Ivabradine
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Ivabradine, sold under the brand name Procoralan among others, is a
medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
, which is a pacemaker current (I''f'') inhibitor, used for the symptomatic management of heart-related chest pain and
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
. Patients who qualify for use of ivabradine for congestive heart failure are patients who have symptomatic heart failure, with reduced ejection fraction, and heart rate at least 70 bpm, and the condition not able to be fully managed by
beta blockers 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 (secondary prevention). ...
. Ivabradine acts by allowing negative chronotropy in the sinoatrial structure, thus reducing the
heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
via specific inhibition of the pacemaker current. It operates by a mechanism different from that of
beta blocker 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 ( secondary prevention ...
s and
calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...
s, which are two commonly prescribed
antianginal An antianginal is a drug used in the treatment of ''angina pectoris'', a symptom of ischaemic heart disease. Myocardial ischemia arises from the dysfunction of coronary macrovascular or microvascular components, leading to a compromised supply o ...
classes of cardiac drugs. Ivabradine has no apparent inotropic properties and may be a cardiotonic agent.


Medical uses

It is used for the symptomatic treatment of chronic stable
angina pectoris 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. Angina is typically the result of part ...
in patients with normal
sinus rhythm A sinus rhythm is any cardiac rhythm in which depolarisation of the cardiac muscle begins at the sinus node. It is necessary, but not sufficient, for normal electrical activity within the heart. On the electrocardiogram (ECG), a sinus rhythm ...
who cannot take
beta blockers 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 (secondary prevention). ...
. It is also being used off-label in the treatment of inappropriate sinus tachycardia (IST). Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST.


Chest pain

Ivabradine is as effective as the beta blocker
atenolol Atenolol is a beta blocker medication primarily used to treat high blood pressure and angina, heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality rate, mortality in those with the condi ...
and comparable with
amlodipine Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat hypertension, high blood pressure, coronary artery disease (CAD) and variant angina (also called Prinzmetal angina or coronary ar ...
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. In people not sufficiently managed with beta blockers for their angina, adding ivabradine can further reduce heart rate and improve total exercise duration.


Heart failure

It is used in combination with beta blockers in people with
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
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.


Tachycardia

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. 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. It has been used experimentally for the treatment of
postural orthostatic tachycardia syndrome Postural orthostatic tachycardia syndrome (POTS) is a condition characterized by an abnormally large increase in heart rate upon sitting up or standing. POTS is a disorder of the autonomic nervous system that can lead to a variety of symptoms, ...
in patients with
long COVID Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...
. It was used for POTS prior to this too. Many cardiologists have found success with this in their POTS patients.


Contraindications

Ivabradine is contraindicated in
sick sinus syndrome Sinus node dysfunction (SND), also known as sick sinus syndrome (SSS), is a group of abnormal heart rhythms (arrhythmias) usually caused by a malfunction of the sinus node, the heart's primary pacemaker. Tachycardia-bradycardia syndrome is a varia ...
. It should also not be used concomitantly with potent inhibitors of
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
, including
azole antifungals Azoles are a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom (i.e. nitrogen, sulfur, or oxygen) as part of the ring. Their names originate from the Hantzsch–Widman nomenclature. T ...
(such as
ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...
),
macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...
antibiotics,
nefazodone Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant medication which is used in the treatment of depression and for other uses. Nefazodone was withdrawn in most countries by ...
and the antiretroviral drugs
nelfinavir Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitor (pharmacology), protease inhibitors (PIs) and like other PIs ...
and
ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhi ...
. Use of ivabradine with
verapamil Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be use ...
or
diltiazem 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 b ...
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 The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
, 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 Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...
(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).
Headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
s were reported in 2.6 to 4.8 percent of cases. Other common
adverse drug reaction An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or may result from the combination of two or more drugs. The meaning of this ...
s (1–10% of patients) include first-degree
AV block AV, Av or A.V. may refer to: Arts and entertainment * The abbreviation of audiovisual, possessing both a sound and a visual component * ''A.V.'' (film), a 2005 Hong Kong film directed by Pang Ho-Cheung * Adult video, an alternative name/synonym ...
, 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 The sinoatrial node (also known as the sinuatrial node, SA node, sinus node or Keith–Flack node) is an ellipse, oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of Cell (biology), cells known as pa ...
. 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 image:ConductionsystemoftheheartwithouttheHeart-en.svg, 350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical conduction system of the heart The cardiac pacemaker is the heart's natural rhythm gener ...
activity, selectively slowing the heart rate and allowing more time for blood to flow to the myocardium. By inhibiting the I''f'' 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 Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. It is the maximum attainable value for the force of contraction of a given heart. The ability to produce changes in force during ...
. 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.


