CORONARY HEART DISEASE

Coronary heart disease (CHD) is the most common form of heart disease and the single most important cause of premature death in Europe, the Baltic states, Russia, North and South America, Australia and New Zealand.

By 2020 it is estimated that it will be the major cause of death in all regions of the world.

In the UK, 1 in 3 men and 1 in 4 women die from CHD, an estimated 330 000 people have a myocardial infarct each year, and approximately 1.3 million people have angina.

The death rates from CHD in the UK are amongst the highest in Western Europe (more than 140000 people) but are falling, particularly in younger age groups; in the last 10 years CHD mortality has fallen by 42% among UK men and women aged 16–64.

However, in Eastern Europe and much of Asia, the rates of CHD are rapidly rising.

Disease of the coronary arteries is almost always due to atheroma and its complications, particularly thrombosis.

Occasionally, the coronary arteries are involved in other disorders such as aortitis, polyarteritis and other connective tissue disorders.

STABLE ANGINA

Angina pectoris is the symptom complex caused by transient myocardial ischaemia and constitutes a clinical syndrome rather than a disease. It may occur whenever there is an imbalance between myocardial oxygen supply and demand.

Coronary atheroma is by far the most common cause of angina, although the symptom may be a manifestation of other forms of heart disease, particularly aortic valve disease and hypertrophic cardiomyopathy.

CLINICAL FEATURES: The history is by far the most important

factor in making the diagnosis. Stable angina is characterized by

central chest pain, discomfort or breathlessness that is precipitated by exertion or other forms of stress, and is promptly relieved by rest.

Some patients find that the discomfort comes when they start walking, and that later it does not return despite greater effort (‘warm-up angina’).

Physical examination is frequently unremarkable but should include a careful search for evidence of valve disease (particularly aortic), important risk factors (e.g. hypertension, diabetes mellitus), left ventricular dysfunction (cardiomegaly, gallop rhythm), other manifestations of arterial disease (carotid bruits, peripheral vascular disease) and unrelated conditions that may exacerbate angina (anaemia, thyrotoxicosis).

INVESTIGATIONS:1) Resting ECG: The ECG may show evidence of previous

MI but is often normal, even in patients with severe coronary artery disease.

Occasionally, there is T-wave flattening or inversion in some leads, providing non-specific evidence of myocardial ischaemia or damage.

The most convincing ECG evidence of myocardial ischaemia is the demonstration of reversible ST segment depression or elevation, with or without T-wave inversion, at the time the patient is experiencing symptoms (whether spontaneous or induced by exercise testing).

2 )Exercise ECG: An exercise tolerance test (ETT) is

usually performed using a standard treadmill or bicycle ergometer protocol while monitoring the patient’s ECG, BP and general condition.

Planar or down-sloping ST segment depression of ≥ 1mm is indicative of ischaemia.

Up-sloping ST depression is less specific and often occurs in normal individuals.

Exercise testing is also a useful means of assessing the severity of coronary disease and identifying high risk individuals.

For example, the amount of exercise that can be tolerated and the extent and degree of any ST segment change provide a useful guide to the likely extent of coronary disease.

Exercise testing is not infallible and may produce false positive results in the presence of digoxin therapy, left ventricular hypertrophy, bundle branch block or WPW syndrome.

The predictive accuracy of exercise testing is lower in women than men.

The test should be classed as inconclusive (rather than negative) if the patient cannot achieve an adequate level of exercise because of locomotor or other non-cardiac problems.

3 )Other forms of stress testing:- Myocardial perfusion scanning: This may be helpful in the evaluation of

patients with an equivocal or uninterpretable exercise test and those who are unable to exercise.

It entails obtaining scintiscans of the myocardium at rest and during stress (either exercise testing or pharmacological stress, such as a controlled infusion of dobutamine) after the administration of an intravenous radioactive isotope, such as 99technetium tetrofosmin.

Thallium and tetrofosmin are taken up by viable perfused myocardium.

A perfusion defect present during stress but not at rest provides evidence of reversible myocardial ischaemia, whereas a persistent perfusion defect seen during both phases of the study is usually indicative of previous MI.

-Stress echocardiography:

This is an alternative to myocardial perfusion scanning and can achieve similar predictive accuracy. It uses transthoracic echocardiography to identify ischaemic segments of myocardium and areas of infarction.

The former characteristically exhibit reversible defects in contractility during exercise or pharmacological stress, and the latter do not contract at rest or during stress.

4 )Coronary arteriography: This provides detailed anatomical

information about the extent and nature of coronary artery disease, and is usually performed with a view to coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention.

In some patients, diagnostic coronary angiography may be indicated when non-invasive tests have failed to establish the cause of atypical chest pain.

The procedure is performed under local anaesthesia and requires specialised radiological equipment, cardiac monitoring and an experienced operating team.

MANAGEMENT :1) General measures: The management of angina pectoris

involves: -a careful assessment of the likely

extent and severity of arterial disease. -the identification and control of risk

factors such as smoking, hypertension and hyperlipidaemia.

-the use of measures to control symptoms.

-the identification of high-risk patients for treatment to improve life expectancy.

Symptoms alone are a poor guide to the extent of coronary artery disease.

Stress testing is therefore advisable in all patients who are potential candidates for revascularisation.

Management should start with a careful explanation of the problem and a discussion of the potential lifestyle and medical interventions that may relieve symptoms and improve prognosis.

Anxiety and misconceptions often contribute to disability; for example, some patients avoid all forms of exertion because they believe that each attack of angina is a ‘mini heart attack’ that results in permanent damage.

Effective management of these psychological factors can make a huge difference to the patient’s quality of life.

2 )Antiplatelet therapy : Low-dose (75mg) aspirin reduces the

risk of adverse events such as MI and should be prescribed for all patients with coronary artery disease indefinitely.

Clopidogrel (75mg daily) is an equally effective antiplatelet agent that can be prescribed if aspirin causes troublesome dyspepsia or other side-effects.

3 )Anti-anginal drug treatment Five groups of drug are used to help

relieve or prevent the symptoms of angina: nitrates, β-blockers, calcium antagonists, potassium channel activators and an If channel antagonist.

a) Nitrates: These drugs act directly on vascular

smooth muscle to produce venous and arteriolar dilatation.

Their beneficial effects are due to a reduction in myocardial oxygen demand (lower preload and afterload) and an increase in myocardial oxygen supply (coronary vasodilatation).

Sublingual glyceryl trinitrate (GTN) administered from a metered-dose aerosol (400 μg per spray) or as a tablet (300 or 500 μg) will relieve an attack of angina in 2–3 minutes.

Side-effects include headache, symptomatic hypotension and, rarely, syncope.

Patients should be encouraged to use the drug prophylactically before taking exercise that is liable to provoke symptoms.

Sublingual GTN has a short duration of action; however, a variety of alternative nitrate preparations can provide a more prolonged therapeutic effect.

GTN can be given transcutaneously as a patch (5–10mg daily), or as a slow-release buccal tablet (1–5mg 6-hourly).

GTN undergoes extensive first-pass metabolism in the liver and is ineffective when swallowed.

Other nitrates such as isosorbide dinitrate (10–20mg 8-hourly) and isosorbide mononitrate (20–60mg once or twice a day) can be given by mouth.

Headache is common but tends to diminish if the patient perseveres with the treatment.

Continuous nitrate therapy can cause pharmacological tolerance.

This can be avoided by a 6–8-hour nitrate-free period, best achieved at night when the patient is inactive.

If nocturnal angina is a predominant symptom, long-acting nitrates can be given at the end of the day.

b) Beta-blockers: These lower myocardial oxygen

demand by reducing heart rate, BP and myocardial contractility, but they may provoke bronchospasm in patients with asthma.

In theory, non-selective β-blockers may aggravate coronary vasospasm by blocking the coronary artery β2-adrenoceptors and so a once-daily cardioselective preparation is used (e.g. slow-release metoprolol 50–200mg daily, bisoprolol 5–15mg daily).

Beta-blockers should not be withdrawn abruptly because this may have a rebound effect and precipitate dangerous arrhythmias, worsening angina or MI: the β-blocker withdrawal syndrome.

c) Calcium channel antagonists: These drugs inhibit the slow inward

current caused by the entry of extracellular calcium through the cell membrane of excitable cells, particularly cardiac and arteriolar smooth muscle, and lower myocardial oxygen demand by reducing BP and myocardial contractility.

Dihydropyridine calcium antagonists, such as nifedipine and nicardipine, often cause a reflex tachycardia.

This may be counterproductive and it is best to use them in combination with a β-blocker.

In contrast, verapamil and diltiazem are particularly suitable for patients who are not receiving a β-blocker (e.g. those with airways obstruction) because they slow SA node firing, inhibit conduction through the AV node and tend to cause a bradycardia.

Calcium channel antagonists reduce myocardial contractility and can aggravate or precipitate heart failure.

Other unwanted effects include peripheral oedema, flushing, headache and dizziness.

d) Potassium channel activators: These have arterial and venous dilating

properties but do not exhibit the tolerance seen with nitrates.

Nicorandil (10–30mg 12-hourly orally) is the only drug in this class currently available for clinical use.

:e) If channel antagonist Ivabradine is the first of this class of drug. It induces bradycardia by modulating ion

channels in the sinus node. In contrast to β-blockers and rate-limiting

calcium antagonists, it does not have other cardiovascular effects.

It appears to be safe to use in patients with heart failure.

Although each of these anti-anginal drugs is superior to placebo in relieving the symptoms of angina, there is little evidence that one group is more effective than another.

It is conventional to start therapy with low-dose aspirin, a statin, sublingual GTN and a β-blocker, and then add a calcium channel antagonist or a long-acting nitrate later if needed.

The goal is the control of angina with minimum side-effects and the simplest possible drug regimen.

There is little evidence that prescribing multiple anti-anginal drugs is of benefit, and revascularisation should be considered if an appropriate combination of two or more drugs fails to achieve an acceptable symptomatic response.

4 )Invasive treatment:a) Percutaneous coronary intervention

(PCI): This is performed by passing a fine guidewire

across a coronary stenosis under radiographic control and using it to position a balloon which is then inflated to dilate the stenosis.

A coronary stent is a piece of coated metallic ‘scaffolding’ that can be deployed on a balloon and used to maximise and maintain dilatation of a stenosed vessel.

The routine use of stents in appropriate vessels reduces both acute complications and the incidence of clinically important restenosis.

PCI provides an effective symptomatic treatment but definitive evidence that it improves survival in patients with chronic stable angina is lacking.

It is mainly used in single or two-vessel disease.

Stenoses in bypass grafts can be dilated, as well as those in the native coronary arteries.

The technique is often used to provide palliative therapy for patients with recurrent angina after CABG.

Coronary surgery is usually the preferred option in patients with three-vessel or left main stem disease, although recent trials have demonstrated that PCI is also feasible in such patients.

The main acute complications of PCI are occlusion of the target vessel or a side branch by thrombus or a loose flap of intima (coronary artery dissection), and consequent myocardial damage.

This occurs in about 2–5% of procedures and can often be corrected by deploying a stent; however, emergency CABG is sometimes required.

Minor myocardial damage, as indicated by elevation of sensitive intracellular markers (troponins), occurs in up to 10% of cases.

The main long-term complication of PCI is restenosis, which occurs in up to one-third of cases.

This is due to a combination of elastic recoil and smooth muscle proliferation (neo-intimal hyperplasia) and tends to occur within 3 months.

Stenting substantially reduces the risk of restenosis, probably because it allows the operator to achieve more complete dilatation in the first place.

Drug-eluting stents can reduce this risk even further by allowing an antiproliferative drug such as sirolimus or paclitaxel to elute slowly from the coating and prevent neo-intimal hyperplasia and in-stent restenosis.

