Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis

Abstract

Background: Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis.

Methods: We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke.

Findings: In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0-2) at final follow-up (1611/3483 [46·3%] vs 1434/3404 [42·1%], OR 1·17, 95% CI 1·06-1·29; p=0·001), absolute increase of 42 (19-66) per 1000 people treated, and favourable outcome (mRS 0-1) absolute increase of 55 (95% CI 33-77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0-2, 365/896 [40·7%] vs 280/883 [31·7%], 1·53, 1·26-1·86, p<0·0001), absolute benefit of 90 (46-135) per 1000 people treated, and mRS 0-1 (283/896 [31·6%] vs 202/883 [22·9%], 1·61, 1·30-1·90; p<0·0001), absolute benefit 87 (46-128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8·9%] vs 174/2728 [6·4%], 1·44, 1·18-1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 [19·1%] vs 640/3464 [18·5%], 1·06, 0·94-1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 [7·7%] vs 63/3463 [1·8%], 3·72, 2·98-4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early.

Interpretation: The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke.

Funding: UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.

Figure 1

Effects of rt-PA on early outcomes (7 days) Data are numbers, unless otherwise indicated. Degrees of freedom is 1. Treatment was administered up to 6 h after the stroke. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial.

Figure 2

Effects of rt-PA on outcomes at final follow-up Data are numbers, unless otherwise indicated. Treatment was administered up to 6 h after the stroke. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial. mRS=modified Rankin Scale.

Figure 3

Effects of rt-PA on alive and independent (mRS 0–2) and death by the end of follow-up and on symptomatic intracranial haemorrhage within the first 7 days, by time to treatment Data are numbers, unless otherwise indicated. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial. mRS=modified Rankin Scale.

Figure 4

Effect of rt-PA on alive and independent at the end of follow-up, subgrouped by age and time to treatment Data are numbers, unless otherwise indicated. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial.