Advice concerning the benefits of smoking cessation, physical activity and healthy dietary choices should be given at a population and individual level. These measures are considered as first-line in any management decisions.

Both the HOPE study1 and the PROGRESS study2 have examined the effects of preventive treatment with an ACE inhibitor in normotensive high-risk patients. In the HOPE study, 9297 patients with CHD, peripheral vascular disease, stroke, or diabetes (types 1 or 2) and an additional risk factor, were randomly allocated to receive ramipril 10 mg daily or placebo. Patients were included irrespective of a history of hypertension, but those with blood pressure greater than 140/90 mmHg or with a specific indication for treatment with an ACE inhibitor (eg, CCF) were excluded. The 3/1 mmHg lower blood pressure in the ramipril group at the end of the study was unlikely to explain the highly significant 22% reduction in the combined endpoint of cardiovascular death, stroke or heart-attack (cardiovascular death [26% reduction; absolute risk-reduction, 2.0%], stroke [32% reduction; absolute risk-reduction, 1.5%], heart attack [20% reduction; absolute risk reduction, 2.2%]; P < 0.05) or the 17% decrease in total mortality (P < 0.05).1 Based on these data, normotensive patients with a history of cardiovascular disease, or with diabetes and one additional risk factor, should be considered for treatment with ramipril 10 mg for prevention of cardiovascular events, unless the practitioner considers that ACE inhibitors are contraindicated. In the PROGRESS study, perindopril 4 mg and indapamide 2.5 mg, when given together, reduced the risk of recurrent stroke (fatal or non-fatal) and major vascular events in both normotensive and hypertensive patients with previous stroke or TIA.2

In the immediate post-infarct management of the normotensive patient, a mortality benefit in the short term has also been demonstrated with β-blockers16 and ACE inhibitors (particularly in patients with associated heart failure),17 with less robust evidence for calcium channel blockers, verapamil and diltiazem.18-20

While epidemiological studies have established that blood pressure is a major risk factor for cardiovascular events in patients with a history of AMI,21 there is no systematic review or RCT that specifically examines blood pressure reduction in patients with established CHD, nor in those with peripheral vascular disease. In our recommendations, and those of both the Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure22 and the National Heart Foundation,23 the benefits of blood pressure lowering in patients with CHD have been extrapolated from primary prevention trials and from studies of patients after AMI.2,16-20 Evidence of event reduction exists for patients taking calcium channel blockers,18-20,24-27 diuretics and β-blockers,27-33 and ACE inhibitors.1,26,33 In patients with elevated blood pressure and a history of stroke or TIA, the evidence is strongest for the use of ACE inhibitors (ramipril 10 mg; and perindopril 4 mg when given with indapamide 2.5 mg),1,2 diuretics and β-blockers.32-36 As over 50% of patients in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) had a history of atherosclerotic cardiovascular disease, the result of this study should be considered when blood pressure lowering is contemplated for such patients.36 Specifically, the results of treatment with either ACE inhibitors, diuretics or calcium channel blockers were comparable.

There is strong RCT evidence that lowering cholesterol levels decreases cardiovascular mortality and morbidity in patients who have been diagnosed with an acute coronary syndrome,37 even if cholesterol levels are normal.3,38,39 The most substantial data are from studies of simvastatin and pravastatin.3,37-39 Of these studies, the Heart Protection Study3 has provided the most complete information of the benefits of lowering cholesterol level in a wide range of circumstances. Both men and women with total cholesterol levels greater than 3.5 mmol/L and with a history of cardiovascular disease (including those with a history of coronary disease, cerebrovascular disease, or peripheral vascular disease) achieved a significant reduction in major vascular events (P < 0.001) irrespective of the starting cholesterol level.

In men with low levels of HDL cholesterol and a history of CHD, gemfibrozil significantly reduced the risk of major cardiovascular events, in the absence of an effect on LDL cholesterol level.40

In patients with diabetes and CHD, the data are strongest for the use of statins,3,37-39 but again in patients with low levels of HDL cholesterol, gemfibrozil is efficacious.40 To date, this evidence has been derived from subgroup analyses. In RCTs, it has been shown that both pravastatin and simvastatin reduce the incidence of stroke in patients with CHD,3,38,39,41 but in those without CHD the evidence is strongest for simvastatin.3 There are no "head-to-head" outcome studies of statins versus fibrates.

In patients with diabetes, "normal" blood pressure is arbitrarily defined as being less than 130/85 mmHg and "ideal" blood pressure as less than 120/80 mmHg.22 As the HOPE study1 only included patients with diabetes if they had at least one cardiovascular risk factor, treatment of low-risk patients with diabetes (ie, those who have no additional cardiovascular risk factors) with an ACE inhibitor to prevent future CHD events is not supported by current data. Observation with repeated measurement of blood pressure at least annually is recommended.

