Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials

Abstract

Background: Low-dose aspirin is of definite and substantial net benefit for many people who already have occlusive vascular disease. We have assessed the benefits and risks in primary prevention.

Methods: We undertook meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95,000 individuals at low average risk, 660,000 person-years, 3554 serious vascular events) and 16 secondary prevention trials (17,000 individuals at high average risk, 43,000 person-years, 3306 serious vascular events) that compared long-term aspirin versus control. We report intention-to-treat analyses of first events during the scheduled treatment period.

Findings: In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0.51% aspirin vs 0.57% control per year, p=0.0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0.18%vs 0.23% per year, p<0.0001). The net effect on stroke was not significant (0.20%vs 0.21% per year, p=0.4: haemorrhagic stroke 0.04%vs 0.03%, p=0.05; other stroke 0.16%vs 0.18% per year, p=0.08). Vascular mortality did not differ significantly (0.19%vs 0.19% per year, p=0.7). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0.10%vs 0.07% per year, p<0.0001), and the main risk factors for coronary disease were also risk factors for bleeding. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6.7%vs 8.2% per year, p<0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2.08%vs 2.54% per year, p=0.002) and in coronary events (4.3%vs 5.3% per year, p<0.0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women.

Interpretation: In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. Further trials are in progress.

Funding: UK Medical Research Council, British Heart Foundation, Cancer Research UK, and the European Community Biomed Programme.

Figure 1

Serious vascular events in primary prevention trials—proportional effects of aspirin allocation Actual numbers for aspirin-allocated trial participants, and adjusted numbers for control-allocated trial participants, are presented, together with the corresponding mean yearly event rate (in parentheses). Participants can contribute only once to the total of serious vascular events. Rate ratios (RRs) for all trials are indicated by squares and their 99% CIs by horizontal lines. Subtotals and their 95% CIs are represented by diamonds. Squares or diamonds to the left of the solid line indicate benefit. MI=myocardial infarction. CHD=coronary heart disease. *Myocardial infarction, stroke, or vascular death. Vascular death is coronary heart disease death, stroke death, or other vascular death (which includes sudden death, death from pulmonary embolism, and death from any haemorrhage, but in the primary prevention trials excludes death from an unknown cause).

Figure 2

Serious vascular events in primary prevention trials—subgroup analyses Actual numbers for aspirin-allocated trial participants, and adjusted numbers for control-allocated trial participants, are presented, together with the corresponding mean yearly event rates (in parentheses). Rate ratios (RRs) for all trials are indicated by squares and their 99% CIs by horizontal lines. Subtotals and their 95% CIs are represented by diamonds. Squares or diamonds to the left of the solid line indicate benefit. A global test for heterogeneity (χ² on 11 degrees of freedom) is provided. Unknown values are not plotted. SBP=systolic blood pressure. DBP=diastolic blood pressure. BMI=body-mass index. CHD=coronary heart disease. *Excluding patients with a history of vascular disease.

Figure 3

Selected outcomes in primary and secondary prevention trials of aspirin, by sex Actual numbers for aspirin-allocated trial participants, and adjusted numbers for control-allocated trial participants, are presented together with the corresponding mean yearly event rate (in parentheses). Rate ratios (RRs) for all trials are indicated by squares and their 99% CIs by horizontal lines. Subtotals and their 95% CIs are represented by diamonds. Squares or diamonds to the left of the solid line indicate benefit. *Myocardial infarction, stroke (haemorrhagic or other), or vascular death.

Figure 4

Stroke subtypes in primary and secondary prevention trials Actual numbers for aspirin-allocated trial participants, and adjusted numbers for control-allocated trial participants, are presented. Rate ratios (RRs) for all trials are indicated by squares and their 99% CIs by horizontal lines. Subtotals and their 95% CIs are represented by diamonds. Squares or diamonds to the left of the solid line indicate benefit. *Haemorrhagic, ischaemic, or unknown cause.

Figure 5

Mortality by cause in primary prevention trials Actual numbers for aspirin-allocated trial participants, and adjusted numbers for control-allocated trial participants, are presented together with the corresponding mean yearly event rate (in parentheses). Rate ratios (RRs) for all trials are indicated by squares and their 99% CIs by horizontal lines. Subtotals and their 95% CIs are represented by diamonds. Squares or diamonds to the left of the solid line indicate benefit. CHD=coronary heart disease. GI=gastointestinal.

Figure 6

Predicted 5-year absolute effects of allocation to aspirin in different categories of age and sex in the primary and secondary prevention trials (ignoring non-vascular mortality) Results are generally for otherwise untreated individuals; other risk reduction measures might approximately halve the vascular event rates in both aspirin (A) and control (C) groups. Three outcomes were analysed: non-fatal gastrointestinal (GI) (or other non-cerebral) bleeds in the primary prevention trials only; non-fatal vascular events in the primary trials and in the secondary trials; and vascular mortality (including any fatal bleeds) in the primary trials and in the secondary trials. For every outcome, the overall risk ratio (aspirin vs control in all participants, irrespective of age or sex) was combined with the absolute yearly risk among the controls in these four categories of sex and age. The risk ratios are those resulting from allocation to daily aspirin, so they underestimate the effects of actually taking aspirin for the whole 5-year period. MI=myocardial infarction.

Figure 7

Predicted 5-year absolute effects of allocation to aspirin in the primary prevention trials in different categories of 5-year risk (if untreated) of coronary heart disease (CHD) (ignoring non-vascular mortality) Three outcomes were analysed in aspirin (A) and control (C) groups: non-fatal gastrointestinal (GI) (or other non-cerebral) bleeds when aspirin is given alone; non-fatal vascular events when aspirin is given alone and when aspirin is added to other drugs that halve risk; and vascular mortality (including any fatal bleeds) when aspirin is given alone and when aspirin is added to other drugs that halve risk. For every outcome, the overall risk ratio, irrespective of risk of coronary heart disease, was combined with the absolute yearly risk among the controls in three categories of predicted 5-year risk of a major coronary event (<5%, 5–10%, >10%). Absolute effects are estimated both directly from the data (middle column) and in the hypothetical situation in which risk is halved by statins and other primary prevention measures (right-hand column).