Aspirin is recommended for
secondary prevention after transient ischaemic attack (TIA) or
ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent
stroke. However, the risk of major
stroke is very high for only the first few days after TIA and minor
ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early
aspirin have been underestimated.
METHODS: Pooling the individual patient data from all randomised trials of
aspirin versus control in
secondary prevention after TIA or
ischaemic stroke, we studied the effects of
aspirin on the risk and severity of recurrent
stroke, stratified by the following time periods: less than 6 weeks, 6-12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent
strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of
aspirin and
dipyridamole in
secondary prevention of
stroke. In a further analysis we pooled data from trials of
aspirin versus control in which patients were randomised less than 48 h after major
acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of
aspirin on risk of recurrent
ischaemic stroke and how this differs by severity at baseline.
FINDINGS: We pooled data for 15,778 participants from 12 trials of
aspirin versus control in
secondary prevention.
Aspirin reduced the 6 week risk of recurrent
ischaemic stroke by about 60% (84 of 8452 participants in the
aspirin group had an
ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0·42, 95% CI 0·32-0·55, p<0·0001) and disabling or fatal
ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0·29, 0·20-0·42, p<0·0001), with greatest benefit noted in patients presenting with TIA or minor
stroke (at 0-2 weeks, two of 6691 participants in the
aspirin group with TIA or minor
stroke had a disabling or fatal
ischaemic stroke vs 23 of 5726 in the control group, HR 0·07, 95% CI 0·02-0·31, p=0·0004; at 0-6 weeks, 14 vs 60 participants, 0·19, 0·11-0·34, p<0·0001). The effect of
aspirin on early recurrent
ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0·42, 0·26-0·70, p=0·0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or
stroke. Some further reduction in risk of
ischaemic stroke accrued for
aspirin only versus control from 6-12 weeks, but there was no benefit after 12 weeks (
stroke risk OR 0·97, 0·84-1·12, p=0·67; severity mRS shift OR 1·00, 0·77-1·29, p=0·97). By contrast,
dipyridamole plus
aspirin versus
aspirin alone had no effect on risk or severity of recurrent
ischaemic stroke within 12 weeks (OR 0·90, 95% CI 0·65-1·25, p=0·53; mRS shift OR 0·90, 0·37-1·72, p=0·99), but
dipyridamole did reduce risk thereafter (0·76, 0·63-0·92, p=0·005), particularly of disabling or fatal
ischaemic stroke (0·64, 0·49-0·84, p=0·0010). We pooled data for 40,531 participants from three trials of
aspirin versus control in major
acute stroke. The reduction in risk of recurrent
ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2-3 day HR 0·37, 95% CI 0·25-0·57, p<0·0001).
INTERPRETATION: Our findings confirm that medical treatment substantially reduces the risk of early recurrent
stroke after TIA and minor
stroke and identify
aspirin as the key intervention. The considerable early benefit from
aspirin warrants public education about
self-administration after possible TIA. The previously unrecognised effect of
aspirin on severity of early recurrent
stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of
dipyridamole have implications for understanding mechanisms of action.
FUNDING: Wellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford.