Early Thrombolysis Reduces Post-stroke Disability

Intravenous recombinant tissue plasminogen activator (tPA) within 4.5 hours of the onset of acute ischemic stroke increases the early risk for death but gives better odds of surviving without significant disability and possibly yields later mortality benefits.

Earlier treatment results in bigger proportional benefits, and tPA, although it does increase the early risk of death from intracerebral hemorrhage, has no significant effect on other causes of early death.

New results at the 9th World Stroke Congress  on behalf of the Stroke Thrombolysis Trialists  meta-analysts.

Support for Current Treatment Window

The study involved data from nine trials comprising 6756 randomly assigned patients. It sought to assess the effect of treatment delay in administering tPA on stroke outcome, the independent effects of age or stroke severity, and the effects of tPA on the risk for symptomatic intracranial hemorrhage (ICH) and death.

The primary efficacy endpoint was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 at 3 to 6 months.

One of the nine trials was the recently completed Third International Stroke Trial (IST-3; n = 3035), which had an average treatment delay of 4.2±1.2 hours. Notably, 53% of the patients were older than 80 years. The other eight previous trials (n = 3721) had an average treatment delay of 3.9±1.2 hours and only 3% of patients older than 80 years.

The average age of IST-3 patients was 77 years vs 66 years for the patients in the other trials. The National Institutes of Health Stroke Scale scores were 12 for both IST-3 and for the eight other studies combined.

A graph of the time to tPA treatment vs the likelihood of achieving a very good outcome of an mRS of 0 or 1.

Treatment at 1 hour was associated with an odds ratio of approximately 1.85, which diminished to about 1.2 at 5 hours.

Therefore, the current time window of 4.5 hours after stroke onset seems reasonable.

Treatment with tPA at up to 3 hours showed a benefit on mRS scores at 3 to 6 months compared with control cases.

The benefit diminished the later that tPA was administered; for every 100 patients treated within 3 hours, an additional 10 make a full recovery, and between 3 and 4 and a half hours.
Proportion of Patients Achieving mRS Score of 0 or 1 at 3 to 6 Months

image

Compared with controls, patients treated with tPA had an increased risk for ICH or death within 7 days.

3 months, the mortality rate was 17.9% for the tPA recipients vs 16.5% for controls, yielding a relative risk of 1.11  which was not a statistically significant difference.

Summari the results earlier treatment yielded bigger proportional benefits and that tPA within 4.5 hours of stroke onset improved the odds of surviving with no significant disability, even among patients older than 80 years.

An early risk for death from ICH in the tPA group appeared to be offset by later survival benefits.

The reality is that when you get beyond 4 and a half hours, you lose the signal of decreasing morbidity, but you also actually pick up a few more deaths; remaining question is whether some subgroup that would benefit from tPA beyond these time points could be identified.

Regarding the increased mortality out to 7 days, he noted that every effective treatment can have risks because if you have something that’s mechanistically very strong it almost always has a negative side to it.

9th World Stroke Congress October 23, 2014.

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