non-ST-elevation myocardial infarction

MEDICAL MANAGEMENT OF ATHEROSCLEROSIS

Management of stable angina and unstable angina/ non-ST-elevation myocardial infarction

What’s new ? • Improvements in the outcome of percutaneous intervention have led to increased use of these techniques in revascularization. There is also increasing use of ‘early invasive’ strategies in patients with unstable angina/non-ST-elevation MI

Graham S Hillis

• There is general acceptance that diagnosis of acute MI should be based primarily on biomarker evidence (preferably cardiac troponin I or T)

Angina is a common symptom associated with considerable morbidity and mortality; with proper management, both can be reduced. All patients (with the possible exception of the very elderly with mild symptoms) should be referred to a cardiologist for assessment. The cornerstones of management include establishing the diagnosis, treating the symptoms, determining the risk of future adverse events, and implementing measures to improve the prognosis. Well-validated tests, effective treatments and excellent scientific data are available to assist the physician. Nevertheless, the optimal management of individual patients remains a matter of clinical judgement. The clinical manifestations of myocardial ischaemia can be divided into several categories. • Stable angina is usually caused by relatively fixed obstructive atherosclerotic lesions within the coronary arteries. • The acute coronary syndromes are caused by rupture or erosion of an atherosclerotic plaque. • In rare cases, angina (and indeed myocardial infarction, MI) may be induced by coronary artery spasm (sometimes termed ‘variant’ or ‘Prinzmetal’s’ angina) or situations in which very high myocardial oxygen demands exceed supply (e.g. severe aortic stenosis). • A few patients with angiographically normal coronary arteries and no evidence of spasm exhibit typical angina and objective evidence of ischaemia on stress testing. It is important to remember that myocardial ischaemia may be associated with other, less specific symptoms such as nausea, sweating, lethargy and/or breathlessness. Many patients with angina exhibit frequent episodes of asymptomatic ischaemia, and about 1/8 patients sustaining an MI experience no symptoms. This contribution focuses on chronic stable angina and unstable angina/non-ST-elevation MI (NSTEMI).

• It is recommended that all patients with non-STelevation acute coronary syndromes should receive dual antiplatelet therapy with aspirin and clopidogrel for a minimum of 3 months, unless contraindicated

Epidemiology Chronic stable angina is the initial manifestation of ischaemic heart disease (IHD) in about 50% of patients and may affect 4–5% of Western populations.1,2 The prevalence is likely to rise as the elderly population increases and survival from MI improves. In addition to the morbidity and socioeconomic costs, stable angina is associated with an annual mortality of about 2–3% and a similar incidence of non-fatal MI. Some subgroups have a poorer prognosis, and identification of such individuals is an important aim in the management of angina. Diagnosis History and examination – angina is a clinical diagnosis established by taking a careful history. Although physical signs have little role in diagnosis, patients experiencing angina may exhibit features of autonomic arousal and/or transient left ventricular (LV) dysfunction. In addition, several signs may be associated with an increased risk of atherosclerosis (e.g. tobacco tar stains on the fingers, xanthomata and/or xanthelasma, elevated blood pressure, diabetic retinopathy, glycosuria), and there may be overt evidence of other vascular disease (e.g. carotid bruits, absent peripheral pulses). Physical examination may also reveal associated conditions that can exacerbate angina, including aortic stenosis, heart failure, anaemia and thyrotoxicosis. Non-invasive testing – resting ECG is of limited value in patients with stable angina and is normal in at least 50% of cases.3 However, it may reveal ischaemic changes or evidence of previous MI, or may expose less specific abnormalities such as LV hypertrophy, conduction defects or arrhythmia, all of which make IHD more likely. About one-half of patients with a normal resting ECG exhibit abnormalities during an episode of angina.3 This may be useful in confirming the diagnosis and, if the abnormalities are unequivocal and occur at a low workload, may obviate the need for further non-invasive testing. Chest radiography is seldom helpful in uncomplicated stable angina, but may establish non-cardiac causes of chest pain or reveal complications such as pulmonary oedema. Haemoglobin, thyroid function, fasting lipoprotein profile and glucose should be measured. In some patients with a classical history, well-control-

Stable angina Stable angina pectoris is a clinical syndrome that manifests as pain, discomfort or ‘tightness’ in the chest, arm or jaw. It is classically precipitated by exertion or emotional stress, is relieved by rest and/or nitroglycerin, lasts for a few minutes, and represents myocardial ischaemia of insufficient severity and/or duration to cause myocyte necrosis.

