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Role of Ivabradine in Management of Stable Angina in Patients with Different Clinical Profiles

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Role of Ivabradine in Management of Stable Angina in Patients with Different Clinical Profiles Open Access Coronary artery disease Open Heart: first published as 10.1136/openhrt-2017-000725 on 9 March 2018. Downloaded from Role of ivabradine in management of stable angina in patients with different clinical profiles Juan Carlos Kaski,1 Steffen Gloekler,2,3 Roberto Ferrari,4,5 Kim Fox,6 Bernard I Lévy,7 Michel Komajda,8 Panos Vardas,9 Paolo G Camici10 To cite: Kaski JC, Gloekler S, ABSTRACT latter being of particular importance consid- Ferrari R, et al. Role of In chronic stable angina, elevated heart rate contributes ering that 90% of coronary flow occurs in ivabradine in management of to the development of symptoms and signs of myocardial stable angina in patients with diastole. In patients with elevated heart rates, ischaemia by increasing myocardial oxygen demand different clinical profiles. Open shortened diastolic duration and impaired and reducing diastolic perfusion time. Accordingly, heart Heart 2018;5:e000725. collateral flow lead to reduced tissue perfu- doi:10.1136/ rate reduction is a well-known strategy for improving sion in myocardial regions downstream of both symptoms of myocardial ischaemia and quality of openhrt-2017-000725 stenoses.3 4 In these regions, myocardial life (QOL). The heart rate-reducing agent ivabradine, a blood flow and contractility are impaired.4–6 direct and selective inhibitor of the If current, decreases Received 10 October 2017 myocardial oxygen consumption while increasing diastolic This review article will focus on the use of Revised 29 December 2017 time, without affecting myocardial contractility or coronary ivabradine, a drug that selectively reduces Accepted 14 February 2018 vasomotor tone. Ivabradine is indicated for treatment of heart rate for the treatment of stable stable angina and chronic heart failure (HF). This review angina pectoris in different clinical condi- examines available evidence regarding the efficacy and 1 tions, including patients with preserved or Molecular and Clinical Sciences safety of ivabradine in stable angina, when used as impaired left ventricular (LV) function. Research Institute, St George’s, monotherapy or in combination with beta-blockers, in University of London, London, By reducing heart rate without affecting UK particular angina subgroups and in patients with stable myocardial inotropic function or coronary 2Department of Cardiology, angina with left ventricular systolic dysfunction (LVSD) or vasomotor tone, ivabradine reduces oxygen HF. Trials involving more than 45 000 patients receiving Schwarzwald-Baar Klinikum, demand and maintains diastolic time.7 Villingen-Schwenningen, treatment with ivabradine have shown that this agent Longer diastole and higher collateral pres- http://openheart.bmj.com/ Germany has antianginal and anti-ischaemic effects, regardless 3Cardiology, Cardiovascular sure enhance coronary flow and contrac- of age, sex, severity of angina, revascularisation status 8–11 Department, Bern University or comorbidities. This heart rate-lowering agent might tility in ischaemic myocardium. This Hospital, Bern, Switzerland also improve prognosis, reduce hospitalisation rates and review explores existing evidence from both 4 Centro Cardiologico improve QOL in angina patients with chronic HF and LVSD. randomised clinical trials and real-world clin- Universitario di Ferrara, ical data regarding the role of ivabradine University of Ferrara, Ferrara, Italy for management of stable angina pectoris in 5Maria Cecilia Hospital, GVM INTRODUCTION patients with and without LV dysfunction and Care & Research, Cotignola, Italy Heart rate is one of the main determinants other comorbidities. Although important for 6 on September 26, 2021 by guest. Protected copyright. National Heart and Lung of myocardial oxygen consumption and, clinical decision making, we do not—in the Institute, Imperial College, under normal circumstances, an increase in present manuscript—discuss reimbursement Institute of Cardiovascular Medicine and Science, Royal heart rate is mirrored by a parallel increase status or cost effectiveness, given the limited 1 Brompton Hospital, London, UK in coronary blood flow. Elevated heart rate data available on the topic. 7PARCC, INSERM U970, Vessels shortens the length of each cardiac cycle, and Blood Institute, Hôpital reducing diastolic perfusion time and thus Lariboisière, Paris, France oxygen supply.1 Elevated heart rate may also IVABRADINE: CLINICAL PHARMACOLOGY 8Department of Cardiology, Université Pierre et Marie Curie enhance the development of atherosclerosis, Pharmacokinetic properties Paris VI, La Pitié-Salpêtrière according to animal data, by increasing the Under physiological conditions, ivabradine Hospital, Paris, France exposure of the endothelium to shear stress.2 is rapidly released from tablets and quickly 9 Cardiology Department, The pathogenesis of chronic stable angina and almost completely absorbed after oral University Hospital of Heraklion, is complex but basically implies an imbal- administration. Under fasting conditions, it Heraklion, Greece 10Cardiology Department, Vita ance between myocardial oxygen supply reaches peak plasma levels in approximately Salute University and San and demand. An elevated heart rate plays 1 hour. Taking ivabradine during meals Raffaele Hospital, Milan, Italy an important role in the development of reduces intraindividual variability in absorp- myocardial ischaemia and angina as a result tion time. Ivabradine is metabolised by both Correspondence to Dr Juan Carlos Kaski; jkaski@ of increased myocardial oxygen demand and the liver and the gut by oxidation through sgul. ac. uk a reduction in diastolic perfusion time, the cytochrome P450 3A4 (CYP3A4). This agent Kaski JC, et al. Open Heart 2018;5:e000725. doi:10.1136/openhrt-2017-000725 1 Open Heart Open Heart: first published as 10.1136/openhrt-2017-000725 on 9 March 2018. Downloaded from Figure 1 Change from baseline in mean heart rate over 24 hours after treatment with ivabradine 7.5 mg twice daily in volunteers. Clinical data from the Institut de Recherches Internationales Servier (IRIS) database. EudraCT record 2011-001665- 40 (data on file). bid, twice a day; bpm, beats per minute. Copied from reference: Deedwania 2013.12 has low affinity for CYP3A4 and does not seem to modify effects of ivabradine on atrioventricular or intraventric- CYP3A4 substrate metabolism or plasma concentrations. ular conduction times or corrected QT interval.14 Potent inhibitors and inducers of CYP3A4, however, may affect the plasma levels of ivabradine. It is for this reason Mechanisms of action http://openheart.bmj.com/ that ivabradine must not be coprescribed with strong Under physiological circumstances, heart rate is deter- or moderate CYP3A4 inhibitors, such as diltiazem and mined by the rate of spontaneous diastolic depolarisation 15 verapamil. Ivabradine’s main half-life is approximately in the sinoatrial node. Spontaneous diastolic depolarisa- 2 hours (70%–75% of the AUC) and its effective half-life tion is influenced by a mixed sodium–potassium current around 11 hours. Of clinical importance, ivabradine can (If) across f-channels. If is directly and selectively inhibited be safely combined with first-line pharmacological agents by ivabradine, which results in reduced diastolic depolar- 16–19 commonly used to improve outcome in the manage- isation rates and the slowing of heart rate (figure 2). Ivabradine enters—and blocks—the f-channel from ment of cardiovascular disease such as aspirin, statins, on September 26, 2021 by guest. Protected copyright. beta-blockers and renin–angiotensin–aldosterone system the cytoplasmic side of the cell membrane and does it 17 inhibitors, as well as antidiabetic agents, proton pump mainly when the channel is in the open state. It has inhibitors and antidepressant agents. been reported that this blocking action reduces the rate of pacemaker activity of the heart, which is more intense Pharmacodynamic effects at a higher firing rate, as suggested by different groups In humans, at the currently recommended doses, heart of investigators.17 20 21 Ivabradine, therefore, is a specific rate reduction—the main pharmacodynamic property heart rate-reducing drug. Indeed, its specificity for the of ivabradine—is approximately 10 bpm both at rest If current guarantees that this compound has no direct and during exercise. A study in 23 healthy volunteers effects on myocardial function, ventricular repolarisation (aged 19–63 years) using ivabradine 7.5 mg twice daily or cardiac conduction.22 23 Of importance, ivabradine’s demonstrated a significant reduction in heart rate over specific mode of action limits its use to patients with sinus 24 hours, without affecting circadian heart rate patterns rhythm and excludes patients in atrial fibrillation or atrial (figure 1).12 flutter. Of major importance in clinical practice and partic- Many studies in humans—including both healthy ularly in subjects with comorbidities, ivabradine does volunteers and patients24–26—have shown that heart rate not influence intracardiac conduction, contractility or reduction with ivabradine largely depends on the dose ventricular repolarisation nor does it affect central aortic used and the individual’s baseline heart rate. In a 6-month pressure (or LV afterload).13 Studies have reported no Holter substudy of the morBidity-mortality EvAlUaTion 2 Kaski JC, et al. Open Heart 2018;5:e000725. doi:10.1136/openhrt-2017-000725 Coronary artery disease Open Heart: first published as 10.1136/openhrt-2017-000725 on 9 March 2018. Downloaded from Figure 2
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