SIGN 97: Risk estimation and the prevention of cardiovascular disease

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8 Antiplatelet therapy

8.1 Use of antiplatelet agents in people with established cardiovascular disease

The favourable benefit to risk profile of aspirin for patients with established cardiovascular disease is well recognised. In meta-analyses, the Antithrombotic Trialist's Collaboration showed clear evidence of a reduction in all cause mortality, vascular mortality, non-fatal reinfarction of the myocardium, and non-fatal stroke in people with acute coronary syndromes, stroke, transient ischaemic attacks (TIAs), or other vascular disease.164,165 The trials used aspirin doses between 50-325 mg/day. The meta-analysis provided no evidence of any greater benefit from high dose aspirin, while adverse effects from aspirin are minimised at lower dosages. Evidence level 1++

A meta-analysis compared the benefit and gastrointestinal risk of low dose (<325 mg) aspirin use for the secondary prevention of thromboembolic events. It showed that aspirin reduced all-cause mortality by 18%, the number of strokes by 20%, myocardial infarctions by 30%, and other vascular events by 30%. Patients who took aspirin were 2.5 times more likely than those in the placebo group to have gastrointestinal tract bleeding. The number needed to treat for aspirin to prevent one death from any cause of mortality was 67, while 100 needed to be treated to detect one nonfatal gastrointestinal tract bleeding.166 Evidence level 1++

The evidence supports daily doses of aspirin in the range of 75?325 mg for the long term prevention of serious vascular events in high risk people, and it is usual practice to prescribe 75 mg daily. Although there is no clinical trial evidence of treatment beyond a few years, there is likely to be ongoing benefit, so it is usual to continue aspirin therapy for life.

AIndividuals with established atherosclerotic disease should be treated with 75 mg aspirin daily.

 

The platelet receptor blocker clopidogrel was equivalent to aspirin in prevention of further events in patients with CHD or ischaemic stroke.167 In subgroup analysis, clopidogrel appeared to be more effective than aspirin among patients with peripheral vascular disease, although the study was not powered to detect a significant effect in any subgroup (see SIGN guideline 89 on diagnosis and management of peripheral arterial disease).168 It is indicated in combination with aspirin in patients with proven troponin-positive acute coronary syndromes for up to three months following the acute event (see SIGN guideline on acute coronary syndromes).169 It is more expensive than aspirin and should be used if aspirin causes side effects.167 Evidence level 1+, 4

[Good practice point] Clopidogrel should be considered in patients with symptomatic cardiovascular disease who have aspirin hypersensitivity or intolerance or in whom aspirin causes unacceptable side effects.

Meta-analysis of two large RCTs with 20,000 patients in each showed that starting daily aspirin (160 - 300 mg) promptly in patients with suspected acute ischaemic stroke reduced the immediate risk of further stroke or death in hospital and the overall risk of death or dependency.170 Relative risk for recurrent ischaemic stroke was reduced by 30% in the group taking aspirin (odds ratio 0.70, p<0.000001; ARR 0.7%). Death without further stroke was reduced by 8% (odds ratio 0.92, p=0.05; ARR 0.4%). In total there was a net decrease of 11% in the overall risk of further stroke or death in hospital (odds ratio 0.89, p=0.001; ARR 0.9%). Evidence level 1++

One RCT assigned patients to aspirin (30 - 325 mg daily, median 75 mg) with (n=1,363) or without (n=1,376) dipyridamole (200 mg twice daily) within six months of a transient ischaemic attack or minor stroke of presumed arterial origin.171 Combination therapy with aspirin and dipyridamole reduced the composite outcome of death from all vascular causes, non-fatal stroke, non-fatal MI or major bleeding complication by 20% (hazard ratio 0.80, 95% CI 0.66 to 0.98; ARR 1.0% per year, 95% CI 0.1 to 1.8). Evidence level 1++

AIndividuals with a history of stroke or transient ischaemic attack and who are in sinus rhythm should be considered for low dose aspirin (75?300mgdaily)and dipyridamole (200mgtwicedaily)to prevent stroke recurrence and other vascular events. If aspirin is contraindicated, or there are side effects, clopidogrel 75 mg daily is an alternative.

8.2 Use of antiplatelet agents in people without cardiovascular disease

Aspirin reduces the risk of MI by approximately 30%, but increases the risk for haemorrhagic strokes by about 40% and of major gastrointestinal bleeding by 70%.172 All-cause mortality has not been shown to be affected. For 1,000 patients with a 10% risk for CHD events over ten years, aspirin would prevent 12 to 40 myocardial infarctions but would cause zero to four haemorrhagic strokes and four to eight major gastrointestinal bleeding events. For patients with a CHD risk of 2% over ten years, aspirin would prevent two to eight myocardial infarctions but would cause zero to four haemorrhagic strokes and four to eight major gastrointestinal bleeding events. In another analysis, a CHD risk of ≥15% over ten years was defined as the point of benefit over harm for aspirin use in patients with no evidence of atherosclerotic disease.173 Evidence level 1++

