NPC Archive Item: More data question the value of aspirin in primary prevention of CV disease

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15th June 2009

This ATT meta-analywsis found that in the primary prevention of cardiovascular (CV) disease, the balance of benefits and risks with aspirin is unclear. While there appears to be a small absolute reduction (around 0.06%) in some CV outcomes (e.g. non-fatal MI), there is also an increased absolute risk of major bleeds (around 0.03%).

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

For the primary prevention of CV disease, we should weigh this small absolute reduction in some CV outcomes against a possible increase in major bleeds. Priority should be given to evidence-based interventions where indicated, e.g. statins, blood pressure management, along with lifestyle measures, e.g. smoking cessation. It seems appropriate to consider prescribing aspirin on an individual patient basis, as the presence of personal risk factors may change the risk:benefit profile.

What is the background to this?
There is good evidence from meta-analyses of randomised controlled trials (RCTs) that aspirin is effective for the secondary prevention of CV events. However, it is less clear whether it is effective in preventing primary CV events in people who are at risk of CV disease, such as those with type 2 diabetes or hypertension.

NICE guidance on type 2 diabetes advises that aspirin 75 mg daily should be offered to people:

  • aged 50 years old or over with blood pressure (BP) below 145/90 mmHg.
  • aged under 50 years old with significant CV risk factors (features of the metabolic syndrome, strong early family history of CV disease, smoking, hypertension, existing CV disease, microalbuminuria).

However, the guideline development group acknowledged that there is little direct evidence to support the use of aspirin for the primary prevention of CV events in patients with type 2 diabetes.

The NICE guidance on hypertension doesn’t make any specific recommendations in relation to aspirin. SIGN guidance on risk estimation and prevention of CV disease recommends that patients with hypertension should be treated with aspirin if their 10–year CV disease risk exceeds 20%, and only if their BP is treated to less than 150/90 mmHg.

What does this study claim?
This meta-analysis of individual patient data from RCTs assessed the benefits and risks of long term aspirin, compared with control in primary and secondary prevention. In the six primary prevention trials (n=95,000), aspirin reduced the relative risk (RR) of any serious vascular event (non-fatal myocardial infarction [MI], stroke or vascular death) by 12% (0.51% aspirin vs 0.57% control per year; RR 0.88, 95% confidence interval [CI] 0.82 to 0.94 P=0.0001, absolute risk reduction [ARR] 0.06%). This was mainly due to a 23% relative risk reduction in non-fatal MI (0.18% aspirin vs 0.23% control per year; RR 0.77, 95%CI 0.67 to 0.89, P<0.0001). There was no statistically significant difference between the aspirin and control groups for any stroke or any vascular death. Aspirin increased the risk of major gastrointestinal and other extracranial bleeds (0.10% aspirin vs 0.07% control per year; RR 1.54, 95%CI 1.30 to 1.82, P<0.0001). The authors concluded that in primary prevention, the balance of benefits and risks with aspirin is unclear as the reduction in occlusive events needs to be weighed against any increase in major bleeds.

How does this relate to other studies?
We have previously blogged the POPADAD trial which found that aspirin was ineffective for primary prevention of CV events in patients with type 2 diabetes and a risk factor for CV disease. This trial highlighted that evidence is accumulating that aspirin does not reduce future CV events in any group of patients who do not have existing CV disease.

Similarly, a Cochrane Review concluded that aspirin cannot be recommended for primary prevention in patients with elevated blood pressure because the magnitude of benefit is negated by a harm of similar magnitude. Based on one large trial (the HOT study), aspirin taken for 5 years reduced MI (absolute risk reduction [ARR] 0.5%, number needed to treat [NNT] 200 for 5 years). However it increased major haemorrhage (absolute risk increase [ARI] 0.7%, number needed to harm [NNH] 154), and did not reduce all cause mortality or CV mortality.

So what?
In the secondary prevention of CV events, the benefits of aspirin are clear. However, this meta-analysis provides more data that question the role of aspirin in primary prevention. Given the risk of major gastrointestinal or other extracranial bleeds associated with aspirin, the balance of benefits and harms in primary prevention may not be favourable. The authors point out that most patients in the primary prevention trials were not taking a statin, which would have reduced their CV risk. The additional absolute benefit of adding aspirin may be too small to warrant the increased risk of bleeding for many patients.

There remains the possibility that for primary prevention, some particular sub groups of individuals will be identified, where the risk:benefit profile for aspirin is favourable. However, until more evidence is available, this new data supports treating patients on an individual basis and will help to inform patient decisions on the benefits and harms of aspirin.

More information on cardiovascular disease can be found on the cardiovascular section of NPC.

Study details
Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–60

Design: Meta-analysis of individual participant data from RCTs (6 primary prevention trials, 16 secondary prevention trials). Intention to treat analysis of first events during scheduled treatment period.

Patients: 95,000 patients in primary prevention trials (660,000 person-years) and 17,000 patients in secondary prevention trials (43,000 person-years). Primary prevention trials excluded individuals with any history of occlusive disease at entry.

Intervention and comparison: Long term aspirin vs no aspirin (control group). No other antiplatelets were allowed in either group.

Outcomes and results: The main outcome was serious vascular events (MI, stroke, vascular death). In the primary prevention trials, there were 1671 serious vascular events (0.51% per year) with aspirin, compared with 1883 events (0.57% per year) in the control group. In the secondary prevention trials, there were 1505 serious vascular events (6.69% per year) with aspirin, compared with 1801 events (8.19% per year) in the control group. For other results, see Table 1 below.

Table 1.

Outcome RR (95%CI) Aspirin vs control† Absolute difference
(% per year)
Secondary prevention Primary
Secondary prevention
Major coronary event 0.82 (0.75 to 0.90) 0.80 (0.73 to 0.88) –0.06 –1.00‡
Non-fatal MI 0.77 (0.69 to 0.86) 0.69 (0.60 to 0.80) –0.05 –0.66
CHD mortality 0.95 (0.82 to 1.10) 0.87 (0.78 to 0.98) –0.01 –0.34
Any stroke 0.95 (0.85 to 1.06) 0.81 (0.71 to 0.92) –0.01 –0.46‡
Haemorrhagic stroke 1.32 (1.00 to 1.75) 1.67 (0.97 to 2.90) 0.01
Ischaemic stroke 0.86 (0.74 to 1.00) 0.78 (0.61 to 0.99) –0.02
Vascular death 0.97 (0.87 to 1.09) 0.91 (0.82 to 1.00) –0.01 –0.29
Any serious vascular event 0.88 (0.82 to 0.94) 0.81 (0.75 to 0.87) –0.06 –1.49‡
Major extracranial bleed 1.54 (1.30 to 1.82) 2.69 (1.25 to 5.76) 0.03

†  Statistically significant results in bold.

‡  Major coronary event rates (% per year, aspirin vs control) 6.0 vs7.4 in post-MI trials and 2.4 vs3.0 in post-cerebral vascular disease trials; corresponding rates of stroke (mainly of unknown cause) 0.6 vs0.8 in post-MI trials and 3.9 vs4.7 in post-cerebral vascular disease trials.

Sponsorship: UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Community Biomed Programme.

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