Graham S Hillis BMEdBiol PhD is Senior Lecturer in Cardiology at Aberdeen Royal Infirmary and the University of Aberdeen. He qualified from the University of Aberdeen and trained in cardiology in Edinburgh and the USA. Conflicts of interest: none.

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led symptoms and factors making coronary revascularization an unattractive therapeutic option, no further investigation is required. However, most patients require some form of stress testing to help confirm the diagnosis and quantify the extent of any myocardial ischaemia. Stress testing – the most widely available form of stress testing is exercise ECG. If it is not possible to induce stress using exercise, various pharmacological agents are available. These include dipyridamole (causes coronary vasodilatation by inhibiting uptake of adenosine, an effect that is blunted in diseased arteries), adenosine (works directly in a similar manner) and dobutamine (a positive inotrope and chronotrope that increases myocardial oxygen demands). The choice of agent and imaging modality depends on local expertise and availability, and on patient factors such as body habitus and the presence of asthma or obstructive pulmonary disease (which may be exacerbated by dipyridamole and adenosine). Coronary angiography is of fundamental importance in the management of stable angina. It is indicated in patients with severe angina (Figure 1) and/or evidence of ischaemia at a low workload. In these circumstances, it has a vital role in risk stratification and the planning of revascularization (see below). However, it is important to recognize that many patients with non-cardiac chest pain have abnormal coronary arteries and, conversely, many individuals with coronary atherosclerosis have no cardiovascular symptoms. Nevertheless, the presence of severe stenosis (≥ 70% luminal narrowing), in the context of chest pain with no other obvious explanation, is highly suggestive. The functional significance

of less severe narrowing is more difficult to assess and, unless the history is clear, angiographic assessment should be combined with the results of functional tests (non-invasive stress tests or coronary pressure/flow measurements). Management Treatment of stable angina (Figure 2) has two main aims – to improve symptoms and to improve prognosis. Improving the symptoms General measures – various lifestyle modifications may reduce morbidity in patients with chronic stable angina; increased physical activity improves fitness and exercise tolerance, weight loss reduces myocardial oxygen demand, and stopping smoking may improve symptoms. In addition, patient education about symptoms may reduce the need for revascularization and drugs. Underlying conditions such as anaemia and thyrotoxicosis should be identified and treated as appropriate, and optimizing therapy for heart failure may improve concomitant angina. Pharmacological treatments – all patients with angina should be provided with a short-acting nitrate and instructed in its use (including prophylaxis); they should take their first dose in the presence of medical or nursing staff. Unless there are contraindications, β-blockers (e.g. atenolol, 50–100 mg daily, metoprolol, 50–100 mg b.d. or t.d.s., bisoprolol, 5–10 mg daily) should be used as first-line anti-anginal agents; in addition to reducing symptoms, they confer prognostic benefits particularly (but not exclusively) in patients with a history of MI and/or impaired LV function. βblockers should be avoided in patients with severe asthma (though this does not preclude cautious use in those with mild asthma or pulmonary disease in which bronchial hyper-reactivity is not a prominent feature). Patients who are intolerant of β-blockers, or in whom adequate doses are insufficient to control symptoms, should be prescribed a long-acting nitrate (with doses timed to provide a nitrate-free period and thereby avoid tolerance), a potassium channel activator (e.g. nicorandil, 10–30 mg b.d.) or a calcium channel antagonist (e.g. a long-acting dihydropyridine such as amlodipine, 5–10 mg daily, or modified-release nifedipine, with doses determined by the preparation chosen). In the absence of a β-blocker, a rate-limiting agent such as diltiazem or verapamil may be preferable, except in patients with moderate or severely impaired LV function. Coronary revascularization – percutaneous coronary interventions (PCIs) such as percutaneous coronary angioplasty and coronary stenting are effective treatments for angina in suitable patients. Stent placement in this setting has a mortality of less than 0.5%, and the incidences of periprocedural Q-wave MI and the need for emergency surgery are less than 1%.4 The restenosis rate depends on many factors, including characteristics of the patient, lesion and stent; the average is about 15–20% with bare metal stents and 5−10% with drug-eluting stents. However, there is no good evidence that PCIs improve prognosis in stable coronary disease, and they should generally be used when medical therapy fails to control symptoms. Coronary artery bypass grafting (CABG) is the most effective treatment for angina; more than 60% of patients are entirely free from symptoms 5 years later.5 However, early mortality is greater than in PCI (up to 5% in multivessel disease with impaired LV function), there is a greater risk of perioperative MI (about 4%),

