Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study.

BACKGROUND: Intravenous alteplase is approved for use within 3 h of ischaemic stroke onset, although a meta-analysis of randomised controlled trials suggests treatment benefit up to 4.5 h. We compared outcome in patients treated between 3 h and 4.5 h versus those treated within 3 h, who were recorded in the in the Safe Implementation of Treatments in Stroke (SITS), a prospective internet-based audit of the International Stroke Thrombolysis Registry (ISTR).

METHODS: We compared 664 patients presenting with ischaemic stroke and given intravenous altepase (0.9 mg/kg total dose) between 3 h and 4.5 h with 11 865 patients treated within 3 h. All patients were otherwise compliant with European summary of product characteristics criteria and had been documented in the international stroke treatment registry between Dec 25, 2002, and Nov 15, 2007. Outcome measures were symptomatic intracerebral haemorrhage within 24 h (haemorrhage type 2 associated with National Institutes of Health Stroke Scale [NIHSS] > or = 4 points deterioration), and mortality and independence (modified Rankin scale of 0-2) at 3 months.

FINDINGS: In the 3-4.5-h cohort, treatment was started at a median of 55 min later after symptom onset (195 min [IQR 187-210] vs 140 min [115-165], p<0.0001), median age was 3 years younger (65 years [55-73] vs 68 years [58-74], p<0.0001), and stroke severity was lower (NIHSS score 11 [7-16] vs 12 [8-17], p<0.0001) than in the 3-h cohort. We recorded no significant differences between the 3-4.5-h cohort and the within 3-h cohort for any outcome measure--rate of symptomatic intracerebral haemorrhage: 2.2% (14 of 649) versus 1.6% (183 of 11 681) (odds ratio [OR] 1.18 [95% CI 0.89-1.55], p=0.24; adjusted OR 1.32 [1.00-1.75], p=0.052); mortality: 12.7% (70 of 551) versus 12.2% (1263 of 10 368) (OR 1.02 [0.90-1.17]; p=0.72; adjusted OR 1.15 [1.00-1.33]; p=0.053); and independence: 58.0% (314 of 541) versus 56.3% (5756 of 10231) (OR 1.04 [0.95-1.13], p=0.42; adjusted OR 0.93 [0.84-1.03], p=0.18).

INTERPRETATION: Alteplase remains safe when given at 3-4.5 h after ischaemic stroke, offering an opportunity for patients who cannot be treated within the standard 3-h timeframe.

FUNDING: Boehringer-Ingelheim, European Union Public Health Executive Authority.