An overview of ivabradine

Coronary artery disease (CAD) claims the lives of more than seven million people in the world every year, and most of those are in developing countries.1,2 Optimal medical therapy is actively encouraged and includes using the recommended guidelines as part of management. Patients who have had CAD not only have an affliction of reduced quality of life, but also have an increased risk associated with cardiovascular events, like angina pectoris and myocardial infarction (MI). Angina pectoris is a common symptom of CAD; percutaneous coronary intervention (PCI) is frequently used to relieve the symptoms of angina. The combination of ivabradine and a suitable β-blocker in patients with angina, who had PCI, has proven to be beneficial.1


Introduction
Coronary artery disease (CAD) claims the lives of more than seven million people in the world every year, and most of those are in developing countries. 1,2Optimal medical therapy is actively encouraged and includes using the recommended guidelines as part of management.Patients who have had CAD not only have an affliction of reduced quality of life, but also have an increased risk associated with cardiovascular events, like angina pectoris and myocardial infarction (MI).Angina pectoris is a common symptom of CAD; percutaneous coronary intervention (PCI) is frequently used to relieve the symptoms of angina.The combination of ivabradine and a suitable β-blocker in patients with angina, who had PCI, has proven to be beneficial. 1   Cardiovascular and all-cause mortality can be associated with resting heart rate, and the mortality benefit of cardiovascular drugs can be linked to their heart rate-lowering effects.3 The development of a pure heart rate-lowering drug proved to be of great interest in establishing the benefits of heart rate reduction alone.Ivabradine is the first pure heart rate-lowering agent that successfully completed clinical trials for the treatment of stable angina pectoris.3

Congestive cardiac failure
Chronic heart failure is a serious and disabling condition, affecting 2-3% of the population.The prognosis of chronic heart failure is fairly poor, and heart rate reduction, especially a reduction in resting heart rate, is particularly important in managing the disease process.⁴Due to its inability to be detected and the lack of conclusive diagnostic assessments, the clinical diagnosis of congestive heart failure (CHF) is reliant on vigilant physical assessment and the use of diagnostic tests, such as chest radiography and the electrocardiogram (ECG).⁵Throughout recent years many advances in treatment have been made, but CHF still claims the lives of many.⁶High mortality and morbidity are seen in patients with CHF.⁴

Angina pectoris
According to Fihn et al.,⁷ angina pectoris is a pain or discomfort in the chest that is due to coronary heart disease that occurs when the heart is deprived of blood.This might be due to blockages or narrowing of the arteries.Although oxygen demand is in close relation to the oxygen consumption of an organ, the two concepts are not the same.Angina pectoris is caused by an imbalance between myocardial perfusion and oxygen demand, causing myocardial ischaemia.⁸ The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd37 if increased, it is accountable for the majority of cardiovascular episodes in congestive cardiac failure (CCF). 11According to the latest South African Medicines Formulary (2016), 12 ivabradine, an I f ion channel inhibitor, is indicated as monotherapy in the treatment of chronic stable angina and stable chronic heart failure, or in combination with suitable beta-blockers.
Myocardial oxygen consumption (MVO2) is the oxygen requirement of the heart muscle or myocardium (refer to Table 1).
By way of comparison, Table 2 provides the MVO2 of other organs in the body.⁹An increasing heart rate increases myocardial oxygen demand, reduces ventricular efficiency and relaxation, and decreases myocardial perfusion by shortening the duration of diastole, thus inducing myocardial ischaemia and subsequent angina. 11,13ised heart rate is also associated with vascular oxidative stress, endothelial dysfunction and the acceleration of atherogenesis. 13 increased heart rate induces restriction of blood supply to tissues, leading to a shortage of oxygen because it increases oxygen demand and therefore reduces myocardial perfusion.

