Figure 2.1
Summary of ESC guidelines for stable angina management (Figure adapted from Task Force Members et al. [1]).aData for patients with diabetesbIf intolerance, consider using clopidogrel
Treatment of Atherosclerosis and Event Prevention
The prognosis of stable angina is generally good, and carries annual mortality rate of 1.2–2.4 % and an annual non-fatal myocardial infarction rate of 0.6–2.7 % [1]. Moreover, only 18 % of cardiac events occur in patients with a prior stable angina [10]. This is largely due to the fact that chronic fibro-atheromatous plaques are less prone to rupture, as the thrombogenic lipid core tends to be smaller and shielded from the lumen by a thick fibrous cap, which is devoid of inflammatory cells and often heavily calcified [11–13]. That being said, atherosclerosis is a systemic, multi-focal disease and therefore the presence of stable coronary plaques may serve as a marker for more vulnerable disease elsewhere. Furthermore, for many patients with stable angina the risk of major cardiac events and death is increased due to co-morbidities, including diabetes and previous myocardial infarction [14]. Therefore secondary preventative measures are hugely important for all patients with stable angina due to atherosclerosis, to slow disease progression and improve long-term outcome.
Lifestyle modification, in the form of healthy eating, exercise, weight reduction and smoking cessation is fundamental. Aside from the positive effects on lowering blood pressure and cholesterol, these interventions alone can result in modest, but measurable, differences in coronary artery stenosis severity and improved myocardial perfusion (probably through changes in the microcirculation) [15]. From the physician’s perspective, stringent treatment of hypertension, dyslipidaemia and diabetes is the cornerstone of atherosclerosis management; currently recommended target thresholds for these are blood pressure <140/90 mmHg, LDL <1.8 mmol/L (<70 mg/dL) or 50 % reduction, and HbA1c <7 % (<53 mmol/mol).
Lower BP targets may benefit certain high-risk patients with angina, such as those with diabetes, however these are often impractical to achieve. There is also a theoretical risk that excessive lowering of diastolic BP can lead to impaired coronary perfusion in patients with angina, and some evidence to suggest that this can lead to an increase in cardiac events [16].
Role of Anti-platelet Therapy
The role of anti-platelets for prevention of death, myocardial infarction and stroke in high-risk patients was demonstrated by a large meta-analysis conducted by the Antithrombotic Trialists’ Collaboration, which included data from 287 studies and reported a 25 % reduction in serious cardiovascular events [17]. The SAPAT (Swedish Angina Pectoris Aspirin Trial) was the first prospective study to evaluate the use of aspirin in patients with angina; this showed a 34 % reduction in myocardial infarction and sudden death over a 50 month period [18].
Aspirin acts as an irreversible cyclo-oxygenase inhibitor to prevent production of thomboxane, platelet aggregation and arterial thrombosis. Long-term aspirin is recommended for all patients with angina and evidence of atherosclerosis. For patients with an allergy or intolerance to aspirin, clopidogrel is recommended. Clopidogrel is a thienopyridine derivative that inhibits platlet aggregation through irreversible inhibition of ADP P2Y12 receptors. In CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), clopidogrel showed marginally superiority to aspirin with a similar safety profile [19]. However, patients with variants of the CYP2C19 gene may have a reduced anti-platelet response to clopidogrel, and point-of-care screening is not currently widely available (or recommended) [20].
Dual anti-platelet therapy with aspirin and clopidogrel is not indicated for stable angina alone, but is common practice in the first year following myocardial infarction and/or coronary artery stenting (to reduce the risk of subsequent events, in-stent thrombosis and early re-stenosis). Newer anti-platelets agents, including prasugrel and ticagrelor, have not yet been evaluated for use in stable angina, and may be associated with increased risk of bleeding. Dipyridamole causes vasodilation of coronary resistence vessels and can provoke exercise-induced ischaemia [2]; it is not recommended for use in stable angina.
Statins: Lipid Lowering and Pleotrophic Effects
Statins inhibit HMG-CoA reductase to lower LDL cholesterol on average by 40–60 %, depending on the drug and dosage [21]. Large meta-analyses performed by the Cholesterol Treatment Trialists’ Collaborative have shown that this translates into roughly a 10 % reduction in all cause mortality and 20 % reduction in major vascular events for every 1.0 mmol/L decrease; irrespective of age, sex, baseline LDL cholesterol or previous cardiovascular disease [22, 23].
