■ DRUG THERAPIES IN... Clinical Medicine 2013, Vol 13, No 1: 63–70 Pharmacological treatment of chronic stable angina pectoris Jason M Tarkin and Juan Carlos Kaski ABSTRACT – Chronic stable angina is the most common Overview of chronic stable angina manifestation of ischaemic heart disease in the developed world and is associated with impaired quality of life and The term angina pectoris refers to William Heberden’s classic increased mortality. The pathogenesis of stable angina is description of the clinical symptoms of angina, as reported to 1 complex and often, albeit not always, involves flow-limiting the Royal College of Physicians in 1768. There is currently no epicardial coronary artery stenoses (atheromatous plaques) systematically agreed definition for angina pectoris and the that reduce the ability of the coronary circulation to deliver term is used to define both the typical chest pain associated appropriate blood supply to the myocardium. The coronary with myocardial ischaemia and the syndrome characterised by microcirculation can also play an important role. An imbal- chest pain, myocardial ischaemia and obstructive atheroscle- ance between myocardial oxygen supply and metabolic rotic coronary artery disease. In this article, we use the term oxygen demand causes the symptoms of angina pectoris ‘angina’ in relation to the occurrence of typical central chest and represents a major therapeutic target. Rational treat- pain associated with myocardial ischaemia, irrespective of the ment requires a multi-faceted approach combining lifestyle presence or absence of flow-limiting organic coronary artery changes, aggressive management of modifiable coronary stenosis. artery disease risk factors, pharmacological therapy and Angina is considered to be ‘chronic’ and ‘stable’ when symp- myocardial revascularisation when appropriate. Despite toms are present for at least two months, without changes in 2 modern therapies, many patients continue to suffer from severity, character or triggering circumstances. angina. Several new anti-anginal drugs have been intro- Stable angina is the most common clinical manifestation of 3 duced that might allow more effective symptom control. ischaemic heart disease, affecting 58% of patients with CAD. Its These novel agents have specific mechanisms of action and prevalence increases with age, rising from roughly 8% in men fewer side effects compared to conventional drugs. The com- and 3% in women aged 55–64 years, to 14% in men and 8% in 4 bined use of traditional and novel treatments is likely to women aged 65–74 years, in England. The annual mortality rate increase the proportion of patients who are managed suc- resulting from coronary heart disease in patients with stable 5 cessfully with medical therapy alone. This article briefly angina is 0.9–1.4% per year. reviews recent advances in the pharmacological manage- Stable angina results from an imbalance between coronary ment of chronic stable angina pectoris, highlighting how an blood supply and myocardial oxygen demand, which is often, understanding of the prevailing pathogenic mechanisms in but not always, associated with the presence of obstructive the individual patient can aid appropriate selection of thera- CAD. Transient myocardial ischaemia typically causes ‘con- peutic strategies and improve clinical outcome. strictive’ chest discomfort, resulting from the activation of mechano- and chemo-sensitive myocardial receptors. Patients with stable angina might or might not present with typical Introduction symptoms, and ‘silent’ myocardial ischaemia can be present in Current treatment strategies for chronic stable angina aim to con- patients with diabetes mellitus and in the elderly. The typical trol symptoms, reduce the ischaemic burden and improve prog- clinical characteristics of chronic stable angina are summarised nosis by preventing the progression of atherosclerotic coronary in Box 1. artery disease (CAD) and its consequences. Ideally, the treatment of angina should be tailored to the individual patient’s needs, Pathophysiological and pathogenic mechanisms: taking into consideration the characteristics and severity of symp- determinants of clinical presentation toms, the location, severity and functional significance of coronary artery stenoses, the presence of co-morbidities and patient prefer- The pathogenesis of angina is often multi-factorial. The basic ence. For each individual patient, the efficacy of the agent and their underlying mechanism that leads to angina is an imbalance of side effects, together with patient compliance, are important deter- myocardial oxygen supply and demand. This often occurs as a minants for the success or the failure of a given treatment. direct result of flow-limiting CAD, but it can also be due to coronary artery spasm limiting blood supply, coronary microv- Jason M Tarkin, cardiology trainee, London Deanery and honorary ascular dysfunction and/or several other contributing mecha- research fellow; Juan Carlos Kaski, professor of cardiovascular science nisms. To a great extent, the underlying pathogenic mechanism and head of Cardiovascular Sciences Research Centre determines the pattern of clinical presentation, leading to effort- Cardiovascular Sciences Research Centre, University of London, UK induced angina, mixed angina or angina at rest. © Royal College of Physicians, 2013. All rights reserved. 