Late alteplase 3- 4.5 hours

Two articles and one editorial
Hacke W. et al. NEJM 359:1317-1329 2008. Also called ECASS III
Trial replicated in many ways the seminal NINDS trials except studied the 3-4.5 hour period. 821 patients were enrolled and randomized 1:1 with primary endpoint being favorable outcome at 90 days (modified Rankin score of 0 or 1). Safety endpoints were death, symptomatic ICH and other SAE's. Median time of enrollment was 3 hours 59 minutes. Treated group had more favorable outcomes (52.4 v. 45.2 %) or stated otherwise number to treat to have one more good outcome is about 14. sICH occurred in 2.4 v. 0.2 % (NTT for one more symptomatic hemorrhage is 45). Overall hemorrhage was 27 v. 17.6 % (NTT for one more hemorrhage is about 11).

Criticism-- did not study severe strokes with high NIHSS scores. Editorial by Lyden P NEJM op cit. 1393-5 also noted study tended not to enroll as many diabetics. Editorial also pointed out data showing earlier treatment is more beneficial earlier and less beneficial later; treatment in 3-4.5 hour bloc is successively less successful than treatment in each earlier time bloc. Authors allowed use of small doses of SQ heparin after alteplase to prevent DVT's.

The article itself explains that prior trials of 3-4.5 hour window ECASS II and Atlantis, were not powered to detect a positive finding in 7-10 % range.

Alteplase in first 90 minutes after stroke is nearly twice as effective as in second ninety minute bloc. Odds ratio for global outcome in first 90 minites is 2.81, in second ninety minutes is 1.55, in the third 90 minutes is 1.40 (based on pooled analysis of prior studies) and in current study is 1.34 in third 90 minutes. Time to needle is still paramount.

The previous article from Lancet cited (Wahlgren et al. Lancet 2008, dubbed the SITS-ISTR trial Safe Implementation of Thrombolysis in Stroke) compared 664 patients receiving alteplase in 3-4.5 hour time period to 11,685 who received it in 3 hour window. The outcome was symptomatic intracranial hemorrhage in first 24 hours with NIHSS deterioration of 4 points or more, and 90 day outcome based on modified Rankin score of 0-2. The result was no difference in any outcome measure and the conclusion is that alteplase is safe when given 3-4.5 hours.