Ivabradine

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Ivabradine
Ivabradine Structural Formula V.1.svg
Ivabradine-based-on-xtal-3D-bs-17.png
Clinical data
Pronunciation /ɪˈvæbrədiːn/
Trade names Corlanor, Procoralan, others
Other namesS-16257
AHFS/Drugs.com Monograph
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 40%
Protein binding 70%
Metabolism Liver (first-pass) >50%, CYP3A4-mediated
Elimination half-life 2 hours
Excretion Kidney and fecal
Identifiers
  • 3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C27H36N2O5
Molar mass 468.594 g·mol−1
3D model (JSmol)
  • O=C2N(CCc1cc(OC)c(OC)cc1C2)CCCN(C[C@@H]4c3cc(OC)c(OC)cc3C4)C
  • InChI=1S/C27H36N2O5/c1-28(17-21-11-20-14-25(33-4)26(34-5)16-22(20)21)8-6-9-29-10-7-18-12-23(31-2)24(32-3)13-19(18)15-27(29)30/h12-14,16,21H,6-11,15,17H2,1-5H3/t21-/m1/s1 Yes check.svgY
  • Key:ACRHBAYQBXXRTO-OAQYLSRUSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [2]

Contents

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.

Medical uses

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). [3] Ivabradine stands as a pharmacological option for controlling HR and rhythm without associated side effects in postoperative CABG patients with IST. [4]

Chest pain

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. [5] [6] In people not sufficiently managed with beta blockers for their angina, adding ivabradine can further reduce heart rate and improve total exercise duration. [7]

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. [8] In people not sufficiently managed with beta blockers for their heart failure adding ivabradine decreases the risk of hospitalization for heart failure. [2]

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. [9]

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. [9]

It has been used experimentally for the treatment of postural orthostatic tachycardia syndrome in patients with long COVID. [10] 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. 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. [11]

Use of ivabradine with verapamil or diltiazem is contraindicated. [12]

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 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. [5]

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). [5] Headaches were reported in 2.6 to 4.8 percent of cases. [5] Other common adverse drug reactions (1–10% of patients) include first-degree AV block, ventricular extrasystoles, dizziness and/or blurred vision. [13]

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. [14] [15] 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. [16]

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: [17]

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. [18]

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. [19] [20]

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. [21] 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. [22] 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. [23]

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 in 2015. [24]

Names

It is marketed by Amgen under the trade name Corlanor in the United States, [25] 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), 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.

Related Research Articles

An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.

<span class="mw-page-title-main">Angina</span> Chest discomfort from heart muscles

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.

<span class="mw-page-title-main">Beta blocker</span> Medications for abnormal heart rhythms

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.

<span class="mw-page-title-main">Verapamil</span> Calcium channel blocker medication

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.

<span class="mw-page-title-main">Amlodipine</span> Medication against high blood pressure

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.

<span class="mw-page-title-main">Nifedipine</span> Calcium channel blocker medication

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.

<span class="mw-page-title-main">Diltiazem</span> Calcium channel blocker medication

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.

<span class="mw-page-title-main">Trimetazidine</span> Drug for angina pectoris sold under many brand names

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.

<span class="mw-page-title-main">Sinus tachycardia</span> Sinus rhythm with a rate that is higher than normal

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.

<span class="mw-page-title-main">Variant angina</span> Medical condition

Variant angina, also known as Prinzmetal angina,vasospastic angina, angina inversa, coronary vessel spasm, or coronary artery vasospasm, is a syndrome typically consisting of angina. Variant angina differs from stable angina in that it commonly occurs in individuals who are at rest or even asleep, whereas stable angina is generally triggered by exertion or intense exercise. Variant angina is caused by vasospasm, a narrowing of the coronary arteries due to contraction of the heart's smooth muscle tissue in the vessel walls. In comparison, stable angina is caused by the permanent occlusion of these vessels by atherosclerosis, which is the buildup of fatty plaque and hardening of the arteries.