Enteric coated products do not prevent the major gastrointestinal complications of aspirin therapy and are significantly more expensive than the standard dispersible formulation.174-176 Evidence level 1++, 2++

8.2.1 Sex differences in response to Aspirin therapy

A meta-analysis of six trials of aspirin in individuals with no evidence of cardiovascular disease included 51,342 women and 44,114 men. It showed that overall low dose aspirin (50-500mg daily) was associated with a reduction in the relative risk of cardiovascular events in both men and women (see Table 6).177 For women, there is a significant reduction in the likelihood of stroke (mainly ischaemic stroke) whereas in men, no significant effect was observed on all strokes, however a significant 32% reduction in the relative risk of MI was seen. There was no evidence that higher doses of aspirin were more effective in reducing the primary clinical endpoints in the doses used in this meta-analysis. In both men and women aspirin was associated with a significantly increased risk of major bleeding. Evidence level 1++

AAsymptomatic individuals without established atherosclerotic disease but with a calculated cardiovascular risk of≥20% over ten years should beconsidered for treatment with aspirin 75 mg daily.

Table 6: Cardiovascular risk reduction in asymptomatic individuals treated with aspirin

Cardiovascular endpoint
Men
Women
OR (95% CI, p-value)
ARR (%)
OR (95% CI, p-value)
ARR (%)
Cardiovascular event (cardiovascular mortality, nonfatal MI or non-fatal stroke) 0.86 (0.78-0.94, p=0.01)
0.35
0.88 (0.79-0.99, p=0.03)
0.3
MI 0.68 (0.54-0.86, p=0.001)
0.85
1.01 (0.84-1.21, p=0.95)
Any stroke 1.13 (0.96-1.33, p=0.14) 0.83 (0.70-0.97, p=0.02)
0.23
Haemorrhagic stroke 1.69 (1.04-2.73, p=0.03)
0.12
1.07 (0.42-2.69, p=0.89)
Ischaemic stroke 1.00 (0.72-1.41, p=0.98) 0.76 (0.63-0.93, p=0.008)
0.25
Cardiovascular mortality 0.99 (0.86-1.14, p=0.87) 0.90 (0.64-1.28, p=0.56)
All cause mortality 0.93 (0.85-1.03, p=0.15 0.94 (0.74-1.19, p=0.62)
Major bleeding 1.72 (1.35-2.20, p<0.001)
-0.32
1.68 (1.13-2.52, p=0.01)
-0.25
OR - odds ratio, CI - confidence interval, ARR - absolute risk reduction
Shaded boxes show significant results

8.3 Individuals with diabetes

There are few data on aspirin for primary prevention among diabetic individuals. The Primary Prevention Project (PPP) trial compared aspirin 100 mg/day with a placebo, vitamin E 300 mg/day, in type 2 diabetes mellitus (DM) patients without established cardiovascular disease.178 Aspirin failed to achieve a significant difference in the composite primary endpoint of cardiovascular death, stroke, or MI in patients with diabetes (relative risk 0.9, 95% CI 0.5 to 1.62, p=0.71). There was no significant reduction in total cardiovascular events in patients with diabetes taking aspirin (RR 0.89, 95% CI 0.62 to 1.26). Evidence level 1+

In the HOT trial there was a reduction by 15% in major cardiovascular events among the 9,399 patients randomised to receive 75 mg aspirin per day (p=0.03). This cohort was defined by existing hypertension and a diastolic blood pressure between 100 mm Hg and 115 mm Hg and included patients with DM.179 No significant effect on overall mortality was reported. Fatal bleeds were equally common in the treatment and control groups, but non-fatal major bleeds were significantly more frequent among patients receiving aspirin than in those receiving placebo (risk ratio 1.8, p<0.001). The trial reported that 2.5 myocardial infarctions could be prevented per 1,000 patient-years in patients with diabetes mellitus. Evidence level 1++

There is conflicting evidence on the benefit of aspirin on stroke outcomes on patients with DM.180 Evidence level 4

The revised Joint British Societies guideline advises that aspirin 75 mg daily is recommended for all people with type 2 diabetes who are over 50 years of age, and selectively in younger people with one of the following criteria:28

[Good practice point] Aspirin 75 mg daily is recommended for all people with type 2 diabetes who are over 50 years of age and for selected younger individuals with diabetes who are considered to be at increased cardiovascular risk.

8.4 Individuals with hypertension

For every individual the risk of bleeding must be considered against the benefits of cardiovascular protection. Low dose aspirin has been shown in one major randomised trial of hypertensive individuals to be of benefit only in those patients at higher baseline risk.179 In patients at lower risk there was neither benefit nor harm. Hypertensive patients with a ten year risk =20% of 1++ cardiovascular disease would be considered to have a high baseline risk, where benefits of antiplatelet treatment would outweigh harms. Patients with uncontrolled blood pressure are at greater risk of cerebral haemorrhage and should not receive antiplatelet therapy until their blood pressure is treated to <150/90 mm Hg. Evidence level 1++

[Good practice point] Patients with hypertension should be treated with aspirin if their ten year cardiovascular disease risk exceeds 20%, and only once their blood pressure is treated to <150/90 mm Hg.

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