Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials

Abstract

Background: Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase.

Methods: We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality.

Findings: Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h.

Interpretation: Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits.

Funding: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Figure 1

Effect of timing of alteplase treatment on good stroke outcome (mRS 0–1) The solid line is the best linear fit between the log odds ratio for a good stroke outcome for patients given alteplase compared with those given control (vertical axis) and treatment delay (horizontal axis; p_interaction=0·016). Estimates are derived from a regression model in which alteplase, time to treatment, age, and stroke severity (handled in a quadratic manner) are included as main effects but the only treatment interaction included is with time to treatment. Only 198 patients (159 from IST–3) had a time from stroke onset to treatment of more than 6 h. The white box shows the point at which the estimated treatment effect crosses 1. The black box shows the point at which the lower 95% CI for the estimated treatment effect first crosses 1·0. mRS=modified Rankin Scale.

Figure 2

Effect of alteplase on good stroke outcome (mRS 0–1), by treatment delay, age, and stroke severity *For each of the three baseline characteristics, estimates were derived from a single logistic regression model stratified by trial, which enables separate estimation of the OR for each subgroup after adjustment for the other two baseline characteristics (but not for possible interactions with those characteristics). mRS=modified Rankin Scale.

Figure 3

Effect of alteplase on a good stroke outcome (mRS 0–1) by age, with different treatment delays Effect of age on the interaction between treatment delay and treatment effect p=0·08 (ie, not significant but, if anything, in the direction of it lengthening, not shortening, the period during which alteplase is effective in older people). *All six estimates derived from a single stratified logistic regression model that enables the odds ratio to be estimated separately for each group (also adjusted for baseline National Institutes of Health Stroke Scale score). mRS=modified Rankin Scale.

Figure 4

Effect of alteplase on fatal intracranial haemorrhage within 7 days by treatment delay, age, and stroke severity *For each of the three baseline characteristics, estimates were derived from a single logistic regression model stratified by trial, which enables separate estimation of the OR for each subgroup after adjustment for the other two baseline characteristics (but not possible interactions with those characteristics). The overall effect in all patients is the trial-stratified logistic regression estimate adjusted only for treatment allocation. NE=not estimable.

Figure 5

Effect of alteplase on 90-day mortality by follow-up period Patients can only contribute to a particular risk period if they have already survived any preceding periods. *Estimated by Cox proportional hazards regression stratified by trial (and adjusted only for treatment allocation). †Includes 91 versus 13 deaths caused by intracranial haemorrhage (with evidence of parenchymal haemorrhage type 2; figure 4) and 191 versus 191 deaths from other causes.

Figure 6

Effect of alteplase on 90-day mortality by treatment delay *Estimated by Cox proportional hazards regression stratified by trial (and adjusted only for treatment allocation). HR=hazard ratio.