<span class="mw-page-title-main">Carvedilol</span> Blood pressure medication

Carvedilol 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.

<span class="mw-page-title-main">Inappropriate sinus tachycardia</span> Syndrome where the sinus heart rate is inexplicably faster than expected

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.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

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.

<span class="mw-page-title-main">Multifocal atrial tachycardia</span> Fast heart rhythm associated with exacerbations of COPD

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.

<span class="mw-page-title-main">Clevidipine</span> Antihypertensive drug of the calcium channel blocker class

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.

<span class="mw-page-title-main">Landiolol</span> Chemical compound

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. Landiolol was developed by modifying the chemical structure of esmolol to produce a compound with a higher rate of cardioselectivity and a greater potency without increasing its duration of action. It is sold as landiolol hydrochloride. Based on its positive benefit risk profile, landiolol has been granted the marketing authorization and introduced to the European markets under the brand names Rapibloc, Raploc, Runrapiq, Landibloc mid 2016. Landiolol is available in Japan under the brand names Onoact (50 mg) and Corbeta.

<span class="mw-page-title-main">Acute decompensated heart failure</span> Medical condition

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.

<span class="mw-page-title-main">Discovery and development of beta-blockers</span>

β adrenergic receptor antagonists were initially developed in the 1960s, for the treatment of angina pectoris but are now also used for hypertension, congestive heart failure and certain arrhythmias. In the 1950s, dichloroisoproterenol (DCI) was discovered to be a β-antagonist that blocked the effects of sympathomimetic amines on bronchodilation, uterine relaxation and heart stimulation. Although DCI had no clinical utility, a change in the compound did provide a clinical candidate, pronethalol, which was introduced in 1962.

<span class="mw-page-title-main">Roberto Ferrari (cardiologist)</span> Italian Cardiologist

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.

