Coronary heart disease

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20 Coronary heart disease

D. McRobbie

Key points

• Coronary heart disease (CHD) is common, often fatal and frequently preventable.
• High dietary fat, smoking and sedentary lifestyle are risk factors for CHD and require modification if present.
• Hypertension, hypercholesterolaemia and diabetes mellitus, obesity and personal stress are also risk factors and require optimal management.
• Stable angina should be managed with nitrates for pain relief and β-blockers, unless contraindicated, for long-term prophylaxis. Where β-blockers are inappropriate, the use of calcium channel blockers and/or nitrates may be considered.
• Acute coronary syndromes arise from unstable atheromatous plaques and may be classified as to whether there is ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI).
• ST elevation on the ECG indicates an occluded coronary artery and is used to determine treatment with fibrinolysis or primary angioplasty.
• Patients with NSTEMI may have experienced myocardial damage, are at increased risk of death and may benefit from a glycoprotein IIb/IIIa inhibitor.

Coronary heart disease (CHD), sometimes described as coronary artery disease (CAD) or ischaemic heart disease (IHD), is a condition in which the vascular supply to the heart is impeded by atheroma, thrombosis or spasm of coronary arteries. This may impair the supply of oxygenated blood to cardiac tissue sufficiently to cause myocardial ischaemia which, if severe or prolonged, may cause the death of cardiac muscle cells. Similarities in the development of atheromatous plaques in other vasculature, in particular the carotid arteries, with the resultant cerebral ischaemia has resulted in the term cardiovascular disease (CVD) being adopted to incorporate CHD, cerebrovascular disease and peripheral vascular disease.

Myocardial ischaemia occurs when the oxygen demand exceeds myocardial oxygen supply. The resultant ischaemic myocardium releases adenosine, the main mediator of chest pain, by stimulating the A1 receptors located on the cardiac nerve endings. Myocardial ischaemia may be ‘silent’ if the duration is of insufficient length, the afferent cardiac nerves are damaged (as with diabetics) or there is inhibition of the pain at the spinal or supraspinal level.

Factors increasing myocardial oxygen demand often precipitate ischaemic episodes and are commonly associated with increased work rate (heart rate) and increased work load (force of contractility). Less commonly, myocardial ischaemia can also arise if oxygen demand is abnormally increased, as may occur in patients with thyrotoxicosis or severe ventricular hypertrophy due to hypertension. Myocardial oxygen supply is dependant on the luminal cross-sectional area of the coronary artery and coronary arteriolar tone. Atheromatous plaques decrease the lumen diameter and, when extensive, reduce the ability of the coronary artery to dilate in response to increased myocardial oxygen demand. Ischaemia may also occur when the oxygen-carrying capacity of blood is impaired, as in iron- deficiency anaemia, or when the circulatory volume is depleted.

CHD kills over 6.5 million people worldwide each year.

Epidemiology

Almost 200,000 people die from CVD in the UK each year with CHD accounting for almost a half of these. About 30% of premature deaths (below 75 years old) in men and 22% of premature deaths in women result from CVD.

The epidemiology of CHD has been studied extensively and risk factors for developing CHD are now well described. Absence of established risk factors does not guarantee freedom from CHD for any individual, and some individuals with several major risk factors seem perversely healthy. Nonetheless, there is evidence that in developed countries, education and publicity about the major risk factors have led to changes in social habits, particularly with respect to a reduction in smoking and fat consumption, and this has contributed to a decrease in the incidence of CHD.

The UK has seen a steady decline in deaths from CHD of about 4.5% per annum since the late 1970s. A recent study indicated that both reductions in major risk factors and improvements in treatment have contributed to this reduction (Unal et al., 2004). While impressive, this rate of decline has not been as great as in other countries like Australia and Finland. In Eastern European countries, the death rates from CHD have increased significantly during the same period.

The improvement in deaths from CHD has been chiefly among those with higher incomes; however, the less prosperous social classes continue to have almost unchanged levels of CHD. Better treatment has also contributed to a decrease in cardiac mortality, although CHD still accounted for some 94,000 deaths in 2006 in the UK, including 70% of sudden natural deaths, 22% of male deaths and 16% of female deaths. In most developed countries, CHD is the leading cause of adult death but in the UK the poor outcome of lung cancer treatments makes cancer marginally the leading cause. In the UK, in comparison with Caucasians, people of South Asian descent have a 45–50% higher death rate from CHD, and Caribbeans and West Africans have a 35–50% lower rate.

Prevalence

About 3.5% of UK adults have symptomatic CHD. One-third of men aged 50–59 years of age have evidence of CHD, and this proportion increases with age. In the UK, there are about 1.3 million people who have survived a myocardial infarction and about 2 million who have, or have had, angina and this equates to about 5% of men and 3% of women. Approximately 260,000 people suffer a myocardial infarction in any year, of whom 40–50% die.

Mortality increases with age and is probably not due to a particular age-related factor but to the cumulative effect of risk factors that lead to atheroma and thrombosis and hence to CAD. In the USA, age-related death rates for CHD have fallen by 25% over a decade, but the total number of CHD deaths has fallen by only 10% because the population is ageing. Similarly, in the UK the death rates are falling but the numbers living with CHD are increasing.

Women appear less susceptible to CHD than men, although they seem to lose this protection after menopause, presumably because of hormonal changes. Race has not proved to be a clear risk factor since the prevalence of CHD seems to depend much more strongly on location and lifestyle than on ethnic origin or place of birth. It has been shown that lower social or economic class is associated with increased obesity, poor cholesterol indicators, higher blood pressure and higher C-reactive protein (CRP) measurements, an indicator of inflammatory activity.

Risk factors

Traditionally, the main potentially modifiable risk factors for CHD have been considered to be hypertension, cigarette smoking, raised serum cholesterol and diabetes. More recently psychological stress and abdominal obesity have gained increased prominence (Box 20.1). Patients with a combination of all these risk factors are at risk of suffering a myocardial infarction some 500 times greater than individuals without any of the risk factors. Stopping smoking, moderating alcohol intake, regular exercise and consumption of fresh fruit and vegetables were associated independently and additively with reduction in the risk of having a myocardial infarction.

Box 20.1 Factors that increase or decrease the risk of developing CHD

Factors that increase the risk of CHD
Cigarette smoking
Raised serum cholesterol
Hypertension
Diabetes
Abdominal obesity
Increased personal stress
Factors that decrease the risk of CHD
Regular consumption of fresh fruit and vegetables
Regular exercise
Moderate alcohol consumption
Modification of factors that increase the risk of CHD

Diabetes mellitus is a positive risk factor for CHD in developed countries with high levels of CHD, but it is not a risk factor in countries with little CHD. Insulin resistance, as defined by high fasting insulin concentrations, is an independent risk factor for CHD in men. In the UK, the mortality rates from CHD are up to five times higher for people with diabetes, while the risk of stroke is up to three times higher.

While unusual physical exertion is associated with an increased risk of infarction, an active lifestyle that includes regular, moderate exercise is beneficial, although the optimum level has not been determined and its beneficial effect appears to be readily overwhelmed by the presence of other risk factors. A family history of CHD is a positive risk factor, independent of diet and other risk factors. Hostility, anxiety or depression are associated with increased CHD and death, especially after myocardial infarction when mortality is doubled by anxiety and quadrupled by depression.

Epidemiological studies have shown associations between CHD and prior infections with several common micro-organisms, including Chlamydia pneumoniae and Helicobacter pylori, but a causal connection has not been shown. The influence of fetal and infant growth conditions, and their interaction with social conditions in childhood and adult life, has been debated strongly for decades but it is clear that lower socio-economic status and thinness in very early life are linked to higher incidences of CHD.

Aetiology

The vast majority of CHD occurs in patients with atherosclerosis of the coronary arteries (see Fig. 20.1) that starts before adulthood. The cause of spontaneous artherosclerosis is unclear, although it is thought that in the presence of hypercholesterolaemia, a non-denuding form of injury occurs to the endothelial lining of coronary arteries and other vessels. This injury is followed by subendothelial migration of monocytes and the accumulation of fatty streaks containing lipid-rich macrophages and T-cells. Almost all adults, and 50% of children aged 11–14 years, have fatty streaks in their coronary arteries. Thereafter, there is migration and proliferation of smooth muscle cells into the intima with further lipid deposition. The smooth muscle cells, together with fibroblasts, synthesise and secrete collagen, proteoglycans, elastin and glycoproteins that make up a fibrous cap surrounding cells and necrotic tissue, together called a plaque. The presence of atherosclerotic plaques results in narrowing of vessels and a reduction in blood flow and a decrease in the ability of the coronary vasculature to dilate and this may become manifest as angina. Associated with the plaque rupture is a loss of endothelium. This can serve as a stimulus for the formation of a thrombus and result in more acute manifestations of CHD, including unstable angina (UA) and myocardial infarction. Plaque rupture caused by physical stresses or plaque erosion may precipitate an acute reaction. Other pathological processes are probably involved, including endothelial dysfunction which alters the fibrin–fibrinolysis balance and the vasoconstriction–vasodilation balance. There is interest in the role of statins and angiotensin-converting enzyme (ACE) inhibitors in modifying endothelial function.

image

Fig. 20.1 Main coronary arteries.

There is also great interest in the role of inflammation, especially in acute episodes. At postmortem, many plaques are found to contain inflammatory cells and inflammatory damage is found at the sites of plaque rupture.