There is an increased risk of late stent thrombosis with drug-eluting stents, although the absolute risk is small (< 0.5%).

Recurrent angina (affecting up to 15–20% of patients receiving an intracoronary stent at 6 months) may require further PCI or bypass grafting.

The risk of complications and the likely success of the procedure are closely related to the morphology of the stenoses, the experience of the operator and the presence of important comorbidity, e.g. diabetes, peripheral arterial disease.

A good outcome is less likely if the target lesion is complex, long, eccentric or calcified, lies on a bend or within a tortuous vessel, involves a branch or contains acute thrombus.

In combination with aspirin and heparin, adjunctive therapy with potent platelet inhibitors, such as clopidogrel or glycoprotein IIb/IIIa receptor antagonists, improves the outcome of PCI, with lower short- and long-term rates of death and MI.

b) Coronary artery bypass grafting (CABG):

The internal mammary arteries, radial arteries or reversed segments of the patient’s own saphenous vein can be used to bypass coronary artery stenoses.

This usually involves major surgery under cardiopulmonary bypass, but in some cases, grafts can be applied to the beating heart: ‘off-pump’ surgery.

The operative mortality is approximately 1.5% but risks are higher in elderly patients, those with poor left ventricular function and those with significant comorbidity, such as renal failure.

Approximately 90% of patients are free of angina 1 year after CABG surgery, but fewer than 60% of patients are asymptomatic after 5 or more years.

Early postoperative angina is usually due to graft failure arising from technical problems during the operation, or poor ‘run-off’ due to disease in the distal native coronary vessels.

Late recurrence of angina may be due to progressive disease in the native coronary arteries or graft degeneration.

Less than 50% of vein grafts are patent 10 years after surgery.

However, arterial grafts have a much better long-term patency rate, with more than 80% of internal mammary artery grafts patent at 10 years.

This has led many surgeons to consider total arterial revascularisation during CABG surgery.

Aspirin (75–150mg daily) and clopidogrel (75mg daily) have both been shown to improve graft patency, and one or other should be prescribed indefinitely if well tolerated.

Intensive lipid-lowering therapy slows the progression of disease in the native coronary arteries and bypass grafts, and reduces clinical cardiovascular events.

There is substantial excess cardiovascular morbidity and mortality in patients who continue to smoke after bypass grafting.

Persistent smokers are twice as likely to die in the 10 years following surgery than those who give up at surgery.

CABG improves survival in symptomatic patients with left main stem stenosis or three-vessel coronary disease (i.e. involving LAD, CX and right coronary arteries) or two-vessel disease involving the proximal LAD coronary artery.

Improvement in survival is most marked in those with impaired left ventricular function or positive stress testing prior to surgery and those who have undergone left internal mammary artery grafting.

Neurological complications are common, with a 1–5% risk of perioperative stroke.

Between 30% and 80% of patients develop short-term cognitive impairment that is often mild and typically resolves within 6 months.

There are also reports of long-term cognitive decline that may be evident in more than 30% of patients at 5 years.

PROGNOSIS: Symptoms are a poor guide to

prognosis; nevertheless, the 5-year mortality of patients with severe angina (NYHA class III or IV) is nearly double that of patients with mild symptoms.

Exercise testing and other forms of stress testing are much more powerful predictors of mortality; for example, in one study, the 4-year mortality of patients with stable angina and a negative exercise test was 1%, compared to more than 20% in those with a strongly positive test.

In general, the prognosis of coronary artery disease is related to the number of diseased vessels and the degree of left ventricular dysfunction.

A patient with single-vessel disease and good left ventricular function has an excellent outlook (5-year survival > 90%), whereas a patient with severe left ventricular dysfunction and extensive three-vessel disease has a poor prognosis (5-year survival < 30%) without revascularisation.

Spontaneous symptomatic improvement due to the development of collateral vessels is common.

ANGINA WITH NORMAL CORONARY :ARTERIES

Approximately 10% of patients who report stable angina on effort will have angiographically normal coronary arteries.

Many of these patients are women and the mechanism of their symptoms is often difficult to establish.

It is important to review the original diagnosis and explore other potential causes.

1 )Coronary artery spasm: Vasospasm in coronary arteries may

coexist with atheroma, especially in unstable angina; in < 1% of cases, vasospasm may occur without angiographically detectable atheroma.

This form of angina is sometimes known as variant angina, and may be accompanied by spontaneous and transient ST elevation on the ECG (Prinzmetal’s angina).

Calcium channel antagonists, nitrates and other coronary vasodilators are the most useful therapeutic agents but may be ineffective.

2 )Syndrome X: The constellation of typical angina on

effort, objective evidence of myocardial ischaemia on stress testing, and angiographically normal coronary arteries is sometimes known as syndrome X.

This disorder is poorly understood but carries a good prognosis and may respond to treatment with anti-anginal therapy.

ACUTE CORONARY SYNDROME

Acute coronary syndrome is a term that encompasses both unstable angina and MI.

Unstable angina is characterized by new-onset or rapidly worsening angina (crescendo angina), angina on minimal exertion or angina at rest in the absence of myocardial damage.

In contrast, MI occurs when symptoms occur at rest and there is evidence of myocardial necrosis, as demonstrated by an elevation in cardiac troponin or creatine kinase-MB isoenzyme.

An acute coronary syndrome may present as a new phenomenon or against a background of chronic stable angina.

The culprit lesion is usually a complex ulcerated or fissured atheromatous plaque with adherent platelet-rich thrombus and local coronary artery spasm.

This is a dynamic process whereby the degree of obstruction may either increase, leading to complete vessel occlusion, or regress due to the effects of platelet disaggregation and endogenous fibrinolysis.

In acute MI, occlusive thrombus is almost always present at the site of rupture or erosion of an atheromatous plaque.

The thrombus may undergo spontaneous lysis over the course of the next few days, although by this time irreversible myocardial damage has occurred.

Without treatment, the infarct-related artery remains permanently occluded in 20–30% of patients.

