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.

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.

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

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.

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.