Measurement of acute phase inflammatory reactions, such as fibrinogen and CRP, has a predictive association with coronary events. High-sensitivity CRP assays have been used in populations without acute illness to stratify individuals into high-, medium- and low-risk groups. In patients with other risk factors, however, CRP adds little prognostic information. CRP is produced by atheroma, in addition to the major producer which is the liver, and is an inflammatory agent as well as a marker of inflammation. Evidence is emerging that drug therapy which reduces CRP in otherwise healthy individuals reduces the incidence of major cardiac events (Ridker, 2008).

Oxidative stress which involves the uncontrolled production of reactive oxygen species (ROS) or a reduction in antioxidant species has been linked in the laboratory to several aspects of cardiovascular pathogenesis including endothelial malfunction, lipid metabolism, atheroma formation and plaque rupture, but the clinical importance is unclear. The use of antioxidants has been disappointingly unsuccessful but there is interest in peroxisome proliferator-activated receptor (PPAR) agonists that modify ROS production; some of these are already in use for treating diabetes and are associated with favourable changes in many metabolic markers for CVD. Other agents that reduce ROS production include statins and drugs that reduce angiotensin production.

Modification of risk factors

Common to all stages of CHD treatment is the need to reduce risk factors (Table 20.1). The patient needs to appreciate the value of the proposed strategy and to be committed to a plan for changing their lifestyle and habits, which may not be easy to achieve after years of smoking or eating a particular diet. Preventing CHD is important but neither instant nor spectacular. It may require many sessions of counseling over several years to initiate and maintain healthy habits. It may also involve persuasion of patients to continue taking medication for asymptomatic disorders such as hypertension or hyperlipidaemia. The general public, with government as its agent, need to agree that a reduction in the incidence of CHD is worth some general changes in lifestyle or liberty, for example, such as prohibiting the freedom to smoke in public. National campaigns to encourage healthy eating or exercise are expensive, as is the long-term medical treatment of hypertension or hyperlipidaemia, and such strategies must have the backing of governments to succeed. It has been argued that community-wide campaigns on cholesterol reduction have had measurable benefits in Finland, the USA and elsewhere, at least in high-risk, well-educated and affluent groups. It follows that the next challenge is to extend that success to poorer, ethnically diverse groups and to those portions of the population with mild-to-moderate risk.

Table 20.1 Effect of interventions on risk of myocardial infarction

Intervention Control Benefit of intervention
Stopping smoking for ≥5 years Current smokers 50–70% lower risk
Reducing serum cholesterol   2% lower risk for each 1% reduction in cholesterol
Treatment of hypertension   2–3% lower risk for each 1 mmHg decrease in diastolic pressure
Active lifestyle Sedentary lifestyle 45% lower risk
Mild to moderate alcohol consumption (approx. 1 unit/day) Total abstainers 25–45% lower risk
Low-dose aspirin Non-users 33% lower risk in men
Postmenopausal oestrogen replacement Non-users 44% lower risk

The quality of data associated with these interventions varies greatly and figures may not apply to all patient groups.

For every individual there is a need to act against the causative factors of CHD. Thus, attempts should be made to control hypertension, heart failure, arrhythmias, dyslipidaemia, obesity, diabetes mellitus, thyroid disease, anaemia and cardiac valve disorders. Apart from medication, these will require careful attention to diet and exercise and will necessitate smoking cessation. Cardiac rehabilitation classes and exercise programmes improve many risk factors including obesity, lipid indices, insulin resistance, psychological state and lifestyle. They also impact on morbidity and mortality.

Epidemiological studies have suggested that antioxidants and hormone replacement therapy may be of benefit in preventing and treating coronary disease. Unfortunately, randomised clinical trials of vitamin E or hormone replacement therapy suggest that these agents are not of benefit and may indeed result in higher rates of cardiovascular events.

Clinical syndromes

The primary clinical manifestation of CHD is chest pain. Chest pain arising from stable coronary atheromatous disease leads to stable angina and normally arises when narrowing of the coronary artery lumen exceeds 50% of the original luminal diameter. Stable angina is characterised by chest pain and breathlessness on exertion; symptoms are relieved promptly by rest.

A stable coronary atheromatous plaque may become unstable as a result of either plaque erosion or rupture. Exposure of the subendothelial lipid and collagen stimulates the formation of thrombus which causes sudden narrowing of the vessel. The spectrum of clinical outcomes that result are grouped together under the term acute coronary syndrome (ACS) and characterised by chest pain of increasing severity either on minimal exertion or, more commonly, at rest. These patients are at high risk of myocardial infarction and death and require prompt hospitalisation. Many aspects of the treatment of stable angina and ACS are similar but there is a much greater urgency and intensity in the management of ACS.

Stable angina

Stable angina is a clinical syndrome characterised by discomfort in the chest, jaw, shoulder, back, or arms, typically elicited by exertion or emotional stress and relieved by rest or nitroglycerin. Characteristically, the discomfort (it is often not described by the patient as a pain) occurs after a predictable level of exertion, classically when climbing hills or stairs, and resolves within a few minutes on resting. Unfortunately, the clinical manifestations of angina are very variable. Many patients mistake the discomfort for indigestion. Some patients, particularly diabetics and the elderly, may not experience pain at all but present with breathlessness or fatigue; this is termed silent ischaemia.

Further investigations are needed to confirm the diagnosis and assess the need for intervention. The resting electrocardiogram (ECG) is normal in more than half of patients with angina. However, an abnormal ECG substantially increases the probability of coronary disease; in particular, it may show signs of previous myocardial infarction. Non-invasive testing is helpful. Exercise testing is useful both in confirming the diagnosis and in giving a guide to prognosis. Alternatives such as myocardial scintigraphy (isotope scanning) and stress echocardiography (ultrasound) provide similar information.

Coronary angiography is regarded as the gold standard for the assessment of CAD and involves the passage of a catheter through the arterial circulation and the injection of radio-opaque contrast media into the coronary arteries. The X-ray images obtained permit confirmation of the diagnosis, aid assessment of prognosis and guide therapy, particularly with regard to suitability for angioplasty and coronary artery bypass grafting.

Non-invasive techniques, including magnetic resonance imaging (MRI) and multi-slice CT scanning, are being developed and tested as alternatives to angiography.

Treatment of stable angina is based on two principles:

• Improve prognosis by preventing myocardial infarction and death.
• Relieve or prevent symptoms.

Pharmacological therapy can be considered a viable alternative to invasive strategies, providing similar results without the complications associated with percutaneous coronary intervention (PCI). An algorithm for addressing both these principles is outlined in Fig. 20.2. In addition, diabetes, hypertension and dyslipidaemia in patients with stable angina should be well controlled. Smoking cessation, without or with pharmacological support, and weight loss should be attempted.

image

Fig. 20.2 Algorithm for the medical management of stable angina

(Fox et al., 2006).

Antithrombotic drugs

One of the major complications arising from atheromatous plaque is thrombus formation. This causes an increase in plaque size and may result in myocardial infarction. Antiplatelet agents, in particular aspirin, are effective in preventing platelet activation and thus thrombus formation. Aspirin is of proven benefit in all forms of established CHD, although the risk–benefit ratio in people at risk of CHD is less clear.

Aspirin

Aspirin acts via irreversible inhibition of platelet COX-1 and thus thromboxane production, which is normally complete with chronic dosing of 75 mg/day. This antiplatelet action is apparent within an hour of taking a dose of 300 mg. The effect on platelets lasts for the lifetime of the platelet.

The optimal maintenance dose seems to be 75–150 mg day with lower doses having limited cardiac risk protection and higher doses increasing the risk of gastro-intestinal side effects. Dyspepsia is relatively common in patients taking aspirin and patients should be advised to take the medicine with or immediately after food. Enteric-coated preparations are no safer, and patients with ongoing symptoms of dyspepsia may require concomitant acid suppression with a proton pump inhibitor or switching to clopidogrel. Adverse reactions to aspirin include allergy, including bronchospasm. The benefits and risk of using aspirin in patients with asthma or a previous history of gastro-intestinal bleeding need to be carefully considered.

Clopidogrel

Clopidogrel inhibits ADP activation of platelets and is useful as an alternative to aspirin in patients who are allergic or cannot tolerate aspirin. Data from one major trial (CAPRIE Steering Committee, 1996) indicate that clopidogrel is at least as effective as aspirin in patients with stable coronary disease. The usual dose is 300 mg once, then 75 mg daily. Although less likely to cause gastric erosion and ulceration, gastro-intestinal bleeding is still a major complication of clopidogrel therapy. There is evidence that the combination of a proton pump inhibitor and aspirin is as effective as using clopidogrel alone in patients with a history of upper gastro-intestinal bleeding.

COX-2 inhibitors

The analgesic and anti-inflammatory action of non-steroidal anti-inflammatory drugs (NSAIDs) is believed to depend mainly on their inhibition of COX-2, and the unwanted gastro-intestinal effects of NSAIDs on their inhibition of COX-1. COX-2 inhibition reduces the production of prostacyclin, which has vasodilatory and platelet-inhibiting effects. Studies have raised concern about the cardiovascular safety of NSAIDs. Initially, the concern was focussed on the selective cyclo-oxygenase-2 inhibitors and a link to an increased cardiovascular risk. Recently, evidence has shown the more traditional non-selective NSAIDs increase cardiovascular risk in both patients with established CVD and in the healthy population (Fosbol et al., 2010). NSAIDs with high COX-2 specificity increase the risk of myocardial infarction and should be avoided where possible in patients with stable angina.

ACE inhibitors

ACE inhibitors are established treatments for hypertension and heart failure, and have proven beneficial post myocardial infarction. In addition to the vasodilation caused by inhibiting the production of angiotensin II, ACE inhibitors have anti-inflammatory, antithrombotic and antiproliferative properties. Some of these effects are mediated by actions on vascular endothelium and might be expected to be of benefit in all patients with CAD. ACE inhibitors also reduce the production of ROS.

