NEW ORLEANS—Intravenous tissue plasminogen activator (t-PA) is the only therapy approved by the FDA shown to reverse the effects of acute ischemic stroke. However, since it must be given within three hours of symptom onset after a confirmatory CT scan, annually only a fraction of the 560,000 patients who experience acute ischemic stroke receive t-PA. Strategies to widen the therapeutic window range from new drugs with improved features to an intra-arterial approach to better imaging techniques.

Researchers at Hospital Universitario Vall d’Hebron in Barcelona opted for the latter approach: Using a multimodal magnetic resonance protocol, they investigated the safety and efficacy of t-PA for the treatment of stroke from three to six hours of symptom onset.

“In a three-hour window, it is very likely that the artery remains occluded, with a considerable amount of savable tissue at risk; thus, most of the patients will benefit from t-PA,” said Marc Ribó, MD, at the 2005 International Stroke Conference. “On the other hand, in the three-to-six-hour window, there is a greater heterogeneity, either in the perfusion status or the ischemic lesion. Thus, information about indices of cerebral injury and perfusion are needed for an adequate selection because some patients will not benefit from t-PA.” Lack of efficacy of t-PA may result from early spontaneous reperfusion, failure to achieve recanalization, an underlying severe irreversible brain lesion, or induction of symptomatic intracerebral hemorrhage, he noted.

ISCHEMIC CHANGES

“Due to the artery occlusion, there is a progressive recruitment of the ischemic penumbra into the fully infarcted tissue. The speed of this recruitment may vary, and many factors can accelerate or slow down these processes, leading to wide interindividual differences in the savable tissue at risk at a certain point of ischemia. And this is especially true in the three-to-six-hour window,” Dr. Ribó reported. “CT scan offers accurate information about the presence of hemorrhage, but the information about the ischemic changes is rather scarce. Improvement in techniques may offer quantitative information about ischemic changes and perfusion status. Therefore, we hypothesized that a meticulous selection of patients with improved imaging techniques may extend the benefit of t-PA after six hours from symptom onset.”

The investigators evaluated all patients with stroke who were admitted within six hours of symptom onset and included those with transcranial Doppler–documented middle cerebral artery occlusion in the study. Patients admitted within three hours of symptom onset were treated according to standard CT-based selection criteria; patients in the three-to-six-hour window were classified according to a multimodal magnetic resonance protocol that included T2-diffusion-weighted imaging, magnetic resonance angiography, and perfusion-weighted imaging. “We used the diffusion/perfusion concept to allocate t-PA treatment; only those patients with a mismatch greater than 20% were treated with t-PA,” Dr. Ribó said.

After t-PA administration, continuous transcranial Doppler monitoring was used to assess clot location and recanalization rates. At 24 hours, the NIH Stroke Scale (NIHSS) was used to assess neurologic status. “We defined clinical improvement and worsening as a decrease or increase of 4 or more points on the scale, and we defined symptomatic intracranial hemorrhage as an increase of 4 points in the NIH scale, accompanied by the presence of any blood in the follow-up CT scan,” Dr. Ribó said. “Long-term outcome was assessed with the modified Rankin scale, and we defined a good outcome as a score lower than 3.”

Of 135 consecutive patients evaluated, 122 received t-PA: 79 in the three-hour window following CT selection criteria, and 43 of 56 in the three-to-six-hour window who met MRI inclusion criteria. Dr. Ribó said the “door to needle time” was 20 to 25 minutes.

Baseline demographics were similar between the two groups. Median age was 73 years in the group that received treatment within three hours and 69 years in those who received treatment within three to six hours; NIHSS score was 17 in both groups. Stroke etiology was cardioembolic in 52% of patients treated within three hours and 44% in the three-to-six-hour treatment group. No differences were observed between variables such as tobacco use; the presence of hypertension, diabetes mellitus, atrial fibrillation, myocardial infarction, or dyslipidemia; and glycemic and systolic blood pressure measurements.

Median time to treatment was 136 minutes (range, 60 to 180 minutes) in the patients treated within three hours of symptom onset and 223 minutes (range, 185 to 360 minutes) in the three-to-six-hour group.

IS IT IN THE CRITERIA?

“When we looked at rates of recanalization, we didn’t see any difference among both groups; 49% and 52% of the patients recanalized in the three-hour group and the three-to-six-hour group, respectively,” Dr. Ribó said. The rate of asymptomatic hemorrhagic transformation was similar: 19% (3.7% symptomatic) in the zero-to-three-hour patients and 27% (2.5% symptomatic) in the three-to-six-hour group.

In the 48 hours following t-PA administration, NIHSS scores decreased 6.3 and 6.1 points, respectively. At discharge, of those patients treated within three hours of symptom onset, 58% had improved, 30% were stable, and 12% had worsened. In the group treated in the three-to-six-hour window, 76% had improved, 27% were stable, and 7% had worsened.

“Most important, when we looked at the final outcome, we observed similar results: As high as 42% in the zero-to-three-hour group and 38% in the three-to-six-hour group achieved functional independence at three months, and only 14% and 12%, respectively, died. So t-PA treatment can be safely and effectively extended to the three-to-six-hour window using multimodal transcranial Doppler/MRI selection criteria,” Dr. Ribó said, adding that using these criteria can provide potentially effective treatment for a substantial number of patients.

NR

—Debra Hughes

Suggested Reading
Ribo M, Molina CA, Rovira A, et al. Safety and efficacy of intravenous tissue plasminogen activator stroke treatment in the 3- to 6-hour window using multimodal transcranial Doppler/MRI selection protocol. Stroke. 2005; 36:602-606.

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