The benefits of statins are greater than can be explained by their lipids lowering effects alone. Pleotropic effects of statins can help to stabilize lesions by decreasing inflammation and altering plaque composition, and can also result in small reductions in plaque volume, improved endothelial function and less reversible ischemia [24]. Statins are recommended for all patients with atherosclerotic coronary artery disease, irrespective of serum cholesterol. When statins cannot be used, other lipid lowering agents such as fibrates, resins, nicotinic acid and ezetimibe may help to lower LDL cholesterol, but the benefit on clinical outcomes with these alternative agents has not yet been shown [1].
High-Risk Patients
For those with stable angina and previous history of myocardial infarction, or left ventricular impairment with ejection fraction ≤40 %, beta-blockers and angiotensin converting enzyme (ACE) inhibitors improve long-term outcome [25, 26], and are recommended along with other cardiac treatments specific to these conditions. ACE inhibitors are also recommended for those with stable angina and diabetes, hypertension or chronic kidney disease, unless contraindicated. Furthermore, combined analysis of the HOPE (Heart Outcomes Prevention Evaluation), EUROPA (European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease) and PEACE (Prevention of Events with ACE inhibition) trials showed a significant reduction in total mortality and fatal and non-fatal cardiovascular events with ACE inhibitors for patients with stable coronary disease without heart failure [27]. This suggests a role for ACE inhibitors in all patients with coronary atherosclerosis. The guidelines also advise influenza vaccination for all patients with atherosclerotic coronary artery disease.
Treatment of Ischaemia and Symptoms
Drugs effective in relieving the symptoms of angina act to restore the balance between myocardial oxygen supply and demand, by reducing myocardial work, improving flow, or both. This is achieved mainly by modulating heart rate, blood pressure, myocardial loading or contractility, vascular tone and diastolic wall tension; these mechanisms alter the threshold at which an angina episode is triggered. See Table 2.1 for summary of recommended anti-angina drugs.
Table 2.1
Summary of anti-angina drugs recommended by ESC*, ACC-AHA† and NICE‡
Drug class | Therapeutic target | Mechanism of action | Side-effects | Contraindications | Notes |
|---|---|---|---|---|---|
First–line drugs | |||||
Beta-blockers*†‡ | β-adrenergic receptor antagonist | Reduces heart rate, blood pressure and contractility Prolongs diastolic filling time | Fatigue Depression Bradycardia Hypotension Bronchospasm Hyper/hypoglycaemia Impotence | Bradycardia, heart block or other conduction disorder Cardiogenic shock, hypotension Asthma Peripheral vascular disease | May worsen angina due to coronary spasm Cardioselective beta-blockers preferable for angina Prognostic benefit for patients with myocardial infarction and/or heart failure |
Calcium channel antagonists*†‡ | l-type Ca2+ channel antagonist | Acts as systemic and coronary vasodilator Rate-limiting agents also reduce heart rate, blood pressure and contractility, and prolong diastole | Dizziness Headache Fatigue Nausea Constipation Peripheral oedema Bradycardia (rate limiting agents) Hypotension | Cardiogenic shock, hypotension Bradycardia (rate-limiting agents) Co-administration of rate-limiting calcium channel blockers with beta-blockers, or other cardiodepressant agents | First-line for angina due to coronary spasm Dose adjustment required for liver and renal impairment Interaction with CYP3A4 enzymes interfering drugs |
Second–line drugs | |||||
Long-acting nitrates*†‡ | Nitric oxide donor, activates cGMP pathway | Acts as systemic and coronary vasodilator | Headache Flushing Hypotension Dizziness | Hypotension Co-administration with PDE-5-inhibitors Aortic stenosis Hypertrophic cardiomyopathy | Nitrate-free interval necessary to avoid tolerance |
Nicorandil*‡ | Nitric oxide donor and K+ ATP channel opener | Acts as a balanced systemic and coronary vasodilator | Headache Dizziness Flushing Nausea Malaise Skin, mucosal and gasto-intestinal tract ulcers (rare) | Cardiogenic shock, hypotension Co-administration with PDE-5-inhibitors Aortic stenosis Hypertrophic cardiomyopathy | Cardio-protection due to ischaemic pre-conditioning K+ ATP channel opening antagonized by sulphonylureas |