The use of ACE inhibitors in patients without myocardial infarction or left ventricular damage is based on two trials: the HOPE study (Yusuf et al., 2000) which studied ramipril and the EUROPA (2003) study which used perindopril. These trials also identified an incidental delay in the onset of diabetes mellitus in susceptible individuals which may be of long-term benefit to them. The HOPE study, a secondary prevention trial, investigated the effect of an ACE inhibitor on patients over 55 years old who had known atherosclerotic disease or diabetes plus one other cardiovascular risk factor. The use of ramipril decreased the combined endpoint of stroke, myocardial infarction or cardiovascular death by approximately 22%. The benefits were independent of blood pressure reduction. This has major implications for the management of CHD patients, both for the decision to treat all and the choice of treatment. At present the use of ACE inhibitors in patients with coronary disease, but without myocardial infarction, has general acceptance and is recommended in European guidelines.

Statins

Studies have repeatedly demonstrated the benefit of reducing cholesterol, especially low-density lipoprotein-cholesterol (LDL-C), in patients with CHD.

Earlier studies focused on patients with ‘elevated’ cholesterol, but all patients with coronary risk factors benefit from reduction of their serum cholesterol level. It is now clear that there is no ‘safe’ level of cholesterol for patients with CAD and that there is a continuum of risk down to very low cholesterol levels. Levels of LDL-C of <2 mmol/L and total cholesterol <4 mmol/L are recommended for patients with established CVD (NICE, 2008). Statins should be prescribed alongside lifestyle advice for both primary prevention of CVD and in those with established CVD (see Chapter 24 for more detail).

In addition to cholesterol-lowering properties, statins also have antithrombotic, anti-inflammatory and antiproliferative properties. They are also important in restoring normal endothelial function and inhibit the production of ROS in the vessel wall. There is some evidence that patients with elevated levels of CRP have better outcomes with statin therapy even if cholesterol levels are not raised. Most patients with stable angina will be on statins for their cholesterol-lowering effects. It is important, however, to recognise that these drugs may have beneficial effects independent of cholesterol lowering and this makes them valuable even in patients with ‘normal’ cholesterol levels.

Symptom relief and prevention

In stable angina, much of the drug treatment is directed towards decreasing the workload of the heart and, to a lesser extent, improving coronary blood supply; this provides symptomatic relief and improves prognosis. Therapy to decrease workload is targeted at both decreasing afterload and controlling heart rate. Recent evidence suggests a prognostic benefit when the resting heart rate is controlled below 70 beats/min. Drug treatment is initiated in a stepwise fashion according to symptom relief and side effects. A number of patients will require a number of anti-anginal medicine to control their angina symptoms.

β-Blockers

Various studies have demonstrated the beneficial effect of β-blockers in angina and they are now considered first-line agents. β-Blockers reduce mortality both in patients who have suffered a previous myocardial infarction and in those with heart failure. They reduce myocardial oxygen demand by blocking β-adrenergic receptors, thereby decreasing the heart rate and force of left ventricular contraction and lowering blood pressure. The decreased heart rate not only reduces the energy demand on the heart but also permits better perfusion of the subendocardium by the coronary circulation. β-Blockers may also reduce energy-demanding supraventricular or atrial arrhythmias and counteract the cardiac effects of hyperthyroidism or phaeochromocytoma.

β-Blockers are particularly useful in exertional angina. Patients treated optimally should have a resting heart rate of around 60 beats/min. Although many patients may dislike the side effects of β-blockers, they should be urged to continue wherever reasonable. β-Blockers should be used with caution in patients with diabetes as the production of insulin is under adrenergic system control and thus their concomitant use may worsen glucose control. β-Blockers can also mask the symptoms of hypoglycaemia and patients in whom the combination is considered of value should be warned of this; however, most clinicians now believe that the benefits of taking β-blockers, even in diabetics, outweigh the risks and they are frequently prescribed.

While β-blockers are widely used, their tendency to cause bronchospasm and peripheral vascular spasm means that they are contraindicated in patients with asthma, and used with caution in chronic obstructive airways diseases and peripheral vascular disease as well as in acute heart failure and bradycardia.

Cardioselective agents such as atenolol, bisoprolol and metoprolol are preferred because of their reduced tendency to cause bronchoconstriction, but no β-blocker is completely specific for the heart. Agents with low lipophilicity, for example, atenolol, penetrate the central nervous system (CNS) to a lesser extent than others, for example, propranolol, metoprolol, and do not so readily cause the nightmares, hallucinations and depression that are sometimes found with lipophilic agents, which should not be used in patients with psychiatric disorders. CNS-mediated fatigue or lethargy is found in some patients with all β-blockers, although it must be distinguished from that of myocardial suppression. β-Blockers should not be stopped abruptly for fear of precipitating angina through rebound receptor hypersensitivity. They are contraindicated in the rare Prinzmetal’s angina where coronary spasm is a major factor.

All β-blockers tend to reduce renal blood flow, but this is only important in renal impairment. Drugs eliminated by the kidney (Table 20.2) may need to be given at lower doses in the renally impaired or in the elderly, who are particularly susceptible to the CNS-mediated lassitude. Drugs eliminated by the liver have a number of theoretical interactions with other agents that affect liver blood flow or metabolic rate, but these are rarely of clinical significance since the dose should be titrated to the effect. Likewise, although there is theoretical support for the use of agents with high intrinsic sympathomimetic activity (ISA) to reduce the incidence or severity of drug-induced heart failure, there is no β-blocker that is free from this problem, and clinical trials of drugs with ISA have generally failed to show any extra benefit.

Table 20.2 Properties and pharmacokinetics of β-blockers

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Calcium channel blockers

Calcium channel blockers (CCBs) act on a variety of smooth muscle and cardiac tissues and there are a large number of agents which have differing specificities for different body tissues.

While short-acting dihydropyridine CCBs have been implicated in the exacerbation of angina due to the phenomenon of ‘coronary steal’, longer acting dihydropyridines, for example, amlodipine and felodipine or longer acting formulations, for example, nifedipine LA, have demonstrated symptom-relieving potential similar to β-blockers. Dihydropyridines have no effect on the conducting tissues and are effective arterial dilators, decreasing afterload and improving coronary perfusion but also causing flushing, headaches and reflex tachycardia. This may be overcome by combination with a β-blocker. The use of dihydropyridines in angina is based on efficacy in trials that have used surrogate markers such as exercise tolerance rather than mortality as the endpoint.

CCBs with myocardial rate control as well as vasodilatory properties, for example, diltiazem, and those with predominantly rate-controlling effects, for example, verapamil, have also been shown to improve symptom control, reduce the frequency of anginal attacks and increase exercise tolerance. They should be avoided in patients with compromised left ventricular function and conduction abnormalities. Verapamil and diltiazem are suitable for rate control patients in whom β-blockers are contraindicated on grounds of respiratory or peripheral vascular disease. They should be used with caution in patients already receiving β-blockers, as bradycardia and heart block have been reported with this combination.

CCBs have a particular role in the management of Prinzmetal’s (variant) angina which is thought to be due to coronary artery spasm.

Nitrates

Organic nitrates are valuable in angina because they dilate veins and thereby decrease preload, dilate arteries to a lesser extent thereby decreasing afterload, and promote flow in collateral coronary vessels, diverting blood from the epicardium to the endocardium. They are available in many forms but all relax vascular smooth muscle by releasing nitric oxide, which was formerly known as endothelium-derived relaxing factor, which acts via cyclic GMP. The production of nitric oxide from nitrates is probably mediated by intracellular thiols, and it has been observed that when tolerance to the action of nitrates occurs, a thiol donor (such as N-acetylcysteine) may partially restore the effectiveness of the nitrate. Antioxidants such as vitamin C have also been used. While clinical trials have not established any mortality gain from the use of oral nitrate preparations, their role in providing symptom relief is well established.

Tolerance is one of the main limitations to the use of nitrates. This develops rapidly, and a ‘nitrate-free’ period of a few hours in each 24-h period is beneficial in maintaining the effectiveness of treatment. The nitrate-free period should coincide with the period of lowest risk, and this is usually night time, but not early morning, which is a high-risk period for infarction. Many patients receiving short-acting nitrates two or three times a day would do well to have their doses between 7 a.m. and 6 p.m. (say, 8 a.m. and 2 p.m. for isosorbide mononitrate), but this is generally not practised in UA where there is no low-risk period and where continuous dosing is used, with increasing doses if tolerance develops.

There are many nitrate preparations available, including intravenous infusions, conventional or slow-release tablets and capsules, transdermal patches, sublingual tablets and sprays and adhesive buccal tablets. Slow-release preparations and transdermal patches are expensive, do not generally offer such flexible dosing regimens as short-acting tablets. Sustained release tablets do not release the drug over the whole 24- h period producing a ‘nitrate free period’, whereas patches need to be removed for a few hours each day. Buccal tablets are expensive and offer no real therapeutic advantage in regular therapy. Like sublingual sprays and tablets, however, they have a rapid onset of action and the drug bypasses the liver, which has an extensive first-pass metabolic effect on oral nitrates. The sublingual preparations, whether sprays or suckable or chewable tablets, are used for the prevention or relief of acute attacks of pain but may elicit the two principal side effects of nitrates: hypotension with dizziness and fainting, and a throbbing headache. To minimise these effects, patients should be advised to sit down, rather than lie or stand, when taking short-acting nitrates, and to spit out or swallow the tablet once the angina is relieved. Sublingual glyceryl trinitrate (GTN) tablets have a very short shelf-life on exposure to air, need to be stored carefully and replaced frequently. As a consequence they are now little used. All nitrates may induce tachycardia.