The process of infarction progresses over several hours and most patients present when it is still possible to salvage myocardium and improve outcome.

CLINICAL FEATURES: Pain is the cardinal symptom of an

acute coronary syndrome but breathlessness, vomiting, and collapse are common features.

The pain occurs in the same sites as angina but is usually more severe and lasts longer; it is often described as a tightness, heaviness or constriction in the chest.

In acute MI, the pain can be excruciating, and the patient’s expression and pallor may vividly convey the seriousness of the situation.

Most patients are breathless and in some this is the only symptom. Indeed, MI may pass unrecognised.

Painless or ‘silent’ MI is particularly common in older patients or those with diabetes mellitus.

If syncope occurs, it is usually due to an arrhythmia or profound hypotension.

Vomiting and sinus bradycardia are often due to vagal stimulation and are particularly common in patients with inferior MI.

Nausea and vomiting may also be caused or aggravated by opiates given for pain relief.

Sometimes infarction occurs in the absence of physical signs.

Sudden death, from VF or asystole, may occur immediately and often within the first hour.

If the patient survives this most critical stage, the liability to dangerous arrhythmias remains, but diminishes as each hour goes by.

It is vital that patients know not to delay calling for help if symptoms occur.

The development of cardiac failure reflects the extent of myocardial ischaemia and is the major cause of death in those who survive the first few hours.

DIAGNOSIS AND RISK STRATIFICATION:

The differential diagnosis is wide and includes most causes of central chest pain or collapse.

The assessment of acute chest pain depends heavily on an analysis of the character of the pain and its associated features, evaluation of the ECG, and serial measurements of biochemical markers of cardiac damage, such as troponin I and T.

A 12-lead ECG is mandatory and defines the initial triage, management and treatment.

Patients with ST segment elevation or new bundle branch block require emergency reperfusion therapy.

In patients with acute coronary syndrome without ST segment elevation, the ECG may show transient or persistent ST/T wave changes including ST depression and T-wave inversion.

Approximately 12% of patients will die within 1 month and a fifth within 6 months of the index event.

The risk markers that are indicative of an adverse prognosis include recurrent ischaemia, extensive ECG changes at rest or during pain, the release of biochemical markers (creatine kinase or troponin), arrhythmias, recurrent ischaemia and haemodynamic complications (e.g. hypotension, mitral regurgitation) during episodes of ischaemia.

Risk stratification is important because it guides the use of more complex pharmacological and interventional treatment.

INVESTIGATIONS:1) Electrocardiography: The ECG is central to confirming the

diagnosis but may be difficult to interpret if there is bundle branch block or previous MI.

The initial ECG may be normal or non-diagnostic in one-third of cases.

Repeated ECGs are important, especially where the diagnosis is uncertain or the patient has recurrent or persistent symptoms.

The earliest ECG change is usually ST-segment deviation.

With proximal occlusion of a major coronary artery, ST-segment elevation (or new bundle branch block) is seen initially with later diminution in the size of the R wave, and in transmural (full thickness) infarction, development of a Q wave.

Subsequently, the T wave becomes inverted because of a change in ventricular repolarisation; this change persists after the ST segment has returned to normal.

These sequential features are sufficiently reliable for the approximate age of the infarct to be deduced.

In non-ST segment elevation acute coronary syndrome, there is partial occlusion of a major vessel or complete occlusion of a minor vessel, causing unstable angina or partial thickness (subendocardial) MI.

This is usually associated with ST-segment depression and T-wave changes.

In the presence of infarction, this may be accompanied by some loss of R waves in the absence of Q waves.

The ECG changes are best seen in the leads that ‘face’ the ischaemic or infarcted area.

When there has been anteroseptal infarction, abnormalities are found in one or more leads from V1 to V4, while anterolateral infarction produces changes from V4 to V6, in aVL and in lead I.

Inferior infarction is best shown in leads II, III and aVF, while at the same time leads I, aVL and the anterior chest leads may show ‘reciprocal’ changes of ST depression.

Infarction of the posterior wall of the LV does not cause ST elevation or Q waves in the standard leads, but can be diagnosed by the presence of reciprocal changes (ST depression and a tall R wave in leads V1–V4).

Some infarctions (especially inferior) also involve the RV.

This may be identified by recording from additional leads placed over the right precordium.

2 )PLASMA CARDIAC MARKERS: In unstable angina, there is no

detectable rise in cardiac markers or enzymes, and the initial diagnosis is made from the clinical history and ECG only.

In contrast, MI causes a rise in the plasma concentration of enzymes and proteins that are normally concentrated within cardiac cells.

These biochemical markers are creatine kinase (CK), a more sensitive and cardiospecific isoform of this enzyme (CK-MB), and the cardiospecific proteins, troponins T and I.

Admission and serial (usually daily) estimations are helpful because it is the change in plasma concentrations of these markers that confirms the diagnosis of MI.

CK starts to rise at 4–6 hours, peaks at about 12 hours and falls to normal within 48–72 hours.

CK is also present in skeletal muscle, and a modest rise in CK (but not CK-MB) may sometimes be due to an intramuscular injection, vigorous physical exercise or, particularly in older people, a fall.

Defibrillation causes significant release of CK but not CK-MB or troponins.

The most sensitive markers of myocardial cell damage are the cardiac troponins T and I, which are released within 4–6 hours and remain elevated for up to 2 weeks.

3 )OTHER BLOOD TESTS: A leucocytosis is usual, reaching a peak

on the first day. The erythrocyte sedimentation rate

(ESR) and C-reactive protein (CRP) are also elevated.

4 )CHEST X-RAY: This may demonstrate pulmonary

oedema that is not evident on clinical examination.

The heart size is often normal but there may be cardiomegaly due to pre-existing myocardial damage.

5 )ECHOCARDIOGRAPHY: This is useful for assessing left and

right ventricular function and for detecting important complications such as mural thrombus, cardiac rupture, ventricular septal defect, mitral regurgitation and pericardial effusion.