A systematic review of RCTs has shown that ACE inhibitors, diuretics, calcium channel blockers and β-blockers are all effective in primary prevention of cardiovascular events in patients with diabetes and hypertension.42 There is no clear evidence that any of these classes is more effective than another in event reduction,26,24 and, currently, drugs of all of these classes are recommended to treat blood pressure in patients with diabetes.22,23 Despite this, an apparent greater reduction in major cardiovascular events occurring with ACE inhibitors, compared with some calcium channel blockers,43-45 has led us to list calcium channel blockers as second-line therapy. In addition to reducing cardiovascular events, ACE inhibitors have a major role in renal protection in patients with type 1 diabetes and hypertension.46 Similar protection has recently been shown with the angiotensin II receptor antagonists irbesartan47,48 and losartan49 in patients with type 2 diabetes.

In the Heart Protection Study,3 patients with diabetes with a total cholesterol level greater than 3.5 mmol/L had significantly fewer major vascular events (P < 0.0001) when taking simvastatin 40 mg, whether or not they had a prior history of CHD. To date, this is the largest intervention trial of statin therapy in patients with diabetes and thus should be considered the definitive trial. These data support the use of a statin for both primary and secondary prevention of major vascular events in patients with diabetes. Furthermore, three large primary prevention RCTs using lovastatin,50 gemfibrozil51 and bezafibrate52 have each shown a benefit in preventing cardiovascular events. Thus, a predominant elevation of total or LDL cholesterol levels indicates a statin is appropriate initial therapy, whereas a fibrate could be an appropriate choice in patients with low levels of HDL cholesterol and raised triglyceride levels. When treating a combined hyperlipidaemia, both classes of drug may be required, but there are no outcome data from using this approach and practitioners should exercise caution in prescribing this combination. Definitive trials on lipid management in patients with dia-betes (eg, the FIELD study) are still to be published.

As the HOPE study included patients with diabetes and dyslipidaemia (total cholesterol level > 5.2 mmol/L and HDL cholesterol level 0.9 mmol/L),53 the use of ramipril, in addition to other therapies, should be advocated in diabetic patients with dyslipidaemia or other cardiovascular risk factors.

Renal insufficiency is a well described predictor of cardiovascular outcomes.54 Hypertension in patients with renal disease is defined as blood pressure greater than 130/85 mmHg,22 although observational studies suggest that even a lower blood pressure confers an increased risk. Despite this, there is no RCT of antihypertensive therapy showing treatment benefit if blood pressure is below this threshold. Ongoing observation with repeated measurement of blood pressure every 6 months is currently recommended for normotensive patients with non-diabetic renal disease.22,55

The benefits of treating hypertension in patients with established renal disease have largely been studied with surrogate endpoints, and the effects of lowering blood pressure on cardiovascular outcomes have not been specifically assessed. Nevertheless, patients with renal dysfunction are at high risk of CHD and it is reasonable to extrapolate from this that aggressive blood pressure lowering will confer a substantial benefit.23

Published data support the use of ACE inhibitors as first-line treatment for hypertension, with greater demonstrated efficacy in reducing proteinuria than calcium channel blockers.46 Furthermore, in a meta-analysis of a number of clinical trials, ACE inhibitors were more effective than other agents in delaying the development of end-stage renal disease; however, it could not be determined whether this was due to the lower blood pressure achieved with ACE inhibitors or to effects independent of blood pressure.56 β-Blockers and diuretics are also recommended.22,23 If calcium channel blockers are used they should be considered second-line therapy after ACE inhibitors.46

Specific trials of lipid-lowering therapy have not been conducted in patients with non-diabetic renal disease. Thresholds for intervention have been derived by consensus, and recommendations for the choice of agents have been based on the lipid-lowering characteristics of specific therapies.

A number of systematic reviews have shown a reduction in total mortality, cardiovascular death, stroke, major coronary events and CCF in patients taking β-blockers, diuretics, ACE inhibitors or calcium channel blockers.22,23,54,58 One unblinded RCT in 6600 people aged 70–84 years, comparing diuretics and/or β-blockers versus calcium channel blockers versus ACE inhibitors, showed no significant difference in blood pressure control or cardiovascular morbidity and mortality.59 The ALLHAT study, involving hypertensive patients with at least one other CHD risk factor, supports these findings.36,60 When the primary outcome was considered (fatal CHD or non-fatal AMI), diuretic-based therapy (chlor-thalidone) was of similar efficacy to either therapy with a calcium channel blocker (amlodipine) or an ACE inhibitor (lisinopril). In fact, patients taking amlodipine had an increased risk of CCF (relative risk, 1.38; 95% CI, 1.25–1.52) and patients taking lisinopril had a higher risk of combined cardiovascular disease, stroke and CCF.36 As amlodipine is a dihydropyridine calcium channel blocker, it may not be possible to extrapolate these results to the non-dihydropyridine calcium channel blockers.60