Three main nitrates are used: GTN (mainly for sublingual, buccal, transdermal and intravenous routes), isosorbide dinitrate and isosorbide mononitrate. All are effective if given in appropriate doses at suitable dose intervals (Table 20.3). Since isosorbide dinitrate is metabolised to the mononitrate, there is a preference for using the more predictable mononitrate, but this is not a significant clinical factor. A more relevant feature may be that whereas the dinitrate is usually given three or four times a day, the mononitrate is given once or twice a day. Slow-release preparations exist for both drugs.

Table 20.3 Properties of commonly used nitrates

image

Nicorandil

Nicorandil is a compound that exhibits the properties of a nitrate but which also activates ATP-dependent potassium channels. The IONA Study Group (2002) compared nicorandil with placebo as ‘add-on’ treatment in 5126 high-risk patients with stable angina. The main benefit for patients in the nicorandil group was a reduction in unplanned admission to hospital with chest pain. The study did not tell us when to add nicorandil to combinations of antianginals such as β-blockers, CCBs and long-acting nitrates. There is a theoretical benefit from these agents in their action to promote ischaemic preconditioning. This phenomenon is seen when myocardial tissue is exposed to a period of ischaemia prior to sustained coronary artery occlusion. Prior exposure to ischaemia renders the myocardial tissue more resistant to permanent damage. This mechanism is mimicked by the action of nicorandil.

Ivabradine

Ivabridine represents a class of antianginal agents which block the If current. If is a mixed Na+–K+ inward current activated by hyperpolarisation and modulated by the autonomic nervous system. This regulates pacemaker activity in the sinoatrial node and controls heart rate. Inhibition, therefore, reduces heart rate without affecting the force of contraction. Ivabridine is similar in efficacy to atenolol and CCBs and may be of particular use in patients in whom β-blockers are contraindicated. The most frequent adverse drug reactions are dose-dependent transient visual symptoms that manifest as transient enhanced brightness commonly associated with abrupt changes in light intensity. They may be related to the action of ivabradine at hyperpolarisation-activated, cyclic nucleotide-gated cation current channels present in the retina. Visual symptoms may resolve spontaneously during therapy or after drug discontinuation.

Ranolazine

Ranolazine, a selective inhibitor of late sodium influx, attenuates the abnormalities of ventricular repolarisation and contractility associated with ischaemia. It has been shown to increase exercise tolerance, reduce anginal episodes and reduce the use of GTN. Side effects include dizziness, constipation, nausea, and the potential for prolongation of the QTc interval. Ranolazine seems to be a safe addition to current traditional drugs for chronic stable angina, especially in aggressive multidrug regimens.

Acute coronary syndrome

Definition and cause

The group of conditions referred to as ACS often present with similar symptoms of chest pain which is not, or only partially, relieved by GTN. These conditions include acute myocardial infarction (AMI), UA and non-ST-elevation myocardial infarction (NSTEMI). AMI with persistent ST segment elevation on the ECG usually develops Q waves, indicating transmural infarction. UA and NSTEMI present without persistent ST segment elevation and are managed differently, although a similar early diagnostic and therapeutic approach is employed. All patients with ACS should be admitted to hospital for evaluation, risk stratification and treatment. The spectrum of ACS is described in Fig. 20.3.

image

Fig. 20.3 The spectrum of acute coronary syndrome

(Thygesen et al., 2007).

ACS arises from the rupture of an unstable atheromatous plaque. This exposes the cholesterol-rich plaque in the intima to the blood, initiating platelet activation and eventual thrombus formation. The volume of the eventual thrombus and the time the vessel is occluded determine the degree of myocardial necrosis that occurs. The major difference in approach to these patients arises from whether the coronary artery involved is felt to be occluded or open.

Patients with an occluded coronary artery suffer myocardial damage, the extent of which is determined by the duration and site of the occlusion. The primary strategy for these patients is the restoration of coronary flow with either a fibrinolystic agent or primary angioplasty. If the coronary artery is patent, however, then fibrinolysis is unnecessary and probably harmful, although angioplasty may still be appropriate. When the vessel is open, for both groups, patient management focuses on the unstable coronary plaque and is, therefore, fundamentally similar.

Troponins (troponin I or troponin T) are cardiac muscle proteins which are released following myocardial cell damage and are highly sensitive and specific for myocardial infarction. They are useful in diagnosing patients with ACS and for predicting response to drug therapy; they are now key to the management of these patients and have replaced cardiac enzymes such as creatinine kinase (CK), aspartate transaminase (AST) and lactate dehydrogenase (LDH).

Diagnostic criteria for AMI have changed to incorporate the increasing availability of new diagnostic techniques with traditional symptoms and ECG changes. The following criteria for AMI, agreed by the European Society of Cardiology, rely on the rise of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischaemia with at least one of the following symptoms of ischaemia:

• ECG changes indicative of new ischaemia: new ST changes (STEMI or new left bundle branch block (LBBB))
• Development of pathological Q waves in the ECG
• Image evidence of new loss of viable myocardium or new regional wall motion abnormality.

Mortality rates of patients with presumed myocardial infarction or ACS in the first month is approximately 50% and of these deaths about half occur within the first 2 h. The prognosis of an individual who has suffered a STEMI and receives hospital treatment has improved following the widespread use of thrombolytic therapy and primary percutaneous intervention

The most dangerous time after a myocardial infarction is the first few hours when ventricular fibrillation (VF) is most likely to occur.

Patients without persistent ST elevation on the ECG may still have experienced myocardial damage due to temporary occlusion of the vessel or emboli from the plaque-related thrombus blocking smaller distal vessels and will have raised levels of troponin. These patients have had a NSTEMI. Patients without ST elevation and without a rise in troponin or cardiac enzymes are defined as having UA. The long-term prognosis in NSTEMI is similar to that of STEMI. The early adverse event rate is lower but these patients are more likely to suffer death, recurrent myocardial infarction or recurrent ischaemia after hospital discharge than patients with STEMI. More emphasis is now placed on improving the treatment of patients with NSTEMI than was previously the case.

The Global Registry of Acute Coronary Events (GRACE; available at http://www.outcomes-umassmed.org/GRACE/) is an international registry which has enrolled patients with ACS (UA, NSTEMI and STEMI) since 1999. The registry indicates a similar incidence of UA, NSTEMI and STEMI.

The classification of ACS based on ECG findings and measurement of troponin is shown in Fig. 20.4.

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Fig. 20.4 Classification of ACS based on ECG and measurement of troponins.

Treatment of ST elevation myocardial infarction

Treatment of STEMI may be divided into three categories:

• provide immediate care to alleviate pain, prevent deterioration and improve cardiac function;
• manage complications, notably heart failure and arrhythmias;
• prevent further infarction or death (secondary prophylaxis).

The management of heart failure and arrhythmias are covered more extensively in Chapters 21 and 22, respectively, and will not be discussed here. The remaining therapeutic aims are to relieve pain, return patency to the coronary arteries, minimise infarct size, provide prophylaxis to arrhythmias and institute secondary prevention.

Immediate care to alleviate pain, prevent deterioration and improve cardiac function

Pain relief. Patients with suspected STEMI should receive sublingual GTN under the tongue, oxygen administered and intravenous access established immediately. If sublingual GTN fails to relieve the chest pain, intravenous morphine may be administered together with an antiemetic such as prochlorperazine or metoclopamide. There is no benefit in leaving a patient in pain while the diagnosis is considered. Pain is associated with sympathetic activation, which causes vasoconstriction, increases the workload of the heart and can exacerbate the underlying condition.

Antiplatelet therapy. An aspirin tablet chewed as soon as possible after the infarct and followed by a daily dose for at least 1 month has been shown to reduce mortality and morbidity. Follow-up studies have demonstrated additional benefit in continuing to take daily aspirin, probably for life. The reduction in mortality is additional to that obtained from thrombolytic therapy (Table 20.4). Clopidogrel, given in addition to aspirin, can further improve coronary artery blood flow but the additional absolute reduction in mortality is small, at approximately 0.4% (Sabatine et al., 2005). In suspected heart attack patients in the UK, both aspirin and clopidogrel may be administered by the ambulance crew.

Table 20.4 Vascular deaths at 35 days in the ISIS-2 study (1990)

Placebo 13.2%
Aspirin 10.7%
Streptokinase 10.4%
Aspirin + streptokinase 8.0%

Restoring coronary flow and myocardial tissue perfusion

In patients with STEMI, early restoration of coronary artery patency results in an improved outcome; this may occur spontaneously in some patients but frequently only after substantial myocardial damage has occurred. Clinical trial data indicate that hospital mortality at 1 month has been reduced from 16% to 4–6% with the widespread use of coronary interventions, fibrinolytic agents and secondary prevention. In practice, available data suggest a higher mortality than that recorded in clinical trials.

The timing of treatment is vital, since myocardial damage after onset of an acute ischaemic episode is progressive and there are pathological data to suggest it is irreversible beyond 6 h. Clinical data from large studies of fibrinolysis have shown that the sooner treatment is started after the onset of pain, the better. All trials show that rapid treatment is important and this has a greater effect than the choice of drug; several studies indicate that giving fibrinolytics an average of 30–60 min earlier can save 15 lives per 1000 treated. Hospitals need to maintain fast-track systems to ensure maximum benefit, although there is still some worthwhile benefit up to 12 h after infarction.

