Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials

Abstract

Background: 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.

Copyright © 2016 Rothwell et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Pooled analysis of the early risk of recurrent vascular events in 12 trials of any aspirin versus control Statistical significance calculated with the log-rank test. TIA=transient ischaemic attack. HR=hazard ratio.

Figure 2

Pooled analysis of the effect of aspirin only versus control in secondary prevention after transient ischaemic attack and ischaemic stroke on the absolute risk of recurrent ischaemic stroke Time course of treatment effect interaction: pinteraction<0·0001 for both outcomes.

Figure 3

Pooled analysis of the effect of aspirin versus control on the severity (mRS score on follow-up) of recurrent ischaemic stroke in the first 6 weeks and the first 12 weeks after randomisation in trials in secondary prevention after transient ischaemic attack and ischaemic stroke OR=odds ratio. mRS=modified Rankin Scale.

Figure 4

Pooled hazard ratios for the effect of aspirin versus control on risk of recurrent ischaemic stroke in patients with mild and moderately severe initial neurological deficits during early follow-up in Chinese Acute Stroke Trial and International Stroke Trial, Data plotted at median timepoint for the following follow-up periods from randomisation: days 0–1, days 2–3, days 4–6, days 7–14, after 15 days. Error bars show 95% CIs. This analysis excludes 3292 (21%) patients with mild or moderately severe stroke in the International Stroke Trial who had received aspirin during the days before randomisation. The equivalent analysis with these patients included is in appendix p 6.