Canadian Cardiovascular Society grading of the severity of angina Class I • Ordinary physical activity does not cause angina • Angina is precipitated only by strenuous, rapid or prolonged exercise Class II • Angina causes slight limitation of ordinary activity • Angina is induced by climbing stairs rapidly, walking uphill, walking or stair-climbing after a meal or in cold or windy conditions, or emotional stress • This class also includes symptoms that occur after walking more than two blocks (about 100–200 metres) on the level, or after climbing more than one flight of stairs under normal conditions or during the first few hours after wakening Class III • Symptoms cause marked limitation of ordinary activity • Angina is induced by walking less than two blocks on the level or by climbing one flight of stairs under normal conditions Class IV • Symptoms occur when undertaking any physical activity or at rest

1

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Suggested algorithm for the management of stable angina Stable angina

Advice regarding lifestyle

Check for exacerbating conditions

Treat hypercholesterolaemia, hypertension, diabetes and/or heart failure aggressively

Commence β-blocker/aspirin/short-acting nitrate (unless contraindicated)

Severe symptoms

Mild/moderate symptoms

Poor candidate for revascularization

Myocardial stress test

Low risk

Intermediate/high risk

Coronary angiography

Mild symptoms

Non-prognostically significant coronary artery disease

1

Prognostically significant coronary artery disease

Moderate/severe symptoms 2 Additional anti-anginal therapy if required

2 Percutaneous coronary intervention

2 Coronary artery bypass grafting

1 Prognostically significant – > 50% left main stem stenosis or three-vessel coronary artery disease with impaired left ventricular systolic function 2 Decision regarding optimal treatment depends on individual preferences, co-morbidity, coronary anatomy and response to/tolerance of additional anti-anginal therapy 2

Recent evidence7 suggests that, in the absence of contraindications, all patients with IHD will benefit from treatment with HMG-CoA reductase inhibitors (‘statins’) aiming to reduce total cholesterol levels below 4.0 mmol/litre and low-density lipoprotein levels below 2 mmol/litre.6 Aspirin reduces adverse vascular events in patients with angina by one-third and should be administered to all those without contraindications. If necessary, clopidogrel (a thienopyridine antiplatelet agent) can be substituted. As discussed above, βblockers confer some prognostic benefit and should be prescribed whenever possible. Angiotensin-converting enzyme inhibitors are indicated in patients with a history of heart failure or impaired LV systolic function, renal dysfunction and/or diabetes. Their value in patients who have IHD but none of these additional indications

and patients suffer the morbidity associated with a major operation. CABG is therefore generally restricted to individuals who are likely to gain prognostic benefit (see below), or whose symptoms are uncontrolled by medical therapy and who are unsuitable for PCI. Improving the prognosis: many of the general measures above may improve prognosis. In particular, indirect evidence suggests that cessation of cigarette smoking improves outcome. Patients should be encouraged to eat a healthy diet and to take more aerobic exercise. Concomitant conditions such as diabetes and hypertension should be managed appropriately; current UK guidelines suggest target blood pressures of less than 140/85 mm Hg (<130/80 mm Hg in patients with diabetes or renal impairment).6

