Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial.
BACKGROUND
In the European Cooperative Acute Stroke Study III (ECASS III), alteplase administered 3.0-4.5 h after the onset of stroke symptoms resulted in a significant benefit in the primary endpoint (modified Rankin scale [mRS] score 0-1) versus placebo, with no difference in mortality between the treatment groups. Compared with the 0-3 h window, there was no excess risk of symptomatic intracranial haemorrhage. We assessed the usefulness of additional endpoints and did subgroup and sensitivity analyses to further investigate the benefit of alteplase.


METHODS
In a double-blind, multicentre study in Europe, patients with acute ischaemic stroke were randomly assigned to intravenous alteplase (0.9 mg/kg bodyweight) or placebo. Additional outcome analyses included functional endpoints at day 90 or day 30 (mRS 0-1 [day 30], mRS 0-2, Barthel index > or =85, and global outcome statistic [day 30]) and treatment response (8-point improvement from baseline or 0-1 score on the National Institutes of Health stroke scale [NIHSS], and a stratified responder analysis by baseline NIHSS score). The subgroup analyses were based on the mRS 0-1 at day 90, symptomatic intracranial haemorrhage, and death. Analyses were by intention to treat and per protocol. This study is registered with ClinicalTrials.gov, number NCT00153036.


RESULTS
418 patients were assigned to alteplase and 403 to placebo. Although not significant in every case, all additional endpoints showed at least a clear trend in favour of alteplase. Alteplase was effective in various subgroups, including older patients (<65 years: odds ratio 1.61, 95% CI 1.05-2.48; > or =65 years: 1.15, 0.80-1.64; p=0.230), and the effectiveness was independent of the severity of stroke at baseline (NIHSS 0-9: 1.28, 0.84-1.96; NIHSS 10-19: 1.16, 0.73-1.84; NIHSS > or =20: 2.32, 0.61-8.90; p=0.631). The incidence of symptomatic intracranial haemorrhage seemed to be independent of previous antiplatelet drug use (no: 2.41, 1.09-5.33; yes: 2.33, 0.79-6.90; p=0.962) and time from onset of symptoms to treatment (181-210 min: 1.62, 0.26-10.25; 211-240 min: 1.97, 0.82-4.76; 241-270 min: 3.15, 1.01-9.79; p=0.761), but not of age dichotomised at 65 years (<65 years: 0.74, 0.28-1.96; > or =65 years: 5.79, 2.18-15.39; p=0.004).


CONCLUSIONS
Our results support the use of alteplase up to 4.5 h after the onset of stroke symptoms across a broad range of subgroups of patients who meet the requirements of the European product label but miss the approved treatment window of 0-3 h.


BACKGROUND
Boehringer Ingelheim.
Bluhmki
Erich
E
Department of Statistics, Boehringer Ingelheim, Biberach, Germany.
Chamorro
Angel
A
Dávalos
Antoni
A
Machnig
Thomas
T
Sauce
Christophe
C
Wahlgren
Nils
N
Wardlaw
Joanna
J
Hacke
Werner
W
D000367:Age Factors; D000368:Aged; D002545:Brain Ischemia / Q000150:complications*; D004311:Double-Blind Method; D023381:Endpoint Determination; D005060:Europe; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012107:Research Design; D020521:Stroke / Q000209:etiology / Q000628:therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator