Abstract
SummaryBackgroundAspirin 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.MethodsPooling 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.FindingsWe 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).InterpretationOur 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.FundingWellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford.
Highlights
The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke.[1,2,3,4] Urgent medical treatment seems to reduce that risk by as much as 80%,5,6 but many patients delay seeking medical attention, often for several days or weeks, even when they make a correct self-diagnosis.[7,8] Public education campaigns, such as the FAST test television campaign, www.thelancet.com Vol 388 July 23, 2016Research in contextEvidence before this study Previous systematic reviews of randomised trials of aspirin versus placebo in secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke reported only a 13% relative reduction in risk of recurrent stroke
We identified 12 trials of 15 778 participants that assessed aspirin versus control in secondary prevention after TIA or ischaemic stroke
Aspirin reduced the severity of recurrent ischaemic stroke during the 6 weeks after randomisation, with a similar effect seen at 12 weeks and when analyses were based only on an modified Rankin Scale (mRS) score higher than 2
Summary
The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke.[1,2,3,4] Urgent medical treatment seems to reduce that risk by as much as 80%,5,6 but many patients delay seeking medical attention, often for several days or weeks, even when they make a correct self-diagnosis.[7,8] Public education campaigns, such as the FAST test television campaign, www.thelancet.com Vol 388 July 23, 2016. Evidence before this study Previous systematic reviews of randomised trials of aspirin versus placebo in secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke reported only a 13% relative reduction in risk of recurrent stroke. We did a pooled analysis of individual patient data from all available trials of aspirin versus control after TIA or ischaemic stroke
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