Treatment within 1 h has been found to be particularly advantageous, although difficult to achieve, for logistical reasons, in anyone who has an infarct outside hospital. Prioritisation of ambulances to emergency calls for chest pain and appropriately equipped paramedics or primary care doctors administering fibrinolytics out of hospital have all helped reduce delay in fibrinolysis administration. Increased numbers of and direct access to hospitals offering primary angioplasty sites has further reduced the time to myocardial tissue reperfusion. Current reperfusion strategies are outlined in Fig. 20.5.

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Fig. 20.5 Reperfusion strategies. The thick arrow (dark blue) indicate the preferred strategy (Van de Werf, 2008).

Fibrinolytics

Fibrinolytic agents (Table 20.5) have transformed the management of these patients by substantially improving coronary artery patency rates which has translated into a 25% relative reduction in mortality. The risk of haemorrhagic stroke (around 1%) and a failure to adequately reperfuse the affected myocardium in approximately 50% of cases have remained despite advances in fibrinolytics.

Table 20.5 Fibrinolytic agents (thrombolytics)

image

Percutaneous coronary intervention

The introduction of primary PCI (angioplasty and/or stent insertion without prior or concomitant fibrinolytic therapy) has demonstrated superiority to fibrinolysis when it can be performed expeditiously by an experienced team in a hospital with an established 24 h a day interventional programme. In this context, primary angioplasty is better than fibrinolysis at reducing the overall short-term death, non-fatal reinfarction and stroke. The target for time from first medical contact to first balloon inflation should be less than 2 h. If the delay to angioplasty is likely to be longer than 2 h, facilitated PCI can be undertaken.

Facilitated PCI involves use of a fibrinolytic to achieve reperfusion prior to a planned PCI. This approach allows the clinical team to bridge an anticipated delay in undertaking a PCI.

Rescue PCI is performed on coronary arteries which remain occluded despite attempts at fibrinolysis. It has better outcomes than repeated fibrinolytic therapy or conservative management.

PCIs encompass various invasive procedures to improve myocardial blood delivery by opening up the blood vessels. PCIs open stenosed coronary vessels and are less invasive than coronary bypass surgery, where the coronary vessels are replaced.

A percutaneous (through the skin) transluminal (through the lumen of the blood vessels) coronary (into the heart) angioplasty (surgery or repair of the blood vessels) (PTCA) was first carried out on a conscious patient in 1977. Now over 2 million people a year undergo PCIs. The procedure is less invasive than coronary artery bypass graft (CABG) surgery.

PCI involves the passing of a catheter via the femoral or radial artery and aorta into the coronary vasculature under radio-contrast guidance. Inflation of a balloon at the end of the catheter in the area of the atheromatous plaques opens the lumen of the artery. For patients undergoing PCI there is a small risk of death, myocardial infarction and long-term restenosis. This is reduced by insertion of a coronary artery stent and the use of pre- and peri-procedural antiplatelet therapy. Over the last 10 years the proportion of patients undergoing PCI and stent insertion has accounted for >95% of all PCI procedures.

Antiplatelet and anticoagulant therapy

After stent insertion there is a short-term risk of thrombus formation until the endothelial lining of the blood vessel has been re-established. The combination of clopidogrel (600 mg initiated pre-procedure and 75 mg daily thereafter) and aspirin has been shown to reduce the risk of myocardial infarction and need for reperfusion therapy and decrease the length of hospital stay.

Patients undergoing primary PCI should receive aspirin and clopidogrel as early as possible. Antiplatelet naïve patients should receive 300 mg of aspirin and 600 mg of clopidogrel. In the UK and elsewhere in Europe, these are administered by paramedics. Prasugrel has less metabolic activation steps and has a faster and more reliable onset of antiplatelet action. In combination with aspirin, it is recommended (NICE, 2009) for preventing atherothrombotic events in individuals undergoing PCI only when:

• immediate primary PCI for STEMI is necessary;
• stent thrombosis has occurred during clopidogrel treatment; and
• the individual has diabetes mellitus.

Heparin is routinely administered during the PCI procedure and is titrated to maintain an activated clotting time (ACT) of 250–350 s. Glycoprotein IIb/IIIa receptor antagonists, particularly abciximab, have been shown to reduce mortality if used during the procedure. These are used in combination with heparin, and a lower ACT (200–250 s) is targeted to reduce bleeding complications. Bivalirudin, a direct thrombin inhibitor, has demonstrated less bleeding compared to abciximab and may be useful in those at risk of increased bleeding.

Much of the evidence for the use of glycoprotein IIb/IIIa receptor antagonists was accumulated before high-dose clopidogrel or more potent antiplatelets were in routine practice. Current recommendations are that in the setting of dual-antiplatelet therapy with unfractionated heparin or bivalirudin as the anticoagulant, glycoprotein IIb/IIIa receptor antagonists can be useful at the time of primary PCI but cannot be recommended as routine therapy.

Intracoronary administration of vasodilators such as adenosine, verapamil, nicorandil, papaverine, and nitroprusside during and after primary PCI has been shown to improve flow in the infarct-related coronary artery and myocardial perfusion, and/or to reduce infarct size, but large prospective randomised trials with hard clinical outcomes are missing.

Fibrinolytics

Fibrinolytic agents fall into two categories: fibrin specific (alteplase, tenecteplase and reteplase) and fibrin non-specific (streptokinase). There are theoretical advantages for the fibrin-specific agents which are superior in terms of achieving coronary artery patency in angiographic studies. Angiographic patency has been shown to correlate well with outcome in thrombolytic trials but it has been difficult to prove that this benefit translates into an improvement in mortality. Studies have demonstrated considerable benefit from fibrinolytics given soon after the onset of pain but little difference between streptokinase and the more expensive tissue plasminogen activator (alteplase) in reducing mortality. Fast injection of fibrin-specific agents is better than slower infusion of streptokinase, especially in younger patients with anterior infarcts. Tenecteplase and reteplase have the advantage that they can be administered by bolus injection, which facilitates pre-hospital administration and reduces errors.

Patients receiving alteplase also receive a 5000 unit heparin bolus followed by a 48-h infusion adjusted to maintain the activated partial thromboplastin time (APTT) in the therapeutic range. Intravenous enoxaparin followed by subcutaneous injections may be an alternative. Heparin has not been compared to placebo in trials of tenecteplase or reteplase but it is standard practice to use heparin with these agents. Heparin has no advantage in addition to streptokinase, which has a longer lasting and less specific fibrinolytic action.

A low dose of fondaparinux, a synthetic, indirect anti-Xa agent, has been found to be superior to placebo or heparin in preventing death and reinfarction in patients who received fibrinolytic therapy (OASIS-6 Trial Group, 2006).

Bivalirudin, a direct thrombin inhibitor, reduces reinfarction rates compared to heparin when given with streptokinase but has not been studied with fibrin-specific agents. This combination resulted in a non-significant increase in non-cerebral bleeding complications (HERO-2 Trial Investigators, 2001).

Trials using various dosing combinations of glycoprotein IIb/IIIa inhibitors with newer fibrinolytic agents have not found a regimen that increases overall survival (Menon et al., 2004).

All fibrinolytics cause haemorrhage, which may present as a stroke or a gastro-intestinal bleed, and there is an increased risk with regimens that use intravenous heparin. Recent strokes, bleeds, pregnancy and surgery are contraindications to fibrinolysis. Streptokinase induces cross-reacting antibodies which reduce its potency and may cause an anaphylactoid response. Patients with exposure to streptokinase, or with a history of rheumatic fever or recent streptococcal infection, should not receive the drug. The use of hydrocortisone to reduce allergic responses has fallen out of favour, but patients should be carefully observed for hypotension during the administration of streptokinase.

Old age is no longer considered to be a contraindication to fibrinolysis. Although the risks are greater, the benefit is also greater, but the doses of alteplase and tenecteplase need to be adjusted for body weight.

All the major trials have used specific ECG criteria for entry, usually ST elevation in adjacent leads or LBBB, and eliminated patients with major contraindications to fibrinolysis (Box 20.2). Confusion often arises about the term ‘relative contraindication’. For example, systolic hypertension is common in AMI, so most protocols recommend lowering the blood pressure with either a β-blocker or intravenous nitrates before commencing fibrinolysis. An increasing number of patients are on warfarin and this again is regarded as a relative contraindication to fibrinolysis; thresholds for the use of fibrinolysis in patients on warfarin vary from an INR of 2–2.4. The use of fibrinolytic therapy in patients with relative contraindications should take into account the site of the myocardial infarction and the likely size of the infarction. For example, in patients with a large anterior myocardial infarction the benefits of fibrinolysis may outweigh risk. In patients where there is a serious concern regarding bleeding following fibrinolysis, primary angioplasty should be considered.

Box 20.2 Contraindications to fibrinolysis

(Van de Werf, 2008)

Absolute contraindications

• Haemorrhagic stroke of unknown origin at any time
• Ischaemic stroke in preceding 6 months
• CNS damage or neoplasms
• Recent major trauma/surgery/head injury (within preceding 3 weeks)
• Gastro-intestinal bleed within the last month
• Known bleeding disorder
• Non-compressible punctures
• Aortic dissection

Relative contraindications

• Transient ischaemic attack in preceding 6 months
• Oral anticoagulant therapy
• Pregnancy or within 1 week postpartum
• Advanced liver disease
• Active peptic ulcer
• Infective endocarditis
• Traumatic resuscitation
• Refractory hypertension (systolic blood pressure >180 mmHg)

Management of complications

Heart failure

Heart failure during the acute phase of STEMI is associated with a poor short- and long-term prognosis. It should be managed with oxygen, intravenous furosemide and nitrates. More severe failure or cardiogenic shock (tissue hypoperfusion resulting from cardiac failure with symptoms of hypotension, peripheral vasoconstriction and diminished pulses, decreased urine output and decreased mental status) should be treated with inotropes and/or inter-aortic balloon pumps to maintain the systolic blood pressure above 90 mmHg. Invasive monitoring may be required.