Ivabradine
Unlike the other treatment options for CHF, ivabradine uses a different mechanism of action.Ivabradine is a selective inhibitor of the I f ion channel found in the cardiac pacemaker cells of the Sinoatrial node (SA).Cardiac pacemaker cells generate the spontaneous slow diastolic depolarisation that drives the membrane voltage away from a hyperpolarised level towards the threshold level for initiating a subsequent action potential.This will generate the rhythmic action potentials that spread through the heart and trigger myocardial contraction.3Ivabradine specifically blocks cardiac pacemaker cell f-channels and exerts significant inhibition of this current at concentrations that do not affect other cardiac ionic currents.3Myocardial contractility and atrioventricular conduction are maintained while heart rate at rest and during exercise is reduced. 13e I f current is a mixed Na + -K + -inward ionic current activated by hyperpolarisation, which determines the slope of the diastolic depolarisation, and in turn controls the rate of heart beat.It is one of the most important ionic currents for regulating pacemaker activity in the sinoatrial (SA) node. 11Ivabradine is the first specific heart rate-lowering agent to have completed clinical development for stable angina pectoris.
Ivabradine is an effective antianginal and anti-ischemic drug, not inferior to the β-blocker, atenolol, and the calcium-channel antagonist (CCA), amlodipine. 14It reduces the frequency of angina attacks and increases the time until symptoms of angina during exercise begin to show.Ivabradine is not associated with the typical adverse reactions associated with the β-blockers or other antianginal drugs, because of its exclusive chronotropic effect (i.e.change in heart rate). 14In addition, it is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic, chronic heart failure with left ventricular ejection fractions ≤ 35%, that are in sinus rhythm with a resting heart rate ≥ 70 beats per minute, and are either on maximally tolerated doses of β-blockers or have a contraindication to β-blocker use.
Ivabradine is indicated in patients that do not respond optimally to therapy previously indicated as antianginal monotherapy or even combination therapy.Ivabradine has also proved to be superior in the reduction of rate-pressure, which is a surrogate marker of myocardial oxygen consumption, as well as of comparable efficacy to amlodipine in improving exercise tolerance. 15

Current available therapeutic options for CHF
Current medical therapies to reduce the symptoms of angina pectoris aim to improve oxygen supply and reduce oxygen demand in the myocardium. 15Beta-blockers competitively bind to and inhibit β-adrenoceptors.This reduces myocardial oxygen demand, thus lowering blood pressure, heart rate and contraction of the myocardium. 12e slowing of the heart rate (bradycardia) prolongs the relaxation state of the heart, which is the diastole, and this will increase optimal coronary blood flow. 16Patients are advised to monitor their body weight, limit salt intake and regularly exercise.The standard pharmacological interventions are indicated in Table lll.

The SHIfT trial
In 2010, the SHIfT trial (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial) evaluating heart rate reduction through the direct sinus node inhibition was conducted.SHIfT was a multinational, parallel-group clinical trial in patients with moderate-to-severe heart failure and left-ventricular systolic dysfunction.⁴It was the first study conducted to assess whether heart rate reduction by direct sinus node inhibition can decrease cardiovascular outcomes in patients with chronic heart failure and left ventricular systolic dysfunction. 13It was found that ivabradine substantially reduced major risks associated with heart failure when combined with guidelinebased treatment.⁴

Conclusion
Strong evidence suggests that heart rate is a marker of risk for cardiovascular disease in the general population, leading to the fact that intervention to reduce elevated heart rate translates into clinical benefit.Some of the groups of drugs used in the treatment of stable angina pectoris, including the β-blockers and some calcium-channel antagonists, remain the first line of treatment for reducing heart rate, although their use may be

Table l :
MVO2 requirements of the heart during different conditions⁹

Table ll :
Oxygen consumption by organs in the human body, measured in ml O2/min per 100 g.⁹

Table lll :
17armacological management of congestive cardiac failure according to the South African Standard Treatment Guidelines and Essential Medicine List, 2012 17 Isosorbide dinitrate SL 5 mg If required, repeat at 5-minute intervals for 3-4 dosages • β-blocker -atenolol 50-100 mg daily • Titrate to resting heart rate of approximately 60 beats per minute • Contraindications and non-tolerance to β-blocker, consider calcium-channel blocker • Long-acting calcium-channel blocker -amlodipine 5 mg oral daily, or nifedipine SR 30 mg oral daily Treatment of Stable Angina Pectoris according to the Standard Treatment Guidelines/Essential Medicines List (STG/EML)17