We found no evidence that lowering cholesterol level reduces total mortality in non-diabetic patients without cardiovascular disease, although systematic reviews and RCTs have shown that cholesterol reduction improves cardiovascular outcomes in high-risk populations.3,50,61-63 The benefit is related to baseline risk and extent of cholesterol reduction rather than initial cholesterol level (within the range studied). A total cholesterol level greater than 5 mmol/L is the current recommended threshold for treatment in patients with associated risk factors or vascular disease.64

We routinely adopt a more proactive approach for monitoring blood pressure than the current guidelines, which advocate that low-risk patients whose blood pressure is considered normal by current criteria should have blood pressure measurements either every 5 years (age < 60 years) or every 1–2 years (> 60 years).23,58 Current clinical practice would also be at variance with the guideline recommendations that drug therapy and lifestyle modification for hypertension should only be introduced in patients under 60 years if their systolic blood pressure is > 180 mmHg or diastolic > 100 mmHg,23,58 or in those over 60 years whose systolic blood pressure is > 160 mmHg.25,27 Despite our personal views we have included the current published recommendations in the desktop reference.23 In the second Australian National Blood Pressure Study (ANBP2), 6083 elderly subjects (aged 65–84 years) with hypertension, treated with either ACE inhibitors or diuretics, were compared. Although a similar number of strokes occurred in each group, taking ACE inhibitors was associated with better cardiovascular outcomes, particularly in men.65

Patients with normal lipid levels should be assessed every 5 years until middle age and then every 1–2 years. In the absence of other risk factors triggering a lower threshold for treatment, lipid-lowering therapy with a statin should be commenced for patients with predominant hypercholesterolaemia (> 6.5 mmol/L), or with a fibrate for patients with low HDL cholesterol and high triglyceride levels.64 (At present, the reimbursement criteria of the Pharmaceutical Benefits Schedule are at variance with current National Heart Foundation guidelines.)

Aspirin (75–325 mg/day) has been shown to have significant benefit in patients with acute coronary syndromes, stroke/TIA, stable angina, peripheral vascular disease, and in those with hypertension,67,68 although blood pressure should be tightly controlled to minimise the risk of haemorrhagic stroke.69 The American Diabetes Association recommends the use of aspirin for patients with diabetes over the age of 30 years,68 but there is no evidence of benefit in primary prevention in low-risk subjects.67

Alternative or additional antithrombotic therapies such as clopidogrel or dipyridamole (stroke/TIA only) may be required if aspirin is not tolerated or the patient experiences recurrent cardiovascular events while taking aspirin.70-72

It is beyond the scope of this review of cardiovascular prevention measures to focus on the management of acute coronary syndromes. However, it is important to highlight the results of a recent trial using combination antiplatelet therapy in patients with acute coronary syndromes — initiating therapy during the acute management phase in hospital was shown to have benefits up to 1 year after the initial presentation. The CURE study (Clopidogrel in Unstable angina to prevent Recurrent Events)73 showed that patients with acute coronary syndromes who were given a loading dose of 300 mg of clopidogrel followed by ongoing treatment with 75 mg/day for 9 months, in addition to their usual therapy (including aspirin), had a 20% reduction in the combined endpoint of cardiovascular death, AMI, and stroke (absolute risk reduction, 2.1%).74 Thus, many patients who leave hospital after an admission with unstable angina or non-ST elevation myocardial infarction will be receiving clopidogrel, in addition to aspirin, as combined antiplatelet therapy for atherothrombosis, and this should be continued as long-term therapy.

The CREDO study (Clopidogrel for the Reduction of Events During Observation) showed a 27% relative risk reduction (absolute risk reduction, 3.0%) in the combined endpoint of death, AMI and stroke at 1 year with the use of clopidogrel added to conventional therapy (including aspirin) after placement of a coronary stent.74 Once again, early treatment translates into long-term preventive therapy, and thus a case can be made for the use of combination antiplatelet therapy (aspirin and clopidogrel) for preventing ischaemic events in appropriate patients. Definitive long-term trials of this combination to prevent events in patients with cardiovascular disease (but who have not presented with an acute coronary syndrome), or to avoid the need for coronary artery stenting, are currently under way.

Long-term anticoagulation to reduce thromboembolism may be required for patients with paroxysmal or chronic atrial fibrillation, proteinuria > 3 g/day, and those with a history of extensive anterior infarction or severe CCF.75,76