Arrhythmias

Life-threatening arrhythmias such as ventricular tachycardia, sustained VF or atrio-ventricular block occur in about one fifth of patients presenting with a STEMI, although this is decreasing due to early reperfusion therapy. β-Blockers have been the subject of many studies because of their anti-arrhythmic potential and because they permit increased subendocardial perfusion. In studies undertaken prior to the widespread use of fibrinolytics, the early administration of an intravenous β-blocker was shown to limit infarct size and reduce mortality from early cardiac events. A post hoc analysis of the use of atenolol in the GUSTO-I trial and a systematic review (Freemantle et al., 1999) did not support the routine, early intravenous use of β-blockers and, therefore, oral β-blockers are started within 24 h of the event. If a β-blocker is contraindicated because of respiratory or vascular disorders, verapamil may be used, since it has been shown to reduce late mortality and reinfarction in patients without heart failure, although it shows no benefit when given immediately after an infarct. Diltiazem is less effective but may be used as an alternative. This is clearly not a class effect; other echannel blockers have produced different results and nifedipine increases mortality in patients following a myocardial infarction.

Initially, magnesium infusions looked promising when given early after infarction. However, in large trials (ISIS-4), no reductions in mortality were found making the routine use of magnesium inappropriate. Magnesium infusions are used, however, to correct low serum magnesium levels if cardiac arrhythmias are present.

Sinus bradycardia and heart block may also occur after a myocardial infarction and patients may require temporary or permanent pacemaker insertion.

Blood glucose

Patients with a myocardial infarction are often found to have high serum and urinary glucose levels, usually described as a stress response. The CREATE-ECLA trial (Mehta et al., 2005) studied more than 20,000 patients and showed a neutral effect of insulin on mortality, cardiac arrest and cardiogenic shock. Current guidelines do not support the routine use of insulin in STEMI in patients not previously known to be diabetic.

Up to 20% of patients who have a myocardial infarction have diabetes. Moreover, diabetic patients are known to do poorly after infarction, with almost double the mortality rate of non-diabetics. In these patients, an intensive insulin regimen, both during admission and for 3 months after, was found to save lives (Malmberg, 1997). However, the follow-up study (Malmberg et al., 2005) did not show any mortality benefit from intensive insulin therapy compared to standard therapy. In patients with diabetes, it appears reasonable, however, to continue to control blood glucose levels within the normal range immediately post-infarct.

Prevention of further infarction or death (secondary prophylaxis)

Lipid-lowering agents

Reduction of cholesterol through diet and use of lipid-lowering agents are effective at reducing subsequent mortality and morbidity in patients with established CAD. Patients with established CHD should be treated to ensure LDL-C is less than 2 mmol/L and total cholesterol less than 4 mmol/L (see Chapter 24). In patients with AMI or high-risk NSTEMI, there was a reduction in the combination end point of death, myocardial infarction, or documented UA requiring hospitalisation, revascularisation or stroke when patients were treated with high intensity statin (atorvastatin 80 mg) compared to standard statin therapy (Cannon et al., 2004). A meta-analysis of studies (Josan et al., 2008) reaffirmed the benefit of high intensity statin therapy especially in those patients with ACSs. An additional finding of particular interest was that the results were significant for the high intensity treatment arms despite approximately half of patients not achieving LDL-C of less than 2 mmol/L.

β-Blockers

Long-term use of a β-blocker has been shown in several studies to decrease mortality in patients in whom there is no contraindication. β-Blockade should be avoided in individuals with heart block, bradycardia, asthma, obstructive airways disease or peripheral vascular disease. One large cohort study compared low and high doses of β-blockers with no therapy and found benefit in all treated patients with similar survival rates but a lower heart failure rate in the low-dose group (Rochon et al., 2000).

Angiotensin-converting enzyme inhibitors

ACE inhibitors have been tried in various doses and durations and have proved beneficial in reducing the incidence of heart failure and mortality. In all but the earliest trials, patients were given an ACE inhibitor for 4–6 weeks and treatment continued in patients with signs or symptoms of heart failure or left ventricular dysfunction. The HOPE study (Yusuf et al., 2000) found that ramipril improved survival in all groups of patients with CHD and this has led clinicians to continue ACE inhibitors in all patients with a myocardial infarction over the age of 55 and in younger patients with evidence of left ventricular dysfunction. Contraindications to their use include hypotension and intractable cough.

There is considerable interest in focusing on the possible benefits of combining ACE inhibition with angiotensin II receptor blockers. Angiotensin blockade alone does not cause the accumulation of bradykinins that may be part of the benefit of using ACE inhibitors. Clinical trials (OPTIMAAL Study Group, 2002; VALIANT Investigators, 2003) have failed to find a benefit over ACE inhibition. Nonetheless, angiotensin receptor blockers are probably suitable in patients who cannot tolerate an ACE inhibitor. The relative benefits of ACE inhibitors and other treatments are shown in Table 20.6.

Table 20.6 Relative benefits of treating 1000 patients for myocardial infarction (MI)

Intervention Events prevented
Intravenous β-adrenoceptor blocker 6 deaths
ACE inhibitor 6 deaths
Aspirin 20–25 deaths
Streptokinase (in hospital) 20–25 deaths
Alteplase (in hospital) 35 deaths
Streptokinase (before hospital) 35–40 deaths
Fibrinolysis 4½–1 h earlier 15 deaths
Long-term aspirin 16 deaths/MI/strokes
Long-term β-blockade 18 deaths/MI
Long-term ACE inhibitor 21–45 deaths/MI
10% reduction in serum cholesterol 7 deaths/MI
Stopping smoking 27 deaths

Adapted from McMurray and Rankin (1994).

Eplerenone

In patients with heart failure, post-AMI, an improvement in survival and decreased cardiovascular mortality and hospitalisation was seen in those taking the aldosterone antagonist eplerenone (EPHESUS Trial; Pitt et al., 2003). Serious hyperkalemia occurred more frequently in the eplerenone arm and monitoring of serum potassium is warranted when used in practice.

Antidepressants

Anxiety is almost inevitable and a quarter of patients who have suffered a myocardial infarction subsequently experience marked depression. Post-myocardial infarction depression is associated with poor medication compliance, a lower quality-of-life score and a four-fold increase in mortality (Januzzi et al., 2000). Antidepressant treatments have not been subjected to formal trials but it seems reasonable to try to reduce the depression. There is concern about the potential for older antidepressants, such as tricyclic antidepressants, to increase the QT interval and cause arrhythmias. Newer antidepressants are less prone to cause these arrhythmias and selective seretonin receptor inhibitors (SSRIs) are preferred.

Rehabilitation programmes, which include some measure of social interaction, physical activity and education, are also of proven benefit. Although psychological stress clearly worsens outcomes, stress reduction interventions have not been tested and proven to work independently of other measures.

Nitrates

Studies on nitrates in myocardial infarction were mostly completed before fibrinolysis was widely used. Nitrates improve collateral blood flow and aid reperfusion, thus limiting infarct size and preserving functional tissue. ISIS-4 (1993) and GISSI-3 (1994) demonstrated that nitrates did not confer a survival advantage in patients receiving fibrinolysis. Sublingual nitrates may be given for immediate pain relief, and the use of intravenous or buccal nitrates can be considered in patients whose infarction pain does not resolve rapidly or who develop ventricular failure.

Anticoagulants and antiplatelets

Anticoagulation with warfarin is not generally recommended following a myocardial infarction, despite promising results in trials that have practiced exceptionally good anticoagulant monitoring. This is partly because of the success of antiplatelet therapy with aspirin. Aspirin does not have the same need for expensive and time-consuming follow-up and monitoring as warfarin, and is associated with fewer drug interactions. Clopidogrel has been shown to be beneficial, in addition to aspirin, in patients who have had a myocardial infarction (COMMIT, 2005). As the number of patients who receive a stent increases, the combination of aspirin and clopidogrel for a year or longer is now more frequent. Routine use of dipyridamole and sulfinpyrazone is not recommended after a myocardial infarction.

Treatment of non-ST elevation acute coronary syndromes

ACS without ST elevation is classified as either UA or NSTEMI. UA is defined as angina that occurs at rest or with minimal exertion, or new (within 1 month) onset of severe angina or worsening of previously stable angina. NSTEMI (or non-Q wave MI) is the more severe manifestation of ACS.

There are about 115,000 new patients diagnosed each year with UA or NSTEMI in England and Wales. Despite the use of standard therapy the rate of adverse outcomes such as death, non-fatal MI or refractory angina requiring revascularisation, remains at 5–7% at 7 days and about 15–30% at 30 days; 5–14% of patient with UA or NSTEMI die within the first year of diagnosis.

There are extensive data for angioplasty following NSTEMI where patients frequently have significant residual coronary artery narrowing despite treatment with antiplatelet agents, heparin and glycoprotein IIb/IIIa antagonists.

Patients with NSTEMI may either be treated with an interventional strategy, where all patients undergo angiography and PCI following admission, or conservatively where they undergo angiography and intervention only if they remain unstable or have a positive exercise test. Initial trials of early intervention did not demonstrate any benefit but with the advent of advanced angioplasty techniques using stents and adjuvant drug therapies including clopidogrel and glycoprotein IIb/IIIa antagonists, there appears to be a clear advantage for an interventional strategy in high-risk patients (Fox et al., 2005).

Patients presenting with UA/NSTEMI can be classified into three categories depending on their risk of death or likelihood of developing an AMI. High-risk patients (those with ST segment changes during chest pain, chest pain within 48 h, troponin T-positive patients and those presenting already on intensive anti-anginal therapy) can be effectively managed with aggressive medical and interventional therapy. This results in fewer individuals progressing to AMI.

