Early administration of intravenous recombinant tissue plasminogen activator (rt-PA)
after ischaemic stroke improves outcome. Previous analysis of combined data from individual
patients suggested potential benefit beyond 3 h from stroke onset. We re-examined
the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic
benefit and clinical risk by adding recent trial data to the analysis.
We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of
common data elements from six other trials of alteplase for acute stroke (2775 patients).
We used multivariate logistic regression to assess the relation of stroke onset to
start of treatment (OTT) with treatment on favourable 3-month outcome (defined as
modified Rankin score 0-1), mortality, and occurrence and outcome of clinically relevant
parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the
patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke.
Vascular imaging was not a requirement in the trials. All patients with confirmed
OTT within 360 min were included in the analysis.
Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated
to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome
increased as OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen
after around 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95%
CI 1.44-4.52) for 0-90 min, 1.64 (1.12-2.40) for 91-180 min, 1.34 (1.06-1.68) for
181-270 min, and 1.22 (0.92-1.61) for 271-360 min in favour of the alteplase group.
Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase
and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted
odds of mortality increased with OTT (p=0.0444) and were 0.78 (0.41-1.48) for 0-90
min, 1.13 (0.70-1.82) for 91-180 min, 1.22 (0.87-1.71) for 181-270 min, and 1.49 (1.00-2.21)
for 271-360 min.
Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous
alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort
should be taken to shorten delay in initiation of treatment. Beyond 4.5 h, risk might
outweigh benefit.
None.
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