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and who are receiving other appropriate therapies is, however, less clear. The value of other pharmacological interventions (e.g. antioxidants, omega-3 fatty acid supplements) is uncertain and they cannot currently be regarded as standard treatments. Risk stratification – the prognosis of patients with IHD is related to five factors: • age and general health • LV systolic function • extent of coronary disease • site of any severe coronary artery stenoses • stability of atherosclerotic plaques. General health can usually be determined from the clinical history. The history and examination may also provide important clues regarding LV function, and chest radiography and resting ECG may provide corroborating evidence. Systolic function is seldom impaired in patients who give no history of breathlessness or previous MI and in whom ECG is normal. If this is not the case, echocardiography is a simple, safe and effective means of assessing LV function, and provides useful additional information on, for example, valve function. If echocardiography is impossible for technical reasons, other imaging modalities such as left ventriculography, radionuclide scanning or MRI can be used to assess LV function. Clues to the extent of coronary disease are available from the history. Greater age, previous MI, diabetes, male gender and typical anginal symptoms are all predictive of more severe disease. Exercise ECG can provide important prognostic information. The extent of ischaemia is a marker for more severe and diffuse disease, and exercise capacity partly reflects age, general health and LV function. Various predictive models have been devised; one of the best documented is the Duke treadmill score (Figure 3). Patients who can complete more than 5 minutes of a Bruce protocol exercise test without chest pain or ST-segment deviation have an excellent prognosis.8 If an exercise test is not possible or cannot be easily interpreted, radionuclide perfusion scanning or stress echocardiography are well-validated alternatives.9 Coronary angiography is the definitive test in patients with high-

risk features. CABG confers a survival benefit in most patients in whom coronary angiography reveals significant (> 50%) left main stem stenosis or disease of all three major epicardial vessels with associated impairment of LV systolic function.5 CABG may also improve the prognosis in patients with two-vessel or three-vessel disease that includes a severe proximal left anterior descending stenosis, particularly if there is also severe proximal circumflex disease, impaired LV function or evidence of ischaemia on noninvasive tests.5 However, other factors such as co-morbidities, the suitability of target vessels and patient preferences must also be taken into account. In addition, outcome data are extracted from studies performed more than 20 years ago, since when all available therapies have developed greatly. Severe proximal coronary lesions are associated with a worse outcome. This is not merely a reflection of the amount of myocardium they subtend. Most coronary atherosclerosis is not apparent angiographically, and there is extensive evidence that insignificant plaques are most likely to rupture, potentially causing MI and/or death. Much of the prognostic value of angiography may relate to the fact that severe disease is an indirect marker for a greater underlying plaque burden. Plaque stability is difficult to assess, though the clinical history may give obvious clues. There is interest in using inflammatory markers and other techniques to detect instability, though none has yet been adopted in routine clinical practice. Unstable angina/non-ST-elevation myocardial infarction Chest pain accounts for more than 5 million presentations to emergency departments each year in the USA. In about one-half of cases, the pain is non-cardiac. In the remainder, it is caused by MI or unstable angina (the acute coronary syndromes). The acute coronary syndromes are caused by plaque erosion or rupture with superimposed platelet aggregation and thrombosis, often accompanied by distal embolization and vasospasm. The consequences are variable, ranging from unstable angina without evidence of myocardial cell necrosis, to ‘classical’ acute ST-elevation MI and/or sudden cardiac death. Classification of these extremes

Mortality according to cardiac troponin I levels at enrolment in the TIMI IIIb trial

Derivation and interpretation of the Duke treadmill score

8 7

Mortality at 42 days (%)

Duke treadmill score = duration of exercise in minutes – 5 x maximal ST-segment deviation in millimetres – 4 x angina index Angina index – 0, no angina; 1, typical angina during test or recovery period; 2, test stopped because of angina Risk

Score

Annual mortality

•Low

≥ +5

0.25%

•Moderate

–10 – +4

1.25%

•High

< –10

5.00%

5 4 3 2 1 0

1.0%

1.7%

3.4%

3.7%

6.0%

7.5%

0–< 0.4

0.4–< 1.0

1.0–< 2.0

2.0–< 5.0

5.0–< 9.0

> 9.0

Cardiac troponin I (ng/ml) Source: Antman E, Tanasijevic M J, Thompson B et al. N Engl J Med 1996; 335: 1342–9.12

Source: Mark D B, Shaw L, Harrell F E Jr et al. N Engl J Med 1991; 325: 849–53.