Various pharmacological agents such as antithrombin and antiplatelet drugs, and coronary revascularisation (particularly PCI) have been shown to improve the outcome of patients with UA or NSTEMI. These interventions are known to be associated with some treatment hazards, particularly bleeding complications. The risks must be balanced against potential treatment benefits for each individual patient. This balance is influenced by the patient’s estimated risk of an adverse cardiovascular outcome as a consequence of the ACS. The absolute magnitude of benefit from an intervention is generally greatest in those at highest risk. A confounding issue is that treatment hazards, such as bleeding complications, are often also greatest in those at highest risk of an ischaemic event.

Measures of risk can be derived from the clinical assessment of a patient and the use of a formal risk scoring system, such as the GRACE, PURSUIT, PREDICT or TIMI scores. Scores based on clinical trial data generally exclude patients who are at high risk of an adverse cardiovascular outcome such as the elderly, or those with renal or heart failure, and as a consequence the evidence for clinical and cost-effectiveness of therapeutic interventions is confined to patients at lower to intermediate levels of risk. Risk score based on registry data, for example, GRACE, may provide a more realistic estimation of risk (Tables 20.7 and 20.8).

Table 20.7 Classification of high-risk patients with NSTEMI as determined by the GRACE prediction score card and nomogram

image

Table 20.8 GRACE prediction nomogram for all cause mortality during in-hospital stay and up to 6 months post discharge

Risk category (tertiles) GRACE risk score In-hospital death (%)
Low <109 <1
Intermediate 109–140 1–3
High >140 >3
Risk category (tertiles) GRACE risk score Post-discharge to 6 months
Low <89 <3
Intermediate 89–118 3–8
High >118 >8

GRACE Registry. Available at www.outcomes-umassmed.org/GRACE/ index.cfm.

In patients with NSTEMI, the immediate administration of 300 mg aspirin can reduce mortality or subsequent myocardial infarction by 50%. Risk stratification according to a recognised tool should be used to guide the subsequent choice of pharmacological and/or surgical intervention. The exclusion of STEMI and confirmation of NSTEMI is important as the use of fibrinolysis in NSTEMI confers no benefit, and merely increases the risk of bleeding. In patients with NSTEMI, the preferred treatment normally involves a combination of antiplatelet agents to reduce the formation of a thrombus.

Antiplatelet and anticoagulant drugs

The current range of antiplatelet and anticoagulant drugs available for the reduction of thrombotic events in ACS leads to the potential for a large number of combinations. In all cases, the benefit of reducing thrombotic events must be balanced against the potential for an increased risk of bleeding.

In the early 1990s, unfractionated heparin, when combined with aspirin showed a reduction in death and subsequent myocardial infarction compared with aspirin alone. The use of the low molecular weight heparin (LMWH), enoxaparin, subsequently demonstrated superiority over unfractionated heparin, with both usually continued for 48 h, or until chest pain resolved or discharge. Both groups of drugs were tested in the era before PCI became part of routine practice.

The CURE study (2001) showed that clopidogrel, given as a loading dose of 300 mg followed by 75 mg daily in combination with aspirin and heparin, reduced the combined end point of death, myocardial infarction and revascularisation in all patients with NSTEMI. Clopidogrel needs to be continued for 12 months but should be stopped 5–7 days before any major surgery to reduce the risk of bleeding.

As PCI has become more routine as part of the management of high-risk NSTEMI patients, more aggressive antiplatelet treatment has been required to reduce both peri-procedural and post-procedural thromboembolic complications.

Expression of glycoprotein IIb/IIIa is one of the final steps in the platelet aggregation cascade. Inhibiting these receptors has been a strategy prior to, and during, PCI for some time. Glycoprotein IIb/IIIa inhibitors bind to the IIb/IIIa receptors on platelets (Fig. 20.6) and prevent cross-linking of platelets by fibrinogen. There are three classes of these agents: murine-human chimeric antibodies, for example, abciximab; synthetic peptides, for example, eptifibatide; and non-peptide synthetics, for example, tirofiban. Oral agents are ineffective and the murine-human chimeric antibodies appear to be effective only in the context of PCI.

image

Fig. 20.6 Schematic representation of mechanism of action of glycoprotein IIb/IIIa inhibitors.

In high-risk patients undergoing PCI and receiving background heparin, triple antiplatelet therapy (aspirin, clopidogrel and a glycoprotein IIb/IIIa inhibitors) has been shown to be superior to standard dose dual-antiplatelet therapy (aspirin and clopidogrel) particularly in troponin positive individuals (Kastrati et al., 2006). However, much of this evidence was generated before the introduction of higher doses of clopidogrel or more potent oral antiplatelet agents.

There is no clear benefit to giving glycoprotein IIb/IIIa inhibitors more than 4 h before PCI (upstream) compared to waiting until immediately before or during the procedure (deferred) (Stone et al., 2007).

Currently, all patients with a likely or definite diagnosis of NSTEMI should receive a loading dose of aspirin 300 mg (see Fig. 20.7). Patients undergoing PCI intervention should have a higher loading dose of 600 mg of clopidogrel or 60 mg of prasugrel, unless contraindicated, to reduce events during and after PCI. Clopidogrel is often given as 300 mg on admission and a further 300 mg when the decision to intervene is made. Prasugrel, with its faster time to maximum effect, has demonstrated some benefit but routine use is not recommended (NICE, 2009). Patients who are not planned for intervention should receive a lower loading dose of clopidogrel 300 mg.

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Fig. 20.7 Treatment options for patients with likely or definite unstable angina (UA) or NSTEMI in relation to time of PCI intervention.

All patients should receive heparin, bivalirudin or fondaparinux. Unfractionated heparin is preferred for patients with compromised renal function. Fondaparinux, a synthetic pentasaccharide factor Xa inhibitor which has predictable and sustained anticoagulation with fixed dose, once-a-day subcutaneous administration, causes less bleeding than enoxaparin, an LMWH. Concerns over catheter related thrombus mean it should not be considered if patients are planned for PCI within 24 h of chest pain. Bivalirudin is a synthetic analogue of hirudin that binds reversibly to thrombin and inhibits clot-bound thrombin and may be considered an alternative.

The decision to use glycoprotein IIb/IIIa inhibitors is dependant on the centre and operator and whether the planned intervention for the patient is to be surgical or pharmacological. The introduction of higher loading doses of clopidogrel and more potent oral agents, as well as an increased focus on the bleeding risks associated with combination therapy, has reduced the use of these agents in many centres.

Recommendation of an anticoagulant regimen has become more complicated by a number of new choices suggested by contemporary trials, some of which do not provide adequate comparative information for common practice settings.

Anti-ischaemic drugs

The use of both β-blockers and nitrates in the management of patients with NSTEMI is based on studies of their use in stable angina and AMI. Their use is, however, well established and based on a firm pathophysiological and pharmacological rationale.

Statins

High intensity statins have been shown to benefit patients when given early in ACS. They are usually started on admission if the diagnosis of CAD is definite, independent of the patient’s cholesterol level. Treatment should aim to achieve total cholesterol of <4 mmol/L and an LDL-C of <2 mmol/L.

Patient care

Patients with CHD range from those who have investigational evidence of CHD but no symptoms to those who have major pain and exercise limitation. All need encouragement in adhering to preventive measures including diet, exercise and smoking cessation. Patients need to be able to discuss concerns about their health.

Exercise must be tailored according to the patient’s threshold for angina. In general, although some patients are too cavalier, most are likely to err on the cautious side and may need to be encouraged to do more. Many centres now run cardiac rehabilitation classes to encourage patients to exercise and adopt a suitable lifestyle.

There are simple treatments and important lifestyle changes that can reduce cardiovascular risk and slow or even reverse progression of established coronary disease. The most important of these to address is smoking cessation. The risk of CHD is two to four times higher in heavy smokers (those who smoke at least 20 cigarettes/day) than in those who do not smoke. Other reports estimate the age-adjusted risk for smokers of more than 25 cigarettes/day is five to 21 times that of non-smokers. Smokers should be encouraged to quit. Within months of stopping smoking, CHD risk begins to decline. Within 5 years of smoking cessation the risk decreases to approximately the level found in people who have never smoked, regardless of the amount smoked, duration of the habit and the age at cessation. The use of nicotine replacement therapy almost doubles a smokers’ chance of successfully stopping smoking (18% vs. 11%). All patients who smoke should be offered advice on cessation and encouraged to attend specialist smokers’ clinics to further improve their chance of quitting.

Patient beliefs about medicines and medication-taking behaviour (and therefore adherence) are also important determinants of outcome and are influenced by many factors. These can largely be divided into beliefs about the importance of the medicine and concerns about the medicine’s harmful effects. In order to assure the patient’s concordance with medication regimens, it is necessary to address each individual patient’s beliefs and concerns. One approach to counselling patients with CHD may be to divide the medication prescribed into those used to reduce risk of heart attacks and death, and those for symptom control. Key points to be discussed will relate to side effects and what to do if they occur, the need to continue medication until told otherwise and to ensure they do not run out of medication. Patients should be encouraged to identify their concerns and these should be addressed as openly and honestly as possible.

Patients also need up-to-date advice when faced with difficult choices regarding medical treatment, angiographic procedures or surgery. Patients have good reason to be anxious at times but some patients restrict their activities unnecessarily out of fear of angina and infarction.

Some of the common therapeutic problems encountered in the management of CHD are described in Table 20.9.

