Ivabradine, sold under the brand name Procoralan among others, is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

, which is a

funny current The pacemaker current (or I''f'', or IK''f'', also referred to as the funny 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 ...

(I_''f'') 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 Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...

. Ivabradine acts by allowing negative chronotropy in the sinoatrial structure thus reducing the

heart rate Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and excr ...

via specific inhibition of the

pacemaker current The pacemaker current (or I''f'', or IK''f'', also referred to as the funny 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 ...

, 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, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...

s and calcium channel blockers, two commonly prescribed

antianginal An antianginal is a drug used in the treatment of ''angina pectoris'', a symptom of ischaemic heart disease. Examples Drugs used are nitrates, beta blockers, or calcium channel blockers. Nitrates Nitrates cause vasodilation of the venous ca ...

classes of cardiac pharmaceuticals. 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 obstru ...

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 characterised by the presence of correctly oriented P waves on the electrocardiogram (ECG). Sinus rhythm is necessary, but not s ...

who cannot take

. It is also being used off-label in the treatment of

inappropriate sinus tachycardia Inappropriate sinus tachycardia (IST) is a rare type of cardiac arrhythmia within the category of supraventricular tachycardia (SVT). IST may be caused by the Sinoatrial node, sinus node itself having an abnormal structure or function, or it may b ...

. Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST

Chest pain

It may be as effective as the beta blocker

atenolol Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Atenolol, however, does not seem to improve mortality in those with high blood pressure. Other uses include the prevention of mi ...

and comparable with

amlodipine Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure and coronary artery disease. It is taken by mouth. Common side effects include swelling, feeling tired, ...

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.

Tachycardia

The clinical use of ivabradine is predicated on its mechanism of action on sinoatrial nodal tissue where it selectively inhibits the funny current (''I_f'') 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/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 standing. Symptoms may include lightheadedness, brain fog, blurred vision, weakness, fatigue, headaches, heart p ...

in patients with

long COVID Long COVID or long-haul COVID (also known as post-COVID-19 syndrome, post-COVID-19 condition, post-acute sequelae of COVID-19 (PASC), or chronic COVID syndrome (CCS)) is a condition characterized by long-term health problems persisting or app ...

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, 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. ...

(such as ketoconazole),

macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...

antibiotics,

nefazodone Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from ...

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 inhibitors (PIs) and like other PIs is almost always used in combination ...

and

ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor ...

. 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 ...

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 The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

, 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 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 result from the combination of two or more drugs. The meaning of this term ...

s (1–10% of patients) include first-degree

AV block Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoa ...

, 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 or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approxima ...

. 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 350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart. The_muscle_contraction.htm ...

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. 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 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 is a protein that in humans is encoded by the ''HCN4'' gene. There are four HCN channels. HCN4 is prominently expressed in the pace maker region of the mammalian hear ...

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 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. 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 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 respon ...

in 2015.

Names

It is marketed by

Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was established in T ...

under the trade name Corlanor in the United States, and by

Servier Servier Laboratories (French: Laboratoires Servier, often abbreviated to Servier) is an international pharmaceutical company governed by a non-profit foundation, with its headquarters in France (Suresnes). The consolidated turnover for the 2018 ...

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), 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 trademark of "bradix" . IVAMAC and Bradia. During its development, ivabradine was known as S-16257.

References

External links

* * {{Portal bar , Medicine Antianginals Benzocyclobutenes Laboratoires Servier Phenol ethers Benzazepanes Lactams Tertiary amines