rt-PA Stroke Trials: Pooled Analysis and Opinion

Abstracts & Commentary

Sources: The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: Pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363:768-774; Caplan LR. Thrombolysis 2004: The good, the bad, and the ugly. Reviews in Neurological Diseases. 2004;1:16-26.

Thrombolysis with intravenous rt-PA (IVrt-PA) is an effective treatment for strokes due to acute cerebral ischemia. Six large, multicenter, randomized, placebo-controlled trials tested the benefits of IVrt-PA for acute stroke within 6 hours of onset (NINDS stroke trial parts 1 and 2, ECASS I and II, and ATLANTIS A and B). The investigators used similar doses of IVrt-PA and had common outcome measures, but the maximum time allowed from stroke onset to start of treatment (OTT) ranged from 3 to 6 hours. The 2 NINDS trials allowed a 3-hour window for treatment and the 2 ECASS trials a 6-hour window; ATLANTIS part A allowed a 6-hour window and part B a 5-hour window. A subsequent analysis of the NINDS trial data indicated that the chance of benefit from IVrt-PA diminished as time elapsed during the first 3 hours after stroke onset.1

In order to determine whether time-to-treatment with IVrt-PA is a critical predictor of therapeutic benefit, the authors pooled common data from the 6 randomized stroke trials. Using multivariable logistic regression, they assessed the relation of OTT on favorable 3-month outcome and the occurrence of clinically relevant cerebral hemorrhage.

Treatment was started within 6 hours of stroke onset in almost 3000 patients randomly allocated to IVrt-PA or placebo. Median age was 68 years. Ethnic background was reported as white in 85%, black in 9%, Hispanic in 2%, Asian in 1%, and "other" or not recorded in 3%. Median baseline National Institute of Health Stroke Scale (NIHSS) score was 11. The median OTT was 243 minutes. Two-thirds of patients were treated more than 180 minutes after symptom onset.

Odds ratios for favorable outcome at 3 months by OTT and NIHSS category were calculated with adjustment for age, baseline glucose concentration, baseline diastolic blood pressure, and previous hypertension. Odds of a favorable 3-month outcome significantly increased as OTT decreased. Odds were 2.8 for 0-90 min, 1.6 for 91-180 min, 1.4 for 181-270 min, and 1.2 for 271-360 min, in favor of the rt-PA group. The hazard ratio for death, adjusted for baseline NIHSS, was 1.0 for all intervals from 0 to 270 min. For the 271-360 min interval, it was 1.45. Cerebral hemorrhage was significantly more common in rt-PA patients (6%) than in controls (1%). Sixty percent of those with parenchymal hematoma died within 3 months (62% in the rt-PA group and 47% in the placebo group). Median age of patients with cerebral hemorrhage was 72 years; median OTT was 261 min (180-300 min) and median baseline NIHSS score was 12 (8-16). Hemorrhage was not associated with OTT or baseline NIHSS score but was significantly associated with rt-PA treatment and age.

This analysis of pooled data confirms that the sooner rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 minutes. The results suggest a potential benefit beyond 3 hours but with a potential for an increased risk of death.

In the inaugural issue of Reviews in Neurological Diseases, Louis Caplan reviews the investigations that preceded and follows the FDA approval and release of rt-PA for clinical use 8 years ago. He presents the current guidelines for the use of IV and intraarterial rt-PA, and in his role as a "2000-year-old" clinician offers his recommendations and sage advice for the acute treatment of ischemic stroke.

Commentary

The pooled analysis of 6 trials of thrombolytic therapy helps to define the limits of the treatment window for rt-PT. Although the results suggest that the benefit of rt-PA could extend beyond 3 hours, it does not extend beyond 6 hours. The odds of a favorable outcome were not different from 1.0 at 360 min. The apparent reduction in benefit from rt-PA at later periods did not result from an increased rate of parenchymal hemorrhage. The investigators surmise that the progressive disappearance of the ischemic penumbra probably accounts for the declining benefit of thrombolytic treatment with time. Nevertheless, subgroups of patients who continue to have potentially viable ischemic brain tissue at later times might still have substantial benefits from treatment. The task of future studies will be to identify such patients who might respond to treatment at the later end or even beyond the suggested therapeutic window. — John J. Caronna, MD, Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital and Associate Editor of Neurology Alert.

Reference

1. Marler JR, et al. Neurology. 2000;55:1649-1655.