4

3

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is relatively simple, but the intermediate manifestations have been a source of confusion in recent years. Much of this derives from uncertainty as to how to ‘label’ patients with marginal elevations of cardiac troponin (cTn) levels. This remains to be resolved, but current guidelines suggest that, in the correct clinical context, any elevation of cTnI or T levels above the 99th percentile for the normal population (at a level where the coefficient of variation for the assay being used is no greater than 10%) represents myocardial infarction.10 The precise ‘cut-off’ will therefore vary with the assay used, and an awareness of the value used locally is required. Although biomarker data are extremely valuable, it is clinically useful to subdivide patients with an acute coronary syndrome according to their presenting ECG. Those with ST-elevation MI

require oxygen, analgesia, aspirin and immediate reperfusion therapy. Management of the remainder, who are designated as having unstable angina or NSTEMI on the basis of their cardiac markers, is largely dependent on their short-term and medium-term risk. Risk stratification of patients with unstable angina/NSTEMI In patients with unstable angina/NSTEMI, the risk of death or (recurrent) MI is about 12% within the subsequent 6 months, mainly during the initial 30 days.11 It is important to remember, however, that the risk may vary considerably between patients, and varies over time, as do the determinants. For example, a patient with chest pain, ST-segment depression and positive cTn is at high risk in the acute setting (largely related to the potential

Suggested algorithm for the management of unstable angina/non ST-elevation myocardial infarction Unstable angina/NSTEMI

Analgesia and oxygen

β-blocker and aspirin (unless contraindicated)

Buccal or intravenous nitrate if ongoing pain

No high-risk clinical features

High-risk clinical features

1 2

Admit to monitored bed/telemetry

1

Admit to coronary care unit 3

Check cardiac troponins 6–12 hours after onset of pain

Negative

Positive

Commence heparin and GpIIb/IIIa inhibitor and/or clopidogrel 5

4

Coronary angiography

4 Myocardial stress test

Low/intermediate risk

High risk

Coronary revascularization if possible

6

Secondary prevention/out-patient review 1 High-risk clinical features are ongoing pain, ST depression or pronounced T-wave inversion, haemodynamic compromise or left ventricular failure 2 Patients with initially favourable prognostic indicators may develop complications and move into a high-risk category 3 The combination of clopidogrel and GpIIb/IIIa inhibitors in this setting is untested 4 There is controversy whether all patients with detectable cardiac troponins should undergo angiography with the intention of early revascularization; in stabilized patients with otherwise favourable prognostic indicators, it may be reasonable to perform further risk stratification by means of myocardial stress testing 5 The optimal timing of angiography is uncertain 6 The preferred method of revascularization depends on patient preferences, co-morbidity, coronary anatomy and left ventricular function 5

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an acute coronary syndrome should receive a β-blocker. If this is contraindicated or poorly tolerated, a rate-limiting calcium channel antagonist can be substituted to achieve symptom control. There is, however, limited evidence that calcium channel antagonists should be prescribed for prognostic reasons and they may be detrimental in patients with LV systolic impairment (see above). Those with ongoing ischaemic pain should be treated with nitrates and/or opiate analgesia. This is usually an indication for an early invasive strategy (see below). Antiplatelet therapy – unless there are contraindications, all patients should receive combination antiplatelet therapy with aspirin and clopidogrel.13 Intravenous glycoprotein IIb/IIIa inhibitors improve the prognosis in patients with a non-ST-elevation acute coronary syndrome, reducing the incidence of early death or recurrent MI by about 1−2%.14 These benefits are principally seen in patients with highrisk clinical features (particularly those with positive cTnI or T) and those undergoing early PCI, and treatment should probably be targeted at such individuals. Antithrombotic therapy – heparin in addition to aspirin appears to slightly improve early outcome. LMWH is superior to unfractionated heparin, but the magnitude of any benefit is modest and the most compelling reason for preferring LMWH is that it can be administered as a twice-daily subcutaneous injection rather than a continuous intravenous infusion and avoids the need for monitoring the activated partial thromboplastin time.