IMMEDIATE MANAGEMENT: THE FIRST 12 HOURS

Patients should be admitted urgently to hospital because there is a significant risk of death or recurrent myocardial ischaemia during the early unstable phase, and appropriate medical therapy can reduce the incidence of these by at least 60%.

Patients are usually managed in a dedicated cardiac unit where the necessary expertise, monitoring and resuscitation facilities can be concentrated.

If there are no complications, the patient can be mobilised from the second day and discharged from hospital after 3–5 days.

-Analgesia:

Adequate analgesia is essential not only to relieve distress, but also to lower adrenergic drive and thereby reduce vascular resistance, BP, infarct size and susceptibility to ventricular arrhythmias.

Intravenous opiates (initially morphine sulphate 5–10 mg or diamorphine 2.5–5 mg) and antiemetics (initially metoclopramide 10mg) should be administered and titrated by giving repeated small aliquots until the patient is comfortable.

Intramuscular injections should be avoided because the clinical effect may be delayed by poor skeletal muscle perfusion, and a painful haematoma may form following thrombolytic or anti-thrombotic therapy.

-Antithrombotic therapy:

a) Antiplatelet therapy: In patients with acute coronary syndrome,

oral administration of 75–300mg aspirin daily improves survival, with a 25% relative risk reduction in mortality.

The first tablet (300mg) should be given orally within the first 12 hours and therapy should be continued indefinitely if there are no side-effects.

In combination with aspirin, the early (within 12 hours) use of clopidogrel 600 mg, followed by 150 mg daily for 1 week and 75mg daily thereafter, confers a further reduction in ischaemic events.

In patients with an acute coronary syndrome with or without ST-segment elevation, ticagrelor (180 mg followed by 90 mg 12-hourly) is more effective than clopidogrel in reducing vascular death, MI or stroke, and all-cause death without affecting overall major bleeding risk.

Glycoprotein IIb/IIIa receptor antagonists, such as tirofiban and abciximab, block the final common pathway of platelet aggregation and are potent inhibitors of platelet-rich thrombus formation.

They are of particular benefit in patients with acute coronary syndromes who undergo PCI, those with recurrent ischaemia and those at particularly high risk, such as patients with diabetes mellitus or an elevated troponin concentration.

b) Anticoagulants: Anticoagulation reduces the risk of

thromboembolic complications, and prevents reinfarction in the absence of reperfusion therapy or after successful thrombolysis.

Anticoagulation can be achieved using unfractionated heparin, fractioned (low molecular weight) heparin or a pentasaccharide.

Comparative clinical trials suggest that the pentasaccharides (subcutaneous fondaparinux 2.5mg daily) have the best safety and efficacy profile, with low molecular weight heparin (subcutaneous enoxaparin 1mg/kg 12-hourly) being a reasonable alternative.

Anticoagulation should be continued for 8 days or until discharge from hospital or coronary revascularisation.

A period of treatment with warfarin should be considered if there is persistent atrial fibrillation or evidence of extensive anterior infarction, or if echocardiography shows mobile mural thrombus, because these patients are at increased risk of systemic thromboembolism.

-Anti-anginal therapy : Sublingual glyceryl trinitrate (300–500

μg) is a valuable first-aid measure in unstable angina or threatened infarction, and intravenous nitrates (GTN 0.6–1.2mg/hour or isosorbide dinitrate 1–2mg/hour) are useful for the treatment of left ventricular failure and the relief of recurrent or persistent ischaemic pain.

Intravenous β-blockers (e.g. atenolol 5–10mg or metoprolol 5–15mg given over 5mins) relieve pain, reduce arrhythmias and improve short-term mortality in patients who present within 12 hours of the onset of symptoms.

However, they should be avoided if there is heart failure (pulmonary oedema), hypotension (systolic BP < 105mmHg) or bradycardia (heart rate < 65/min).

A dihydropyridine calcium channel antagonist (e.g. nifedipine or amlodipine) can be added to the β-blocker if there is persistent chest discomfort but may cause an unwanted tachycardia if used alone.

Because of their rate-limiting action, verapamil and diltiazem are the calcium channel antagonists of choice if a β-blocker is contraindicated.

-Reperfusion therapy:a) Non-ST segment elevation acute

coronary syndrome: Immediate emergency reperfusion therapy

has no demonstrable benefit in patients with non-ST segment elevation MI and thrombolytic therapy may be harmful.

Selected medium- to high-risk patients do benefit from in-hospital coronary angiography and coronary revascularisation but this does not need to take place in the first 12 hours.

b) ST segment elevation acute coronary syndrome :

Immediate reperfusion therapy restores coronary artery patency, preserves left ventricular function and improves survival.

Successful therapy is associated with pain relief, resolution of acute ST elevation and sometimes transient arrhythmias (e.g. idioventricular rhythm).

Primary percutaneous coronary intervention (PCI):

This is the treatment of choice for ST segment elevation MI.

Outcomes are best when it is used in combination with glycoprotein IIb/IIIa receptor antagonists and intracoronary stent implantation.

In comparison to thrombolytic therapy, it is associated with a greater reduction in the risk of death, recurrent MI or stroke.

The universal use of primary PCI has been limited by availability of the necessary resources to provide this highly specialised emergency service.

Thus, intravenous thrombolytic therapy remains the first-line reperfusion treatment in many hospitals, especially those in rural or remote areas.

When primary PCI cannot be achieved within 2 hours of diagnosis, thrombolytic therapy should be administered.

Thrombolysis: The appropriate use of thrombolytic

therapy can reduce hospital mortality by 25–50% and this survival advantage is maintained for at least 10 years.

The benefit is greatest in those patients who receive treatment within the first few hours: ‘minutes mean muscle’.

Alteplase (human tissue plasminogen activator or tPA) is a genetically engineered drug that is given over 90 minutes (bolus dose of 15mg, followed by 0.75mg/kg body weight, but not exceeding 50mg, over 30mins and then 0.5mg/kg body weight, but not exceeding 35mg, over 60mins).

