PHOENIX—Researchers appear to be closer to extending the treatment window for therapy in acute stroke. In a study of 133 patients presenting with acute ischemic stroke, investigators at the University of Heidelberg in Germany discovered that patients treated with tissue plasminogen activator (t-PA) between three and six hours after stroke onset had a rate of mortality (4%) and symptomatic intracranial bleeding (4.5%) at three months comparable to patients treated within three hours (15.7% and 5.6%, respectively). The three- to six-hour group also had a higher ratio of patients with no or mild disability (63.6% versus 49.4% in the up-to-three-hour group).

MOVING AWAY FROM THE CLOCK

A key to the Heidelberg group’s protocol for treating patients beyond the accepted treatment window is the use of MRI. Patients who arrived at the hospital within three hours of symptom onset were given a CT scan to rule out hemorrhage and received intravenous t-PA if they met certain eligibility criteria, according to the strict protocol-based National Institute of Neurological Disorders and Stroke (NINDS) rt-PA study.

When a patient fell into the three- to six-hour window, however, the investigators dispensed with the NINDS protocol in favor of an MR-based algorithm, including use of diffusion-weighted imaging, perfusion-weighted imaging, and MR angiography. Treatment with intravenous t-PA was given only to those patients for whom the MRI scans demonstrated a diffusion/perfusion mismatch, indicating the presence of salvageable brain tissue.

The future of thrombolytic therapy may involve moving away from a rigid adherence to the clock and more toward using the brain itself as a measure for determining eligibility, suggested lead author Sonja Külkens, MD. “We believe that our algorithm is one way to get a more pathophysiologic-based treatment of acute ischemic stroke instead of the strictly time-based algorithms used today,” she said. Dr. Külkens presented her team’s findings at the 28th International Stroke Conference.

THROMBOTIC THERAPY THROUGH TIME

The three-hour treatment window was established largely by the NINDS trial, results of which were published in 1995. Thrombolytic therapy with intravenous t-PA has since been approved in the United States and several European countries, including Germany, but only for use within three hours of symptom onset.

Getting stroke patients to the hospital in time to receive treatment when they meet other eligibility criteria has been a major issue with respect to t-PA use. Another concern involves bleeding if t-PA is given to hemorrhagic stroke patients or to ischemic stroke patients who do not meet the strict criteria for thrombolysis devised by the NINDS trial as well as by a few other major acute stroke trials. For these reasons, only a relatively small percentage of patients presenting with acute stroke ever receive t-PA.

Previous research efforts to extend the three-hour window have, for the most part, not been successful. In the first European-Australasian Cooperative Acute Stroke Study (ECASS), results of which also were reported in 1995, no meaningful comparison between time windows was possible because an insufficient number of patients were treated within three hours. As a result of these negative findings, the ECASS authors sought to reinvestigate the six-hour time limit using a lower dose of t-PA and other clinical improvements.

UP FROM ATLANTIS

However, both ECASS II and another trial designed to answer the question of whether t-PA treatment beyond three hours was effective—the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS), published in 1999—were generally perceived to be either negative or neutral at best. However, a post-hoc analysis of ECASS II data suggested that some patients, if properly selected, could benefit when treated beyond three hours. One of the principal authors of that analysis was Werner Hacke, MD.

In 1999, Dr. Hacke and colleagues published a meta-analysis of the NINDS trial and the two ECASS trials showing that intravenous t-PA, although most effective in the three-hour window, still had a beneficial effect when given up to six hours following symptom onset. The results of this meta-analysis helped spur Dr. Hacke and his stroke team to further investigate t-PA use in the six-hour period, thereby leading to the development of the MR-based algorithm.

REDEFINING THE ELIGIBILITY CRITERIA

Two related studies conducted by the Heidelberg researchers cast further positive light on their systemic thrombolytic protocol. In a trial in which 106 acute ischemic stroke patients treated with intravenous t-PA were closely matched with the same number of untreated patients, Dr. Külkens and colleagues found that the three-month outcome differences between the treated and nontreated groups were comparable with those of a large study such as ECASS II. The similarity of results, showed that systemic thrombolysis can be performed safely and efficiently in daily clinical practice, with a benefit for patients approaching that found in a randomized controlled trial, the authors concluded.

The results of a third study suggest that thrombolytic therapy can be extended in terms of chronologic age as well as over sequential time. Using a database of all patients treated for stroke in their hospital’s stroke or intensive care unit, Dr. Külkens and colleagues stratified patients by age, with 75 years as the cutoff. Looking at rates of complications and mortality, the research team saw no statistically significant differences, leading them to conclude that thorough clinical examination, individual history, and results of imaging studies such as diffusion- and perfusion-weighted imaging—and not age—should form the criteria for whether a patient receives thrombolysis.

MRI-BASED DECISION MAKING BEYOND THREE HOURS

Of the three Heidelberg studies presented at the International Stroke Conference, it is the one addressing the time frame that is likely to have the most far-reaching clinical implications. These were hinted at in the oral presentation given by Dr. Külkens, who suggested that a major reason the study was successful may have been the selection of patients using MRI.

“Our data support our opinion that thrombolytic therapy with intravenous t-PA can also be beneficial in selected patients in a time window after three hours from symptom onset,” she said. “MRI seems to be an especially helpful tool for such a selection…. There are some hints that this method improved outcome compared to CT-based treatment.

“In the future we have to do randomized trials for MRI up to six hours after symptom onset,” Dr. Külkens concluded.

NR

—Fred Balzac

Suggested Reading
Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245-1251.

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