Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke: reanalysis of ECASS III trial to assess robustness of findings across statistical models

Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke: reanalysis of ECASS III trial to assess robustness of findings across statistical models

None

None of the research team has any financial conflicts of interest related to the use of alteplase for the treatment of stroke. The research team members other than the statistician have published a summary of available evidence on thrombolytics for stroke and noted the absence of an independent analysis of this data. The research team has no pre-existing desire to find “for” or “against” any particular outcome but is engaged in following through on developing and reporting this independent analysis.

For many patients the only available treatment for reversing the effects of a stroke is alteplase, a drug that breaks up blood clots. When a stroke is caused by blood clots in the arteries leading to the brain, using alteplase soon after stroke onset may reverse the process and minimize the brain damage that occurs which in turn leads to more patients surviving the stroke with less functional deficit. However, a stroke involves damaged brain tissue and a risk or side effect of using a clot-busting drug can be bleeding at the site of this damaged brain tissue which results in a serious worsening of function and can cause death.

Alteplase was initially used up to 3 hours following stroke onset based on a trial reported in 1995 showing such use would increase the chance of being alive with minimal symptoms three months after a stroke. A trial reported in 1999 that tested use of alteplase 3-5 hours after stroke onset did not find this benefit but found an increase in the chance of dying from bleeding. For many years the standard of stroke treatment was the use of alteplase within 3 hours of stroke onset and not after 3 hours.

In 2008 the ECASS III trial reported that use of alteplase 3-4.5 hours after stroke increased the chance of being alive with minimal symptoms 3 months after stroke. However it is unclear how much of this difference is related to the effect of the drug (a true benefit) and how much is related to differences between the drug group and the placebo group that were occurring at the time of trial entry (called baseline difference, leading to a false signal of benefit). There are multiple valid methods for adjusting for baseline differences. Analyses using these different methods would further support the finding of “true benefit” if the results are consistent (considered robustness of results), whereas finding different results would mean that we are less certain the “benefit” is related to use of alteplase and more concerned the results are influenced by baseline differences.

We will evaluate the ECASS III trial data for three functional outcome measures at 90 days after stroke (being alive with no symptoms, being alive with minimal symptoms, and being alive without dependence) and three adverse effect outcome measures (symptomatic bleeding in the head at 7 days, death at 7 days, and death at 90 days) with analyses adjusting for baseline differences in different ways.

When completed, the ability to view the spectrum of outcomes (and not just a selection of outcomes) and the robustness of these results will allow clinical decision-makers and policy-makers a greater view to expected results with the alteplase decision in this timeframe. These results will be reported publicly through a major medical journal.

The results will help patients (or their proxy) further understand and balance the risks and benefits while deciding to consent for alteplase therapy.

[{ "PostingID": 3097, "Title": "*BI-135.312", "Description": "ECASS III - European Cooperative Acute Stroke Study III: A Placebo Controlled Trial of Alteplase (Rt-PA) in Acute Ischemic Hemispheric Stroke Where Thrombolysis is Initiated Between 3 and 4 Hours 30 Minutes After Stroke Onset

Medicine: alteplase, Condition: Acute Ischemic Hemispheric Stroke, Phase: 3, Clinical Study ID: 135.312, Sponsor: Boehringer Ingelheim" }]

The publication citation will be added after the research is published.