Its use is associated with better survival rates than other thrombolytic agents, such as streptokinase, but carries a slightly higher risk of intracerebral bleeding (10 per 1000 increased survival, but 1 per 1000 more non-fatal stroke).

Analogues of tPA, such as tenecteplase and reteplase, have a longer plasma half-life than alteplase and can be given as an intravenous bolus.

Tenecteplase (TNK) is as effective as alteplase at reducing death and MI whilst conferring similar intracerebral bleeding risks.

However, other major bleeding and transfusion risks are lower and the practical advantages of bolus administration may provide opportunities for prompt treatment in the emergency department or in the pre-hospital setting.

Reteplase (rPA) is administered as a double bolus and also produces a similar outcome to that achieved with alteplase, although some of the bleeding risks appear slightly higher.

An overview of all the large randomised trials confirms that thrombolytic therapy reduces short-term mortality in patients with MI if it is given within 12 hours of the onset of symptoms and the ECG shows bundle branch block or characteristic ST segment elevation > 1 mm in the limb leads or 2 mm in the chest leads.

Thrombolysis appears to be of little net benefit and may be harmful in those who present more than 12 hours after the onset of symptoms and in those with a normal ECG or ST depression.

In patients with ST elevation or bundle branch block, the absolute benefit of thrombolysis plus aspirin is approximately 50 lives saved per 1000 patients treated within 6 hours and 40 lives saved per 1000 patients treated between 7 and 12 hours after the onset of symptoms.

The benefit is greatest for patients treated within the first 2 hours.

The major hazard of thrombolytic therapy is bleeding.

Cerebral haemorrhage causes 4 extra strokes per 1000 patients treated and the incidence of other major bleeds is between 0.5% and 1%.

Accordingly, the treatment should be withheld if there is a significant risk of serious bleeding.

For some patients, thrombolytic therapy is contraindicated or fails to achieve coronary arterial reperfusion.

Early emergency PCI may then be considered, particularly where there is evidence of cardiogenic shock.

COMPLICATIONS OF ACUTE CORONARY SYNDROME:

Complications are seen in all forms of acute coronary syndrome, although the frequency and extent vary with the severity of ischaemia and infarction.

Major mechanical and structural complications are only seen with significant, often transmural, MI.

1 )Arrhythmias: Many patients with acute coronary

syndrome have some form of arrhythmia.

In the majority of cases this is transient and of no haemodynamic or prognostic importance.

Pain relief, rest and the correction of hypokalaemia may help prevent them.

a) Ventricular fibrillation :

This occurs in about 5–10% of patients who reach hospital and is thought to be the major cause of death in those who die before receiving medical attention.

Prompt defibrillation will usually restore sinus rhythm and is lifesaving.

The prognosis of patients with early ventricular fibrillation (within the first 48 hours) who are successfully and promptly resuscitated is identical to that of patients who do not suffer ventricular fibrillation.

b) Atrial fibrillation:

This is common but frequently transient, and usually does not require emergency treatment.

However, if the arrhythmia causes a rapid ventricular rate with hypotension or circulatory collapse, prompt cardioversion by immediate synchronised DC shock is essential.

In other situations, digoxin or a β-blocker is usually the treatment of choice.

Atrial fibrillation (due to acute atrial stretch) is often a feature of impending or overt left ventricular failure, and therapy may be ineffective if heart failure is not recognised and treated appropriately.

Anticoagulation is required if atrial fibrillation persists.

c) Bradycardia: This does not usually require

treatment, but if there is hypotension or haemodynamic deterioration, atropine (0.6–1.2mg i.v.) may be given.

AV block complicating inferior infarction is usually temporary and often resolves following reperfusion therapy.

If there is clinical deterioration due to second-degree or complete AV block, a temporary pacemaker should be considered.

AV block complicating anterior infarction is more serious because asystole may suddenly supervene; a prophylactic temporary pacemaker should be inserted.

2 )Ischaemia: Patients who develop recurrent angina

at rest or on minimal exertion following an acute coronary syndrome are at high risk and should be considered for prompt coronary angiography with a view to revascularisation.

Patients with dynamic ECG changes and ongoing pain should be treated with intravenous glycoprotein IIb/IIIa receptor antagonists.

Patients with resistant pain or marked haemodynamic changes should be considered for intra-aortic balloon counterpulsation and emergency coronary revascularisation.

Post-infarct angina occurs in up to 50% of patients treated with thrombolysis.

Most patients have a residual stenosis in the infarct-related vessel despite successful thrombolysis, and this may cause angina if there is still viable myocardium downstream.

For this reason, all patients who have received successful thrombolysis should be considered for early (within the first 6–24 hours) coronary angiography with a view to coronary revascularisation.

3 )Acute circulatory failure: Acute circulatory failure usually reflects

extensive myocardial damage and indicates a bad prognosis.

All the other complications of MI are more likely to occur when acute heart failure is present.

4 )Pericarditis: This only occurs following infarction

and is particularly common on the second and third days.

The patient may recognise that a different pain has developed, even though it is at the same site, and that it is positional and tends to be worse or sometimes only present on inspiration.

A pericardial rub may be audible. Opiate-based analgesia should be used. Non-steroidal and steroidal anti-

inflammatory drugs may increase the risk of aneurysm formation and myocardial rupture in the early recovery period, and so should be avoided.

The post-MI syndrome (Dressler’s syndrome) is characterised by persistent fever, pericarditis and pleurisy, and is probably due to autoimmunity.

The symptoms tend to occur a few weeks or even months after the infarct and often subside after a few days; prolonged or severe symptoms may require treatment with high-dose aspirin, NSAIDs or even corticosteroids.

5 )Mechanical complications:Part of the necrotic muscle in a fresh

infarct may tear or rupture, with devastating consequences:

a) Rupture of the papillary muscle can cause acute pulmonary oedema and shock due to the sudden onset of severe mitral regurgitation, which presents with a pansystolic murmur and third heart sound.

