in improving coronary artery disease outcomes in patients with heart rates of 70 bpm or more. [19]
The SIGNIFY trial randomised 19102 patients with stable coronary artery disease and an elevated heart rate greater than 70 beats per minute were assigned to an intervention of ivabradine or placebo in addition to standard therapy. Ivabradine did not significantly improve the secondary outcomes in patient groups, however did demonstrate a reduction in heart rate. When compared to the SHIFT study, a reduction in cardiovascular death or hospital admission was also demonstrated and hence should be considered when additional therapy is in question. [20] [21]
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. [22] 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. [23] A 2020 Cochrane review found no difference in cardiovascular mortality and serious adverse events between long-term treatment with ivabradine and placebo/usual care/no treatment in participants with heart failure with a reduced ejection fraction. [24]
A note of caution must be emphasised. Ivabradine, though indicated for chronic heart failure in patients who are clinically stable, is not indicated in acute heart failure where the enhanced heart rate represents cardiac reserve. Indiscriminate use of Ivabradine could destabilise these patients.
Ivabradine was approved by the European Medicines Agency in 2005, and by the United States Food and Drug Administration in 2015. [25]
It is marketed by Amgen under the brand name Corlanor in the United States, [26] and by Servier in the rest of the world under the brand names Procoralan (worldwide), Coralan (in Hong Kong, Singapore, Australia and some other countries), Corlentor (in Armenia, Spain, Italy and Romania), Lancora (in Canada) and Coraxan (in Russia and Serbia). It is also marketed in India under the brand names Ivabrad, Ivabid. In Iran it's sold under the brand name "bradix" . IVAMAC and Bradia. During its development, ivabradine was known as S-16257.
An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.
Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathologic processes, it is commonly a physiologic response to cardiovascular conditioning or due to asymptomatic type 1 atrioventricular block.
Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.
Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina, and supraventricular tachycardia. It may also be used for the prevention of migraines and cluster headaches. It is given by mouth or by injection into a vein.
Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure, coronary artery disease (CAD) and variant angina. It is taken orally.
Nifedipine, sold under the brand name Procardia among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. It is one of the treatments of choice for Prinzmetal angina. It may be used to treat severe high blood pressure in pregnancy. Its use in preterm labor may allow more time for steroids to improve the baby's lung function and provide time for transfer of the mother to a well qualified medical facility before delivery. It is a calcium channel blocker of the dihydropyridine type. Nifedipine is taken by mouth and comes in fast- and slow-release formulations.
Diltiazem, sold under the brand name Cardizem among others, is a nondihydropyridine calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used. It is taken by mouth or injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours.
Metoprolol, sold under the brand name Lopressor among others, is a medication used to treat angina and a number of conditions involving an abnormally fast heart rate. It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with migraines. It is a selectiveβ1 receptor blocker medication. It is taken by mouth or is given intravenously.
Trimetazidine is a drug sold under many brand names for angina pectoris. Trimetazidine is described as the first cytoprotective anti-ischemic agent developed and marketed by Laboratoires Servier (France). It is an anti-ischemic (antianginal) metabolic agent of the fatty acid oxidation inhibitor class, meaning that it improves the heart muscle's ability to use glucose as a fuel by inhibiting its use of fatty acid metabolism. It has become controversial for its use as a performance-enhancing drug, with several scandals involving its use erupting at successive Olympic games.
Sinus tachycardia is a sinus rhythm of the heart, with an increased rate of electrical discharge from the sinoatrial node, resulting in a tachycardia, a heart rate that is higher than the upper limit of normal.
Carvedilol, sold under the brand name Coreg among others, is a beta blocker medication, that may be prescribed for the treatment of high blood pressure (hypertension) and chronic heart failure with reduced ejection fraction. Beta-blockers as a collective medication class are not recommended as routine first-line treatment of high blood pressure for all patients, due to evidence demonstrating less effective cardiovascular protection and a less favourable safety profile when compared to other classes of blood pressure-lowering medications.
Inappropriate sinus tachycardia (IST) is defined as sinus tachycardia that is not caused by identifiable medical ailments, a physiological reaction, or pharmaceuticals (a diagnosis of exclusion) and is accompanied by symptoms, frequently invalidating and affecting quality of life. IST symptoms include palpitations, chest discomfort, exhaustion, shortness of breath, presyncope, and syncope.
Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.
The pacemaker current is an electric current in the heart that flows through the HCN channel or pacemaker channel. Such channels are important parts of the electrical conduction system of the heart and form a component of the natural pacemaker.
Multifocal atrial tachycardia (MAT) is an abnormal heart rhythm, specifically a type of supraventricular tachycardia, that is particularly common in older people and is associated with exacerbations of chronic obstructive pulmonary disease (COPD). Normally, the heart rate is controlled by a cluster of cells called the sinoatrial node. When a number of different clusters of cells outside the SA node take over control of the heart rate, and the rate exceeds 100 beats per minute, this is called multifocal atrial tachycardia.
Clevidipine is a dihydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Clevidipine is used IV only and practitioners titrate this drug to lower blood pressure. It has a half-life of approximately one minute. It is rapidly inactivated by esterases.
Landiolol (INN) is an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other beta blockers, landiolol has the shortest elimination half-life, ultra-rapid onset of effect, and predictable effectiveness with inactive metabolites. The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired. It is used as landiolol hydrochloride.
Acute decompensated heart failure (ADHF) is a sudden worsening of the signs and symptoms of heart failure, which typically includes difficulty breathing (dyspnea), leg or feet swelling, and fatigue. ADHF is a common and potentially serious cause of acute respiratory distress. The condition is caused by severe congestion of multiple organs by fluid that is inadequately circulated by the failing heart. An attack of decompensation can be caused by underlying medical illness, such as myocardial infarction, an abnormal heart rhythm, infection, or thyroid disease.
Roberto Ferrari is an Italian cardiologist who holds the position of Emeritus Professor at the University of Ferrara, where besides he was the chair of the Cardiology in the School of Medicine until the 2019–2020 academic year.
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