for ventricular arrhythmia). If he recovers with no further chest pain, normal echocardiography and a reassuring exercise test, his risk has decreased. Furthermore, risk stratification can never be entirely accurate, because it is difficult to apply probabilities obtained from large populations to an individual. About 50% of deaths from IHD are sudden events, principally related to ventricular arrhythmia and often occurring before the individual can seek medical help. By the time patients present to medical services, they have already survived one of the most dangerous periods of their illness. Early risk stratification in these survivors is mainly directed at identifying patients with ongoing instability. Predictors of adverse outcome Clinical factors – continuing ischaemic chest pain despite conventional medical therapy (see below) is an unequivocal indication for emergent angiography and revascularization, if possible. Development of heart failure is also indicative of higher risk but, when possible, it is usually preferable to stabilize such patients medically and then reassess the need for intervention. Patients with cardiogenic shock are an exception to this rule; their prognosis may be improved by early, aggressive revascularization strategies. The ECG provides considerable prognostic information. STsegment deviation is an ominous sign, particularly when the changes are ongoing, fluctuant and associated with residual pain. Even temporary severe ST-segment shift or deep T-wave inversion indicates a poorer prognosis and may favour early revascularization. Other ECG abnormalities such as conduction problems and early ventricular arrhythmia are also associated with an adverse prognosis, but there is little evidence that specific therapies influence this. In contrast, the adverse outcome predicted by late ventricular arrhythmia may be improved by revascularization or use of implantable defibrillators. Biochemical markers – elevation of any marker of myocardial cell necrosis is an indicator of poorer outcome in patients with an acute coronary syndrome. However, the discriminatory value is closely related to the specificity of the marker for cardiac damage. Use of cTn has significant advantages, because these are almost exclusively myocardial in origin. Outcome in an acute coronary syndrome is directly proportional to the extent of myocardial injury, so there is an excellent correlation between cTn levels and prognosis (Figure 4).12 Mildly elevated cTn levels are thought to principally reflect embolization from an unstable lesion. For this reason, the greatest benefit from low molecular weight heparin (LMWH) and glycoprotein IIb/IIIa inhibitors is seen in cTn-positive patients (though this may also be because many cTn-negative patients have non-cardiac chest pain and/or are at such low risk that it is difficult to reduce it further). Inflammatory markers and byproducts of the coagulation cascade are elevated in many patients with an acute coronary syndrome, and may be associated with an adverse outcome. There is some evidence that they add to conventional means of risk stratification, but their use may be limited in heterogeneous populations with chest pain. They are therefore not measured routinely.

Revascularization: high-risk patients (Figure 6) with unstable angina/NSTEMI should undergo early angiography and revascularization when possible.14,15,16

Indications for an early invasive strategy in patients with unstable angina/non-ST-elevation myocardial infarction • Ongoing or recurrent ischaemic symptoms at rest/on minimal exertion despite medical therapy (see text) • New/presumed new ST-segment depression and/or dynamic ST-segment changes • Haemodynamic instability • Sustained or recurrent ventricular arrhythmia • Elevated cardiac troponin level • Reduced left ventricular systolic function (ejection fraction < 40%) and/or clinical evidence of heart failure (particularly when associated with evidence of ongoing/recurrent ischaemia) • Extensive reversible ischaemia or other high-risk features on non-invasive testing • Recent (within previous 6 months) percutaneous coronary intervention • Prior coronary artery bypass grafting • Diabetes Sources: Braunwald E, Antman E M, Beasley J W et al. www.acc.org/clinical/ guidelines/unstable/incorporated/UA_incorporated.pdf and Bertrand M E, Simoons M L, Fox K A et al. Eur Heart J 2002; 23: 1809–40.