63 CCMJ1301-63-70-Kaski.inddMJ1301-63-70-Kaski.indd 6633 11/17/13/17/13 99:40:08:40:08 AAMM Jason M Tarkin and Juan Carlos Kaski Box 1. Typical clinical characteristics of stable angina. Adapted from X — defined as typical exertional angina, positive stress test current clinical practice guidelines.5,15 responses and normal coronary angiograms — experience • Constricting, tight, heavy or pressure-like chest discomfort (often transient myocardial ischaemia resulting from impaired felt near the sternum) that may radiate along the ulnar border of endothelial function, which leads to abnormal coronary the left arm and hand, to the neck and jaw, the epigastrium or back microvascular vasodilatation, increased coronary vasocon- • Precipitated by a predictable and reproducible level of physical striction, or both.10–12 exertion (symptoms may also be triggered by emotional stress, cold In the ACOVA (Abnormal Coronary VAsomotion in patients weather or a heavy meal) with stable angina and unobstructed coronary arteries) study, • Relieved by rest or GTN, usually within 1–5 minutes. approximately two-thirds of patients without significant epicar- *All three of the features above are defined as typical angina. Two of the three dial CAD had positive intra-coronary acetylcholine tests for features above are defined as atypical angina. One or none of the features above 13 is likely to represent non-anginal chest pain. distal epicardial or microvascular spasm. Clinicians should be NB Shortness of breath, faintness or fatigue may represent ‘angina equivalents’ in encouraged to think about the possibility of microvascular dys- the elderly and ‘silent’ ischaemia may also occur, particularly in those with function or coronary microvascular spasm in patients who diabetes mellitius. present with typical angina despite having angiographically normal coronary arteries. Effort-induced angina Other contributing mechanisms Long-standing obstructive epicardial CAD causes angina by providing a fixed limitation of coronary blood flow, which pre- Following transient myocardial ischaemia, impaired diastolic vents physiological matching of coronary blood supply to relaxation and increased wall tension caused by calcium over- exercise-induced increases in myocardial metabolic demand. A load, which results from intracellular acidosis, and activation of stenosis of 50% or more in the left main coronary artery, or late inward sodium currents worsens the oxygen imbalance and 2 70% or more in another major epicardial artery, is defined as prolongs the angina episode. Further metabolic derangement, ‘obstructive’.6 Symptoms of effort-induced stable angina including abnormalities of substrate supply and utilisation, resulting from flow-limiting coronary stenoses often occur at a enzymatic activities and mitochondrial function, can also con- 8 predictable and reproducible threshold, triggered by physical tribute to the pathogenesis. Aortic stenosis, hypertrophic car- activity and/or emotional stress. The Canadian Cardiovascular diomyopathy, severe anaemia and thyrotoxicosis (when present) Society (CCS) grading of angina is a functional classification of are other potential contributory factors that can worsen myocar- 2 exercise tolerance that can be related to metabolic equivalent dial ischaemia. units (METs) and it is used in the assessment of exercise stress testing.7,8 Diagnosis and management Importance of the clinical history for diagnosis and ‘Mixed’ angina management of stable angina pectoris The imbalance of myocardial oxygen supply and demand in The accurate diagnosis of chronic stable angina (and the recog- angina can also result from combined mechanisms. Excessive nition of possible underlying pathogenic mechanisms) relies coronary artery vasoconstriction at the site of organic stenoses largely on obtaining a detailed clinical history. The severity of manifests clinically as ‘mixed angina pectoris’, in which patients chest pain does not necessarily correlate to the extent of under- present with variable-threshold effort angina and occasionally lying CAD, but the burden of symptoms experienced by an angina at rest.5,9 individual