Table 20.9 Common therapeutic problems in coronary heart disease

Problem Comment
Used incorrectly, nitrates may cause hypotensive episodes or collapse Advise to sit down when using nitrate sprays or sublingual tablets
A daily nitrate-free period is required to maintain efficacy of nitrates Avoid long-acting preparations and prescribe asymmetrically (e.g. 8 a.m. and 2 p.m.)
NSAIDs are associated with renal failure when given with ACE inhibitors Warn patients to use paracetamol as their analgesic of choice
Speed is essential when patients need fibrinolytic drugs after infarction Arrange emergency admission to hospital where fast-track systems should exist
Aspirin may cause gastro-intestinal bleeding Advise on taking with food and water. Consider use of prophylactic agents in high-risk patients
β-Blockers are often considered unpleasant to take Encourage patient to use regularly. Change the time of day. Consider a vasodilator if cold extremities are a problem. Consider verapamil or diltiazem
β-Blockers are contraindicated in respiratory and peripheral vascular disease Consider verapamil or diltiazem. Pay strict attention to other treatments and removal of precipitating factors
Patients often receive multiple drugs for prophylaxis and for treatment of co-existing disorders Use once-daily preparations, dosing aids and intensive social and educational support. Avoid all unnecessary drugs
ACE inhibitors are contraindicated in pregnancy, especially the first trimester Advise women of child-bearing years to avoid conception or seek specialist advice first

Case studies

Case 20.1

A 55-year-old man presents to his primary care doctor complaining of tightness in his chest when he digs the garden. It eases when he has a rest. On investigation he has a raised serum glucose concentration and is considered to be a newly diagnosed non-insulin-dependent type II diabetic.

Question

What cardiovascular investigations and treatments should this patient receive?

Answer

The patient’s blood pressure and ECG should be checked and he should be examined for signs of hypertensive or diabetic target organ damage, including albuminuria. His serum lipid profile should be measured.

He should receive GTN spray or sublingual tablets for the chest symptoms that are almost certainly angina. He should take aspirin daily and a statin if his lipid profile is abnormal. Some prescribers would give a statin in almost all diabetic, CHD patients and likewise an ACE inhibitor. Certainly, any hypertension should be treated aggressively so that the diastolic pressure is less than 80 mmHg. A β-blocker may also be useful to control blood pressure and prevent further episodes of angina, but many prescribers would wait until there was evidence of failure of the other therapies. In view of his relatively young age, a referral to a cardiologist for possible angiography would be considered. Dietary advice and help to stop smoking, if needed, would be given. Diabetic treatments should be given (see Chapter 44).

Case 20.2

The following patients are admitted for treatment of myocardial infarction:

1. an asthmatic
2. a man previously treated for infarction
3. a patient with rheumatoid arthritis.

Question

What contraindications, or possible contraindications, are there to standard treatments in the above patients?

Answers

1. An asthmatic should not receive a β-blocker without careful consideration and supervision because of the risk of bronchoconstriction; there is also a small risk of bronchoconstriction with aspirin.
2. A previous infarct may have been treated with streptokinase and a repeat dose should be avoided. Tissue plasminogen activator should be used instead.
3. Fibrinolytics are contraindicated if there is a serious risk of bleeding. A patient with rheumatoid arthritis may be receiving NSAIDs or steroids and enquiries must be made into any history of gastro-intestinal bleeding. NSAIDs would also not be prescribed with ACE inhibitors because of the risk of impaired renal function. Aspirin is not contraindicated with NSAIDs, and may be useful, but will increase the risk of gastro-intestinal bleeding.

Case 20.3

A patient with rheumatoid disease, treated with naproxen, has CHD.

Question

Is there any benefit or harm in adding aspirin to his treatment?

Answer

Aspirin is more beneficial than any other non-steroidal anti-inflammatory agent in modifying platelet activity and reducing mortality and morbidity in CHD. There is an increased risk of gastro-intestinal bleeding if two agents are given but at low doses of aspirin this should not be a major consideration. There is some evidence, however, that some NSAIDs interfere with the action of aspirin by blocking access to the active site on the COX-1 enzyme. Such agents should be avoided. Diclofenac does not block the receptor and ibuprofen has a short action and is acceptable if given 2 h after the daily dose of aspirin.

Acknowledgement

Permission to use material prepared for versions of this chapter which appeared in earlier editions of this textbook by D.K. Scott and J. Dwight is gratefully acknowledged.

References

Cannon C.P., Braunwald E., McCabe C.H., et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med.. 2004;350:1495-1504.

CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339.

COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1607-1621.

CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med.. 2001;345:494-502.

EUROPA Study Investigators. The EURopean trial On reduction of cardiac events with perindopril in stable coronary artery disease investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.

Fosbøl E.L., Folke F., Jacobsen S., et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among healthy individuals. Circ. Cardiovasc. Qual. Outcomes. 2010;3:395-405. doi:10.1161/CIRCOUTCOMES.109.861104

Fox K.A.A., Poole-Wilson P., Clayton T., et al. Five-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial. Lancet. 2005;366:914-920.

Fox K., Garcia M.A.A., Ardissino D., et al. The task force on the management of stable angina pectoris of the European Society of Cardiology. Guidelines on the management of stable angina pectoris. Eur. Heart J.. 2006;27:1341-1381. doi:10.1093/eurheartj/ehl001

Freemantle N., Cleland J., Young P., et al. Beta blockade after myocardial infarction: systematic review and meta regression analysis. Br. Med. J.. 1999;318:1730-1737.

GISSI-3 (Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico). Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994;343:1115-1122.

HERO (Hirulog and Early Reperfusion or Occlusion)-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet. 2001;358:1855-1863.

IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002;349:1269-1275.

ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. In-hospital mortality and clinical course of 20, 891 patients with suspected acute myocardial infarction randomised between tissue plasminogen activator or streptokinase with or without heparin. Lancet. 1990;336:71-75.

ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669-685.

Januzzi J.L., Stern T.A., Pasternak R.C., et al. The influence of anxiety and depression on outcomes of patients with coronary artery disease. Arch. Intern. Med.. 2000;160:1913-1921.

Josan K., Majumdar S.R., McAlister F.A. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. Can. Med. Assoc. J.. 2008;178:576-584.

Kastrati A., Mehilli J., Neumann F.J., et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. J. Am. Med. Assoc.. 2006;295:1531-1538.

Malmberg K., for the DIGAMI (Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Aacute Myocardial Infarction) Study Group. Br. Med. J.. 1997;314:1512-1515.

Malmberg K., Ryden L., Wedel H., et al. Intense metabolic control by means of insulin in patients with Diabetes Mellitus and Acute Myocardial Infarction (DIGAMI 2): effects on mortality and morbidity. Eur. Heart J.. 2005;26:650-661.

McMurray J.J.V., Rankin A.C. Treatment of myocardial infarction, unstable angina and angina pectoris. Br. Med. J.. 1994;309:1343-1350.

Mehta S.R., Yusuf S., Diaz R., et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. J. Am. Med. Assoc.. 2005;293:437-446.

Menon V., Harrington R.A., Hochman J.S., et al. Thrombolysis and adjunctive therapy in acute myocardial infarction. Chest. 2004;126:549S-575S.

National Institute for Health and Clinical Excellence. Cardiovascular Risk Assessment and the Modification of Blood Lipids for the Primary and Secondary Prevention of Cardiovascular Disease. London: NICE; 2008. Available at: http://www.nice.org.uk/CG067

National Institute for Health and Clinical Excellence. Prasugrel for the Treatment of Acute Coronary Syndromes with Percutaneous Coronary Intervention. London: NICE; 2009. Available at http://guidance.nice.org.uk/TA182

OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction. J. Am. Med. Assoc.. 2006;295:1519-1530.

OPTIMAAL Study Group. Effect of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomized trial. Lancet. 2002;360:752-780.

Pitt B., Remme W., Zannad F., for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med.. 2003;348:1309-1321.

Ridker P.M., Danielson E., Fonseca F.A.H., for the JUPITER Study Group, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med.. 2008;359:2195-2207.

Rochon P.A., Tu J.V., Anderson G.M., et al. Rate of heart failure and 1-year survival for older people receiving low-dose β-blocker therapy after myocardial infarction. Lancet. 2000;356:639-644.

Sabatine M.S., Cannon C.P., Gibson C.M., for the CLARITY-TIMI 28 Investigators, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N. Engl. J. Med.. 2005;352:1179-1189.

Stone G.W., Bertrand M.E., Moses J.W., et al. Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing Trial. J. Am. Med. Assoc.. 2007;297:591-602.

Thygesen K., Alpert J.S., White H.D., et al. Joint ESC/ACCF/AHA/WHF Task Force for the redefinition of myocardial infarction. Universal definition of myocardial infarction. Eur. Heart J.. 2007;28:2525-2538.

Unal B., Critchley J.A., Capewell S. Explaining the decline in coronary heart disease mortality in England and Wales between 1981 and 2000. Circulation. 2004;109:1101-1107.

VALIANT (VALsartan In Acute myocardial iNfarction Trial) Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N. Engl. J. Med.. 2003;349:1893-1906.

Van de Werf F., Bax J., Betriu A., et al. The task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation. Eur. Heart J.. 2008;29:2909-2945.

Yusuf S., Sleight P., Pogue J., et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. N. Engl. J. Med.. 2000;342:145-153.

Further reading

Montalescot G., Wiviott S.D., Braunwald E., et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373:723-731.

National Institute for Health and Clinical Excellence. Unstable Angina and NSTEMI. The Early Management of Unstable Angina and Non-ST-Segment-Elevation Myocardial Infarction. London: NICE; 2010. Available at: http://www.nice.org.uk/guidance/CG94

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