Ranolazine*†‡ | Inhibitor of late inward Na+ current | Reduces diastolic wall tension | Dizziness Constipation Nausea Abdominal pain Headache QT prolongation | Prolonged QT-interval, QT-interval prolonging drugs Liver or renal failure Previous ventricular tachycardia | Improves HbA1c in diabetic patients Dose adjustment for elderly, renal and liver impairment Interaction with CYP3A4, CYP2D6 enzyme and P-glycoprotein substrate interfering drugs |
Ivabradine*‡ | I f channel inhibitor | Reduces heart rate | Flashing lights Blurred vision Headache Dizziness Bradycardia First degree heart block | Heart block, bradycardia Atrial fibrillation Acute MI or HF Liver or renal failure Pregnancy and breast-feeding | Contraindicated during pregnancy and breast-feeding (due to risk of teratogenicity) Interaction with CYP3A4 enzyme interfering drugs |
Trimetazidine* | Mitochondrial long-chain 3- ketoacyl CoA thiolase inhibitor | Improves myocardial metabolic efficiency by preventing β-oxidation of free fatty acid, thus increasing glucose usage | Heartburn Nausea Headache Diarrhoea Movement disorders | Parkinson’s disease, movement disorders Severe renal impairment | Dose reduction required for renal impairment |
Treatment of Acute Angina Episodes
Episodes of angina are treated with sublingual glyceryltrinitrate (GTN). GTN is rapidly absorbed and acts as a nitric oxide donor to cause systemic and coronary vasodilatation, improving myocardial blood flow, and providing relief of symptoms within several minutes. GTN is recommended for all patients with symptoms of angina, without contraindication. There is a risk of profound hypotension with GTN if administered within 24 h of a phosphodiesterase-5 inhibitor (e.g. sildenfil), are therefore these two medications should not be prescribed together. Other contraindications include aortic stenosis and hypertrophic cardiomyopathy, again due to the risk of acute hypotension (in the presence of significant outflow tract gradient). Common side-effects are headache, flushing and dizziness. When prescribing GTN, patients should be counseled on how and when to use GTN, to anticipate potential side-effects, and to seek medical attention if their symptoms persist despite treatment.
First-Line Agents
β-adrenergic receptor antagonists (beta-blockers) and l-type calcium channel receptor antagonists (calcium channel blockers) are recommended first-line agents to prevent myocardial ischaemia and the symptoms of angina. ACC-AHA guidance supports beta-blockers over calcium channel blockers as the first option where possible, whereas ESC and NICE do not. Evidence for the use of beta-blockers and calcium channels blockers in stable angina comes from studies such as TIBET (Total Ischemic Burden European Trial) and APSIS (Angina Prognosis Study in Stockholm) [28, 29]. Beta-blockers (e.g. bisoprolol) and non-dihydropyridines calcium channel blockers (e.g. diltiazem) reduce myocardial work through negative chronotropic and inotropic actions. These agents also act by prolonging diastole to improve myocardial oxygen supply. In addition, calcium channel blockers act as systemic and coronary vasodilators.
The type of angina, co-morbidities, contra-indications and patient preference guides the choice of first-line agent. Beta-blockers are recommended for all patients with previous myocardial infarction and/ or heart failure as these have proven prognostic benefit in this context. Longer acting formulations that lack intrinsic sympathomimetic activity are preferred, at a dose titrated to achieve a target heart rate of 50–60 beats per minute. The potential prognostic benefit of beta-blockers in patients with angina alone has been extrapolated from post-myocardial infarction studies and current evidence is lacking [30]. For patients with asthma (or other contra-indications to beta-blockers), and those with primary vasospastic angina, calcium channel blockers are recommended. When a beta-blocker and a calcium channel blocker are used together in combination therapy, a non-rate limiting dihydropiridine (e.g. nifedipine) is advised.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
