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Although beneficial within 4.5 hours of stroke onset, administering recombinant tissue plasminogen activator (tPA) beyond that window appears to increase the risk of dying, a pooled analysis of eight clinical trials showed.

Compared with placebo, alteplase (Activase) administration beyond 4.5 hours was associated with a 1.49-fold increase in the odds of dying (OR 1.49, 95% CI 1.00 to 2.21), according to Kennedy Lees, MD, of the University of Glasgow, and colleagues.

There was no effect of alteplase on mortality in the earlier time window but a clear benefit for functional outcomes, the researchers reported in the May 15 issue of The Lancet.

The information, which reinforces the idea that earlier treatment is better, might help assist in clinical decision-making, they wrote.

"The stroke community is expending much effort to identify patients who might benefit from treatment given at the end of the therapeutic time window," Lees and his colleagues wrote.

"However, the pooled data suggest that the greatest population benefit would occur by treating more patients early, and by improving the effectiveness of alteplase by getting more arteries open quickly," they continued. "We should organize our services to make early thrombolysis possible more often."

Agreeing in an accompanying editorial were Jeffrey Saver, MD, of the University of California Los Angeles, and Steven Levine, MD, of Mount Sinai Medical Center in New York City.

Earlier treatment could be accomplished, they wrote, "by better educating the public to recognize stroke warning signs and activate the emergency medical system at the first sign of potential stroke, training prehospital personnel to scoop and go, having field personnel provide prearrival notification to receiving centers, and by routing ambulances carrying possible stroke patients directly to designated stroke centers."

Stroke centers should also take steps to achieve door-to-needle times of less than an hour in the majority of patients, they said.

Studies have demonstrated the benefits of early administration of tPA following an ischemic stroke.

Last year, the American Heart Association/American Stroke Association broadened its recommendation for timing of tPA administration from within three hours of stroke onset to within 4.5 hours based on recent trial results.

Lees and his colleagues added data from two recent trials -- ECASS III and EPITHET -- to those from six older trials -- two NINDS trials, the first two ECASS trials, and two ATLANTIS trials.

Overall, there were 1,850 patients who received alteplase within six hours and 1,820 who received placebo. The mean age of the patients was 66 and the mean time from stroke onset to treatment was 233 minutes (3.88 hours).

The odds of having a favorable outcome at three months follow-up, defined as a Rankin score of 0 or 1, declined significantly as treatment time increased (P=0.0269).

Compared with placebo, the odds of a favorable outcome with alteplase in each time window were as follows:

• OR 2.55 (95% CI 1.44 to 4.52) for up to 90 minutes
• OR 1.64 (95% CI 1.12 to 2.40) for 91 to 180 minutes
• OR 1.34 (95% CI 1.06 to 1.68) for 181 to 270 minutes
• OR 1.22 (95% CI 0.92 to 1.61) for 271 to 360 minutes

The benefit disappeared after 4.5 hours (270 minutes).

At treatment times less than 4.5 hours after stroke onset, there was no significant association between mortality and use of alteplase.

However, the odds of dying in the alteplase group increased with growing delay in treatment time (P=0.0444), with significantly elevated odds of dying among patients who received tPA from 4.5 hours to six hours after stroke onset compared with those who received placebo.

The higher mortality risk does not appear to be related to the higher rate of large parenchymal hemorrhage in the alteplase group (5.2% versus 1%) because there was no significant relationship between this outcome and time to treatment (P=0.4140).

But editorialists Saver and Levine said that severe parenchymal hemorrhages may have actually increased with time, noting that the study was underpowered to detect the trend.

They said another three possibilities to explain the increase in mortality were:

• "Small parenchymal hematomas (type 1) increase mortality mildly, and probably increased, as did all hemorrhages, with time.
• Treatment-induced mortality was not increasing but was steady over time while treatment-induced rescue from mortality declined with time, yielding a net mortality increase.
• Reperfusion attempts at later times might have increased cerebral edemas that were potentially fatal."