TORONTO—Six years ago, publication of the tissue plasminogen activator (t-PA) study from the National Institutes of Neurological Disorders and Stroke (NINDS) revolutionized the treatment of stroke. For the first time, doctors could interrupt the natural course of the event with a thrombolytic agent. Now, researchers are becoming increasingly aggressive, exploring new ways to open occluded vessels in the brain and to expedite the delivery of t-PA and other thrombolytic agents.

At the 2000 North American Stroke Association Meeting, Richard Latchaw, MD, Professor of Radiology and Chief of Neuroradiology, University of Pittsburgh, Pennsylvania, and Werner Hacke, MD, Professor and Director of the Department of Neurology, University of Heidelberg, Germany, discussed the time-to-treatment window and the pros and cons of imaging and examined some of the new directions now being taken in detecting and addressing occlusive clots in the brain.

OPENING THE TIME-TO-TREATMENT WINDOW

When it comes to acute ischemic stroke, it is agreed that the quicker the treatment, the better. The NINDS clinical trial found that patients who received intravenous t-PA within three hours of their initial stroke symptoms were at least 30% more likely than untreated patients to recover from their stroke with little or no disability after three months. But many patients present well after three hours after stroke onset, and clinicians often cannot ascertain the exact time of symptom onset. However, results from the second Prolyse in Acute Cerebral Thromboembolism (PROACT II) trial demonstrated that the treatment window can be stretched to six hours.

The PROACT II trial, which was published in JAMAin 1999, demonstrated the effectiveness of intra-arterial prourokinase when given within six hours of a stroke caused by middle cerebral artery occlusion. After 90 days, 40% of those who received intra-arterial thrombolysis achieved a modified Rankin score of 2 or less—compared with 25% of those in the heparin control group. Mortality was similar between the groups. However, the risk of intracranial hemorrhage within 24 hours of stroke onset was higher in the thrombolysis group (10%) than in the control group (2%).

A review of the NINDS trial and the first and second European Cooperative Acute Stroke Study (ECASS) gave more interesting insight to the three-hour treatment window, Dr. Hacke said. While efficacy of treatment clearly goes down over time, the risk of hemorrhage does not go up. A 3.2-fold increase in risk was associated with both the zero- to three-hour treatment group and the three- to six-hour group. The increased rate of hemorrhage among the treated patients did not increase mortality, probably because there was an increase in the rate of herniation among control patients, Dr. Hacke said.

WEIGHING THE RISKS OF TREATMENT

Which patient will benefit the most from treatment? According to the NINDS protocol for thrombolytic therapy, patients with a National Institutes of Health Stroke Scale (NIHSS) score of 1 to 36 are considered eligible for treatment. The recommendations were in agreement with the American Academy of Neurology and American Stroke Association guidelines. However, Dr. Hacke questioned whether it was fair to compare the risks of treatment in a patient who has a score of 1 with the risk in a patient who has a score of 25 or more.

Despite the successful trial results, thrombolysis in acute stroke is still underused, Dr. Hacke said. Although for stroke, seven patients treated with thrombolysis are neded in order to prevent one patient from death or dependence. For myocardial infarction, the number of patients needed is 31, he continued. Still, only 2% of stroke patients in the US get this promising therapy.

Clinicians should take stroke severity, as well as visual proof of vessel occlusion, into consideration when treating a patient, Dr. Hacke said. Many imaging methods are currently available, such as computed tomography (CT) scanning, transcranial Doppler ultrasonography, and magnetic resonance imaging (MRI) techniques, including MR angiography and diffusion/perfusion mismatch techniques.

IS IMAGING A WASTE OF TIME?

Although some clinicians believe that "we shouldn't be playing around with all these fancy imaging techniques, trying to determine who's a good candidate for intra-arterial therapy, because we're taking too much time," Drs. Latchaw and Hacke agreed that imaging can be performed relatively quickly and that it can help determine an appropriate treatment.

"I must tell you if I get perfusion/diffusion, MRA, and T1-weighted images of a patient and then a special sequence to detect hemorrhage, it needs only 20 minutes—and this is not time-consuming," Dr. Hacke said. In many cases, CT is bypassed altogether, he said. The mismatch technique, which identifies still-viable ischemic tissue, can help determine which patients will benefit from therapy up to eight and nine hours after the infarct, Dr. Hacke added. However, he acknowledged that imaging centers would need to offer imaging 24 hours a day. "As you know, strokes do not usually come in between eight and four."

Approaches such as diffusion/perfusion–weighted imaging are essential for the immediate evaluation of post-recanalization status, including hemorrhage or reperfusion injury, Dr. Latchaw continued. He noted that researchers from the University of Minnesota combined a short-board magnetic resonance scanner with a fluoroscopy table. "The patient comes right from the emergency room, gets on that scanner, we look for blood…and the patient never leaves this room," Dr. Latchaw explained. Thrombolysis is administered, and the patient is monitored for treatment efficacy and reperfusion injury right on the table.

WHERE DO WE GO FROM HERE?

Despite its apparent benefit, prourokinase is still experimental; the US Food and Drug Administration did not consider the PROACT II results to be sufficient for the drug's approval. As urokinase has since been taken from the market, that leaves t-PA for use in this intra-arterial application, Dr Latchaw said. "As a thoughtful physician, [I] have the right to use any approved drug in any manner I wish, but I'd better have the literature on my side," he said. "Bottom line here is that the t-PA is used, but I haven't a clue as to how much is the correct dosage." A similar problem exists for other agents, such as reteplase, he reported.

This quandary has forced physicians to cast about for other approaches. One strategy advocated by Thomas Brott, MD, a neurologist from the Mayo Clinic, Jacksonville, Florida, involves an early start of intravenous t-PA, followed by an angiogram and intra-arterial thrombolysis of any remaining clot. Results from the Emergency Management of Stroke pilot study suggested that this combination therapy might be feasible, particularly when treatment is reserved for patients with a NIHSS score of at least 9. The hemorrhage rate was similar to that with the intravenous drug alone. "So there is some evidence that this kind of approach will work, and we are looking at it becoming a new funded study," Dr. Latchaw said.

"I'm pretty happy to announce that with 99% probability there will be a PROACT III trial," Dr. Hacke said. The PROACT III study will concentrate on patients with NIHSS scores of 8 to 25 and will include a substudy using MRI for proof of vessel occlusion prior to angiography, he noted.

New agents that are currently undergoing investigation include an anticoagulant factor derived from the saliva of the vampire bat, Dr. Hacke said. Because of very promising pilot data, phase II and phase III trials of this single-dose agent are planned. For the first time, the trials will be completely based on diffusion/perfusion imaging, he pointed out.

ROOM FOR IMPROVEMENT

Alternative approaches to thrombolysis are also being investigated, noted Dr. Hacke. Although the results of laser-induced clot disruption have been disappointing, encouraging results have been seen with ultrasound-enhanced thrombolytic therapy. "We have now done three patients, and they have opened up very, very fast, (although) I cannot tell you anything about efficacy and risk," Dr. Hacke said.

Balloons or snares are also being tested, Dr. Latchaw added. One of the most promising of these has been the AngioJet® Rheolytic™ thrombectomy system, which uses a high-speed injection of saline to dissolve and then aspirate the clot. However, this approach is currently limited by the size and inflexibility of the catheter used.

There is room for improvement in all aspects of stroke management, including better thrombolytic drugs, mechanical techniques to decrease the time required to remove the clot, and the administration of neuroprotective agents, they concluded.

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