Management (Figure 5) General management Anti-ischaemic therapy – whenever possible, patients with

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Long-term management and secondary prevention: once the acute phase is over, the prognosis of survivors is determined by factors similar to those that influence the outcome in patients with stable angina. In patients not undergoing early angiography, clinical factors, echocardiography and stress testing are useful to determine who requires invasive investigation (Figure 6). Stress testing is also useful in determining the need for revascularization. This is easy to justify when the stress test reveals residual ischaemia at a low workload, particularly when associated with symptoms. If it does not, and the disease pattern at angiography does not indicate CABG on prognostic grounds, the need for revascularization can be reviewed after the patient has undertaken normal activities for a few weeks. 

segment elevation. Eur Heart J 2002; 23: 1809–40. 15 Wallentin L, Lagerqvist B, Husted S et al. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary artery disease: the FRISC II Invasive Randomised Trial. Lancet 2000; 356: 9–16. 16 Cannon C P, Weintrub W S, Demopoulos L A et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001; 344: 1879–87. FURTHER READING Bertrand M E, Simoons M L, Fox K A et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002; 23: 1809–40. (European guidelines, also available at the European Society of Cardiology web site, www.escardio.org; an accompanying slide set is available.) Braunwald E, Antman E M, Beasley J W et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee on the management of patients with unstable angina). www.acc.org/clinical/guidelines/ unstable/incorporated/UA_incorporated.pdf (Comprehensive background information and extensive references; a teaching slide set based on the guidelines is also available to download from the American College of Cardiology web site, www.acc. org) Gibbons R J, Abrams J, Chatterjee K et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to update the 1999 guidelines for the management of patients with chronic stable angina). (Extensively referenced and generally applicable guidelines, more useful as a reference document because of its size and complexity.) Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J 1997; 18: 394–413. (Equivalent European guidelines, less comprehensive but more ‘reader friendly’; also available from the European Society of Cardiology web site, www.escardio.org) Myocardial infarction redefined – a consensus document of the Joint European Society of Cardiology/American College of Cardiology committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36: 959–69. (Guidance on how MI should be defined in the era of sensitive and specific markers of myocardial necrosis; available at www.acc.org)

REFERENCES 1 British Heart Foundation statistics.www.heartstats.org/homepage 2 WHO. www.who.int/cardiovascular_diseases/en 3 Morrow D A, Gersh B J, Braunwald E. Chronic coronary artery disease In: Zipes, Libby, Bonow et al., eds. Heart disease. A textbook of cardiovascular medicine. 7th ed. Philadelphia: Elsevier Saunders, 2005. 4 British Coronary Intervention Society audit data. www.bcis.org. uk/resources/documents/returns2003.ppt 5 Eagle K A, Guyton R A, Davidoff R et al. ACC/AHA guidelines for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1991 guidelines for coronary artery bypass graft surgery). J Am Coll Cardiol 1999; 34: 1262–46. 6 Williams B, Poulter N R, Brown M J et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society 2004-BHS IV. J Hum Hypertens 2004; 18: 139–85. 7 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7–22. 8 Mark D B, Shaw L, Harrell F E Jr et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 1991; 325: 849–53. 9 Lee T H, Boucher C A. Non-invasive tests in patients with stable coronary artery disease. N Engl J Med 2001; 344: 1840–5. 10 Myocardial infarction redefined – a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 2000; 36: 959–69. 11 Collinson J, Flather M D, Fox K A et al. Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation. Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK). Eur Heart J 2000; 21: 1450–7. 12 Antman E M, Tanasijevic M J, Thompson B et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996; 335: 1342–9. 13 Yusuf S, Zhao F, Mehta S R et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med 2001; 345: 494–502. 14 Bertrand M E, Simoons M L, Fox K A et al. Management of acute coronary syndromes in patients presenting without persistent ST-

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