Clinical trials


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 baseline 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). 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. 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.


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. 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. 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.


Society and culture


Approval

Ivabradine was approved by the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
in 2005, and by the United States
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
in 2015.


Alleged conflict of interest

According to a documentary and article of the Danish media channel TV2 in September 2024, a former president of the
European Society of Cardiology The European Society of Cardiology (ESC) is an independent Nonprofit organisation, non-profit, non-governmental professional association that works to advance the prevention, diagnosis and management of diseases of the heart and blood vessels, a ...
during 2006-2008, professor Kim Fox, had a conflict of interest in relation to clinical trials of ivabradine and his recommendation of ivabradine based on the trials. According to TV2, Fox and his partner founded a company, Heart Research Ltd., which performed clinical trials and received payments from the pharmaceutical industry, allowing them to extract a total profit of 500 million DKK (67 million euro) during 2003-2015, mostly from a cooperation with the French pharmaceutical company
Servier Servier Laboratories (French: Laboratoires Servier, often abbreviated to Servier) is an international Pharmaceutical industry, pharmaceutical company governed by a non-profit foundation, with its headquarters in France (Suresnes). The consolida ...
. According to TV2's research of
financial statement Financial statements (or financial reports) are formal records of the financial activities and position of a business, person, or other entity. Relevant financial information is presented in a structured manner and in a form which is easy to un ...
s of the company, in the period of 2004-2006, the couple received a salary of over 20 million DKK (2.7 million euro) from their company, while during the same period, Kim Fox was chairman of the taskforce recommending ivabradine, and as president of the European Society of Cardiology, he also had the role of presenting the research results and recommending ivabradin as a "gold standard" treatment at a European cardiological conference in 2008. Karsten Juhl Jørgensen, professor of medicine and
conflict of interests A conflict of interest (COI) is a situation in which a person or organization is involved in multiple interests, financial or otherwise, and serving one interest could involve working against another. Typically, this relates to situations in whi ...
expert at
Odense University Odense University was a university in Odense, Denmark. It was established in 1966. In 1998, the university was merged with two other institutions to form the University of Southern Denmark. Its campus is now known as University of Southern Denmar ...
and the Nordic Cochrane Centre, commented that the conflict of interest was "probably the largest he had seen". Danish
chief physician A chief physician, also called a head physician, physician in chief, senior consultant, or chief of medicine, is a physician in a senior management position at a hospital or other institution. In many institutions, it is the title of the most sen ...
Niels Holmark Andersen commented that Fox's conflict of interest was of an " oligarchal magnitude" and "the mother of all conflicts of interests" because Fox was involved in all parts of the process, that the clinical results did not sustain claims of the superiority of the medication which has serious adverse effect, and further that Servier had marketed ivabradine "aggressively" and offered physicians exclusive trips to castles in France to promote the medication during the decade of 2000-2010., (in Danish)


Names

It is marketed by
Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has a ...
under the brand name Corlanor in the United States, and by
Servier Servier Laboratories (French: Laboratoires Servier, often abbreviated to Servier) is an international Pharmaceutical industry, pharmaceutical company governed by a non-profit foundation, with its headquarters in France (Suresnes). The consolida ...
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.


References


External links

{{Authority control Antianginals Benzocyclobutenes Methoxyphenethylamines Laboratoires Servier Phenol ethers Benzazepanes Lactams Tertiary amines