In the presence of severe valvular regurgitation, the murmur may be quiet or absent.

The diagnosis is confirmed by echocardiography and emergency mitral valve replacement may be necessary.

Lesser degrees of mitral regurgitation due to papillary muscle dysfunction are common and may be transient.

b) Rupture of the interventricular septum causes left-to-right shunting through a ventricular septal defect.

This usually presents with sudden haemodynamic deterioration accompanied by a new loud pansystolic murmur radiating to the right sternal border, but may be difficult to distinguish from acute mitral regurgitation.

However, patients with an acquired ventricular septal defect tend to develop right heart failure rather than pulmonary oedema.

Doppler echocardiography and right heart catheterisation will confirm the diagnosis.

Without prompt surgery, the condition is usually fatal.

c) Rupture of the ventricle may lead to cardiac tamponade and is usually fatal, although it may rarely be possible to support a patient with an incomplete rupture until emergency surgery is performed.

6 )Embolism: Thrombus often forms on the endocardial

surface of freshly infarcted myocardium. This can lead to systemic embolism and

occasionally causes a stroke or ischaemic limb.

Venous thrombosis and pulmonary embolism may occur but have become less common with the use of prophylactic anticoagulants and early mobilisation.

7 )Impaired ventricular function, remodelling and ventricular aneurysm

Acute transmural MI is often followed by thinning and stretching of the infarcted segment (infarct expansion).

This leads to an increase in wall stress with progressive dilatation and hypertrophy of the remaining ventricle (ventricular remodelling).

As the ventricle dilates, it becomes less efficient and heart failure may supervene.

Infarct expansion occurs over a few days and weeks but ventricular remodelling can take years.

ACE inhibitor therapy reduces late ventricular remodelling and can prevent the onset of heart failure.

A left ventricular aneurysm develops in approximately 10% of patients with MI and is particularly common when there is persistent occlusion of the infarct-related vessel.

Heart failure, ventricular arrhythmias, mural thrombus and systemic embolism are all recognised complications of aneurysm formation.

Other clinical features include a paradoxical impulse on the chest wall, persistent ST elevation on the ECG, and sometimes an unusual bulge from the cardiac silhouette on the chest X-ray.

Echocardiography is usually diagnostic. Surgical removal of a left ventricular

aneurysm carries a high morbidity and mortality but is sometimes necessary.

LATER IN-HOSPITAL MANAGEMENT:

Risk stratification and further investigation:

Simple clinical tools can be used to identify medium-to high-risk patients.

The GRACE score is a simple method of calculating early mortality that can help guide which patients should be selected for intensive therapy, and specifically early inpatient coronary angiography.

The prognosis of patients who have survived an acute coronary syndrome is related to the extent of residual myocardial ischaemia, the degree of myocardial damage and the presence of ventricular arrhythmias.

Left ventricular function: The degree of left ventricular dysfunction can

be crudely assessed from physical findings (tachycardia, third heart sound, crackles at the lung bases, elevated venous pressure and so on), ECG changes and chest X-ray (size of the heart and presence of pulmonary oedema).

However, formal assessment with echocardiography should be undertaken in the early recovery phase.

Ischemia: Patients with early ischaemia following

an acute coronary syndrome should undergo coronary angiography with a view to revascularisation.

Low-risk patients without spontaneous ischaemia should undergo an exercise tolerance test approximately 4 weeks after the acute coronary syndrome.

This will help to identify those individuals with residual myocardial ischaemia who require further investigation and may help to boost the confidence of the remainder.

If the exercise test is negative and the patient has a good effort tolerance, the outlook is good, with a 1–4% chance of an adverse event in the next 12 months.

In contrast, patients with residual ischaemia in the form of chest pain or ECG changes at low exercise levels are at high risk, with a 15–25% chance of suffering a further ischaemic event in the next 12 months.

Arrhythmias: The presence of ventricular

arrhythmias during the convalescent phase of acute coronary syndrome may be a marker of poor ventricular function and may herald sudden death.

Although empirical anti-arrhythmic treatment is of no value and even hazardous, selected patients may benefit from electrophysiological testing and specific anti-arrhythmic therapy (including implantable cardiac defibrillators).

Recurrent ventricular arrhythmias are sometimes manifestations of myocardial ischaemia or impaired left ventricular function and may respond to appropriate treatment directed at the underlying problem.

Lifestyle and risk factor modification:

Smoking: The 5-year mortality of patients who

continue to smoke cigarettes is double that of those who quit smoking at the time of their acute coronary syndrome.

Giving up smoking is the single most effective contribution a patient can make to his or her future.

The success of smoking cessation can be increased by supportive advice and pharmacological therapy.

Hyperlipidaemia: The importance of lowering serum

cholesterol following acute coronary syndrome has been demonstrated in large-scale randomised clinical trials.

Lipids should be measured within 24 hours of presentation because there is often a transient fall in blood cholesterol in the 3 months following infarction.

HMG CoA reductase enzyme inhibitors (‘statins’) can produce marked reductions in total (and LDL) cholesterol and reduce the subsequent risk of death, reinfarction, stroke and the need for revascularisation.

Irrespective of serum cholesterol concentrations, all patients should receive statin therapy after acute coronary syndrome, but those with serum LDL cholesterol concentrations > 3.2mmol/L (∼120mg/dL) benefit from more intensive lipid-lowering, such as atorvastatin 80mg daily.

Other risk factors: Maintaining an ideal body weight,

eating a Mediterranean-style diet, taking regular exercise, and achieving good control of hypertension and diabetes mellitus may all improve the long-term outlook.

Mobilisation and rehabilitation: The necrotic muscle of an acute myocardial

infarct takes 4–6 weeks to be replaced with fibrous tissue and it is conventional to restrict physical activities during this period.

When there are no complications, the patient can mobilise on the second day, return home in 3–5 days and gradually increase activity with the aim of returning to work in 4–6 weeks.