References

  1. ↑ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada . 14 March 2017. Retrieved 7 April 2024.
  2. 1 2 Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, et al. (September 2016). "2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America". Circulation. 134 (13): e282–e293. doi: 10.1161/CIR.0000000000000435 . PMID   27208050.
  3. ↑ Yusuf S, Camm AJ (June 2003). "Sinus tachyarrhythmias and the specific bradycardic agents: a marriage made in heaven?". Journal of Cardiovascular Pharmacology and Therapeutics. 8 (2): 89–105. doi:10.1177/107424840300800202. PMID   12808482. S2CID   25305128.
  4. ↑ Bhatt P, Bhavsar N, Naik D, Shah D (2021-07-01). "Comparative effectiveness of metoprolol, ivabradine, and its combination in the management of inappropriate sinus tachycardia in coronary artery bypass graft patients". Indian Journal of Pharmacology. 53 (4): 264–269. doi: 10.4103/ijp.IJP_478_19 . PMC   8411959 . PMID   34414903.
  5. 1 2 3 4 Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K (December 2005). "Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina". European Heart Journal. 26 (23): 2529–2536. doi: 10.1093/eurheartj/ehi586 . PMID   16214830.
  6. ↑ 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. S2CID   25325838.
  7. ↑ Tardif JC, Ponikowski P, Kahan T (March 2009). "Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial". European Heart Journal. 30 (5): 540–548. doi:10.1093/eurheartj/ehn571. PMC   2649284 . PMID   19136486.
  8. ↑ McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. (July 2012). "ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC". European Heart Journal. 33 (14): 1787–1847. doi: 10.1093/eurheartj/ehs104 . PMID   22611136.
  9. 1 2 "The Clinical Use of Ivabradine". American College of Cardiology. Retrieved 2022-02-03.
  10. ↑ O'Sullivan JS, Lyne A, Vaughan CJ (June 2021). "COVID-19-induced postural orthostatic tachycardia syndrome treated with ivabradine". BMJ Case Reports. 14 (6): e243585. doi:10.1136/bcr-2021-243585. PMC   8204164 . PMID   34127505.
  11. ↑ "European Medicine Agency, Procoralan Summary of Product Characteristics" (PDF). Archived from the original (PDF) on 2012-05-19. Retrieved 2010-09-13.
  12. ↑ "Press release: European Medicines Agency recommends measures to reduce risk of heart problems with Corlentor/Procoralan (ivabradine)". European Medicines Agency. 21 November 2014. Archived from the original on 21 June 2018. Retrieved 15 December 2014.
  13. ↑ Anonymous (2006). "New medicines: Procoralan". Pharmaceutical Journal. 276 (7386): 131. Archived from the original on 2008-03-17. Retrieved 2007-10-14.
  14. ↑ Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP (May 1994). "Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49". British Journal of Pharmacology. 112 (1): 37–42. doi:10.1111/j.1476-5381.1994.tb13025.x. PMC   1910295 . PMID   8032660.
  15. ↑ Sulfi S, Timmis AD (February 2006). "Ivabradine -- the first selective sinus node I(f) channel inhibitor in the treatment of stable angina". International Journal of Clinical Practice. 60 (2): 222–228. doi:10.1111/j.1742-1241.2006.00817.x. PMC   1448693 . PMID   16451297.
  16. ↑ Bucchi A, Baruscotti M, Nardini M, Barbuti A, Micheloni S, Bolognesi M, DiFrancesco D (2013). "Identification of the molecular site of ivabradine binding to HCN4 channels". PLOS ONE. 8 (1): e53132. Bibcode:2013PLoSO...853132B. doi: 10.1371/journal.pone.0053132 . PMC   3537762 . PMID   23308150.
  17. ↑ Fox K, Ford I, Steg PG, Tendera M, Ferrari R (September 2008). "Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial". Lancet. 372 (9641): 807–816. doi:10.1016/S0140-6736(08)61170-8. PMID   18757088. S2CID   26282333.
  18. ↑ Borovac JA, Kowalski M, Pericic TP, Vidak M, Schwarz K, D'Amario D, et al. (May 2022). "Clinical use of ivabradine in the acute coronary syndrome: A systematic review and narrative synthesis of current evidence". American Heart Journal Plus: Cardiology Research and Practice. 17: 100158. doi: 10.1016/j.ahjo.2022.100158 . ISSN   2666-6022. PMC   10978351 . PMID   38559878. S2CID   249941448.
  19. ↑ Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R (September 2014). "Ivabradine in stable coronary artery disease without clinical heart failure". The New England Journal of Medicine. 371 (12): 1091–1099. doi: 10.1056/NEJMoa1406430 . hdl: 20.500.11820/d9aed159-0654-4fa1-a6d9-8c5fb6dd325a . PMID   25176136. S2CID   19002896.
  20. ↑ Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. (September 2010). "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study". Lancet. 376 (9744): 875–885. doi:10.1016/s0140-6736(10)61198-1. PMID   20801500. S2CID   21196422.
  21. ↑ Stiles S. "SHIFT: Adding HR-slowing agent ivabradine to HF meds cuts mortality, hospitalization". TheHeart.org. Retrieved 1 April 2011.
  22. ↑ Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. (September 2010). "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study". Lancet. 376 (9744): 875–885. doi:10.1016/S0140-6736(10)61198-1. PMID   20801500. S2CID   21196422.
  23. ↑ Benstoem C, Kalvelage C, Breuer T, Heussen N, Marx G, Stoppe C, Brandenburg V (November 2020). "Ivabradine as adjuvant treatment for chronic heart failure". The Cochrane Database of Systematic Reviews. 2020 (11): CD013004. doi:10.1002/14651858.CD013004.pub2. PMC   8094176 . PMID   33147368.
  24. ↑ "FDA approves Corlanor to treat heart failure". www.fda.gov. Archived from the original on 2015-04-16. Retrieved 2015-04-16.
  25. ↑ "Amgen and Servier announce product collaboration". www.servier.com. Archived from the original on 2016-03-04. Retrieved 2015-12-29.
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