Thrombolysis 3-4.5 Hours After Stroke Onset May Increase Mortality Without Clear Benefit

EBM Focus - Volume 10, Issue 11

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Reference: BMJ 2015;350:h1075

Thrombolysis with alteplase (tissue-type plasminogen activator, t-PA) given up to 3 hours after the onset of acute ischemic stroke is associated with an increased likelihood of survival without disability at 90 days. Multiple systematic reviews have suggested the benefit of t-PA is found for use up to 4.5 hours after stroke onset. The data supporting t-PA for up to 4.5 hours after stroke onset has led to strong recommendations for such use in guidelines in the United States, United Kingdom, Canada, Europe, France, Japan, Australia, and South Africa. Drug licensing for t-PA after stroke is limited to the first 3 hours in the US but is extended to 4.5 hours in the UK and Australia.

A recent analysis of the data looking specifically at the 3-4.5 hour timeframe (with coauthors including DynaMed Editors Brian S. Alper, MD, MSPH, FAAFP, Meghan Malone-Moses, MPH, and James S. McLellan, PhD) found consistent evidence that t-PA use during this time window increases the risk for symptomatic intracranial hemorrhage and fatal intracranial hemorrhage within 7 days (level 1 [likely reliable] evidence), with a best current estimate of the number needed to harm (NNH) of 44 for fatal intracranial hemorrhage. t-PA during this time window might also increase 90-day mortality (level 2 [mid-level] evidence) (NNH 49), but this result was not statistically significant (hazard ratio 1.14, 95% CI 0.95-1.36).

The evidence for the effects of t-PA use on functional independence, however, is uncertain and inconsistent. The one trial reporting significant benefit (ECASS III with 821 patients, N Engl J Med 2008 Sep 25;359(13):1317) had baseline differences in prior stroke history potentially biasing the conclusion. In ECASS III, t-PA was associated with an increased likelihood of survival without any disability (NNT 14). The benefit observed in this trial was no longer statistically significant in a 2014 report limited to the 89% of ECASS III patients without a history of prior stroke. The largest trial (IST-3, Lancet 2012 Jun 23;379(9834):2352) was unblinded. In the subgroup of 1,177 patients treated 3-4.5 hours after stroke, t-PA was associated with a decreased likelihood of survival without moderate or severe disability (NNH 16).

Analyses of these trials and others have been reported in reviews suggesting an overall benefit of t-PA use at 3-4.5 hours after stroke onset. Guidelines have used these results to recommend such therapy, but the conclusions of these reviews and original trial reports do not clearly match the underlying data when viewed precisely for the 3-4.5 hour time window. This examination of the inconsistencies between the data and their interpretation calls for a re-evaluation of guidelines and drug licensing considerations. Until policy-makers can fully evaluate the underlying data and update recommendations, clinicians should be aware of the potential for harm and uncertainty regarding benefit when considering t-PA more than 3 hours after stroke onset.

For more information, see the Thrombolytics for acute stroke topic in DynaMed.