The majority of patients may resume driving after 4–6 weeks, although in most countries vocational driving licence holders (e.g. heavy goods and public service vehicles) require special assessment.

Emotional problems, such as denial, anxiety and depression, are common and must be addressed.

Many patients are severely and even permanently incapacitated as a result of the psychological rather than the physical effects of acute coronary syndrome, and all benefit from thoughtful explanation, counselling and reassurance at every stage of the illness.

Many patients mistakenly believe that ‘stress’ was the cause of their heart attack and may restrict their activity inappropriately.

The patient’s spouse or partner will also require emotional support, information and counselling.

Formal rehabilitation programmes based on graded exercise protocols with individual and group counselling are often very successful, and in some cases have been shown to improve the long-term outcome.

Secondary prevention drug therapy:

a) Aspirin and clopidogrel: Low-dose aspirin therapy reduces the

risk of further infarction and other vascular events by approximately 25% and should be continued indefinitely if there are no unwanted effects.

Clopidogrel should be given in combination with aspirin for at least 3 months.

If patients are intolerant of long-term aspirin, clopidogrel is a suitable alternative.

b) Beta-blockers: Continuous treatment with an oral β-

blocker reduces long-term mortality by approximately 25% among the survivors of acute MI.

Unfortunately, a minority of patients do not tolerate β-blockers because of bradycardia, AV block, hypotension or asthma.

Patients with heart failure, irreversible chronic obstructive pulmonary disease or peripheral vascular disease derive similar, if not greater secondary preventative benefits from β-blocker therapy if they can tolerate it, so it should be tried.

The secondary preventative role of β-blockers in patients with unstable angina is unknown.

c) ACE inhibitors: Several clinical trials have shown that

long-term treatment with an ACE inhibitor (e.g. enalapril 10mg 12-hourly or ramipril 2.5–5mg 12-hourly) can counteract ventricular remodelling, prevent the onset of heart failure, improve survival, reduce recurrent MI and avoid rehospitalisation.

The benefits are greatest in those with overt heart failure (clinical or radiological) but extend to patients with asymptomatic left ventricular dysfunction and those with preserved left ventricular function.

They should therefore be considered in all patients with acute coronary syndrome.

Caution must be exercised in hypovolaemic or hypotensive patients because the introduction of an ACE inhibitor may exacerbate hypotension and impair coronary perfusion.

In patients intolerant of ACE inhibitor therapy, angiotensin receptor blockers (e.g. valsartan 40–160mg 12-hourly or candesartan 4–16mg daily) are suitable alternatives and are better tolerated.

Patients with acute MI and left ventricular dysfunction (ejection fraction < 35%) and either pulmonary oedema or diabetes mellitus further benefit from additional aldosterone receptor antagonism (e.g. eplerenone 25–50mg daily).

Coronary revascularisation: Most low-risk patients stabilise with

aspirin, clopidogrel, anticoagulation and anti-anginal therapy, and can be rapidly mobilised.

In the absence of recurrent symptoms, low-risk patients do not benefit from routine coronary angiography.

Coronary angiography should be considered with a view to revascularisation in all patients at moderate or high risk, including those who fail to settle on medical therapy, those with extensive ECG changes, those with an elevated plasma troponin and those with severe pre-existing stable angina.

This often reveals disease that is amenable to PCI or urgent CABG.

In these cases coronary revascularisation is associated with short- and long-term benefits, including reductions in MI and death.

Device therapy:

Implantable cardiac defibrillators are of benefit in preventing sudden cardiac death in patients who have severe left ventricular impairment (ejection fraction ≤ 30%) after MI.

Prognosis:

In almost one-quarter of all cases of MI, death occurs within a few minutes without medical care.

Half the deaths occur within 24 hours of the onset of symptoms and about 40% of all affected patients die within the first month.

The prognosis of those who survive to reach hospital is much better, with a 28-day survival of more than 85%.

Patients with unstable angina have a mortality approximately half those with MI.

Early death is usually due to an arrhythmia and is independent of the extent of MI.

However, late outcomes are determined by the extent of myocardial damage and unfavourable features include poor left ventricular function, AV block and persistent ventricular arrhythmias.

The prognosis is worse for anterior than for inferior infarcts.

Bundle branch block and high cardiac marker levels both indicate extensive myocardial damage.

Old age, depression and social isolation are also associated with a higher mortality.

Of those who survive an acute attack, more than 80% live for a further year, about 75% for 5 years, 50% for 10 years and 25% for 20 years.

CARDIAC RISK OF NON-CARDIAC SURGERY

Non-cardiac surgery, particularly major vascular, abdominal or thoracic surgery, can precipitate serious perioperative cardiac complication such as MI and death in patients with coronary artery and other forms of heart disease.

Careful pre-operative cardiac assessment may help to determine the balance of benefit versus risk on an individual basis, and identify measures that minimise the operative risk.

A hypercoagulable state is part of the normal physiological response to surgery, and may promote coronary thrombosis leading to an acute coronary syndrome in the early post-operative period.

Patients with a history of recent PCI or acute coronary syndrome are at greatest risk and, whenever possible, elective non-cardiac surgery should be avoided for 3 months after such an event.

Antiplatelet agents, statins and β-blockers reduce the risk of perioperative MI in patients with coronary artery disease and, where possible, should be prescribed throughout the perioperative period.

Careful attention to fluid balance during and after surgery is particularly important in patients with impaired left ventricular function and valvular heart disease because antidiuretic hormone is released as part of the normal physiological response to surgery, and in these circumstances the overzealous administration of intravenous fluids can easily precipitate heart failure.

Patients with severe valvular heart disease, particularly aortic stenosis and mitral stenosis, are also at increased risk because they may not be able to increase their cardiac output in response to the stress of surgery.

Atrial fibrillation may be triggered by hypoxia, myocardial ischaemia or heart failure, and is a common postoperative complication in patients with pre-existing heart disease.

It usually terminates spontaneously when the precipitating factors have been eliminated, but digoxin or β-blockers can be prescribed to control the heart rate.