Early Thrombolysis Reduces Post-stroke Disability

Daniel M. Keller, PhD

November 11, 2014

ISTANBUL, Turkey — 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, a recent meta-analysis shows.

"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," Peter Sandercock, MD, professor of medical neurology at the University of Edinburgh, United Kingdom, reported.

Dr Sandercock reported the new results here at the 9th World Stroke Congress (WSC) on behalf of the Stroke Thrombolysis Trialists' Collaboration, a cooperative effort among trialists and 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.

Dr Sandercock showed 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, he said.

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.

Expressed another way, Dr Sandercock said, "for every 100 patients treated within 3 hours, an additional 10 make a full recovery, and between 3 and 4 and a half hours, [an additional] five will make a full recovery."

Table. Proportion of Patients Achieving mRS Score of 0 or 1 at 3 to 6 Months

Treatment Delay tPA (n = 3391) (%) Control (n = 3365) (%)
≤3 h 33 23
>3 and ≤4.5 h 35 30
>4.5 h 33 31


Compared with controls, patients treated with tPA had an increased risk for ICH or death within 7 days. The relative risk for ICH was 5.55 to 6.67, depending on the criteria used. The relative risk for fatal ICH within 7 days was 7.14.

But by 3 months, the mortality rate was 17.9% for the tPA recipients vs 16.5% for controls, yielding a relative risk of 1.11 (95% confidence interval, 0.99 - 1.25), which was not a statistically significant difference.

Dr Sandercock summarized the results, saying that 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.

Asked for comment about the study, session moderator Joseph Broderick, MD, professor of neurology at the University of Cincinnati Neuroscience Institute in Ohio, said that the beneficial effect of tPA was lost if it was administered at 5 hours or later after stroke onset.

"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," he told Medscape Medical News. A 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."

Dr Sandercock and Dr Broderick have disclosed no relevant financial relationships.

9th World Stroke Congress (WSC). Session FC01 (no abstract number). Presented October 23, 2014.


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