MRI Opens Thrombolysis Window After Stroke


NEW ORLEANS – The presence of a favorable pattern of cerebral perfusion on magnetic resonance imaging may tell physicians which patients with acute ischemic stroke stand to benefit from thrombolysis even hours after the onset of symptoms.

Findings from two phase II studies using MRI show that some patients were able to safely receive a thrombolytic drug as long as 9 hours after the onset of their stroke symptoms. Results from the most recent of these studies were reported at the 30th International Stroke Conference.

Results from the prior study, which was conducted in Europe, were published in January.

“These are the first trials to test the hypothesis that selecting patients with favorable imaging patterns can extend treatment beyond the current 3-hour window,” said Anthony J. Furlan, M.D., head of the section of stroke and neurologic intensive care at the Cleveland Clinic and principal investigator of the new study.

“If this hypothesis is borne out, it could have an enormous impact on how we use thrombolytic therapy for stroke,” he added. “It has the potential to at least triple the number of acute stroke patients who are eligible for thrombolytic therapy.”

Like the study done in Europe, Dr. Furlan's research used a combination of perfusion-weighted and diffusion-weighted imaging by MR to identify patients with at least a 20% mismatch between the two.

The mismatch is a marker for patients with a significant penumbra region in their brain, tissue that might be salvageable by thrombolytic therapy because it is still viable despite being hypoperfused. “Most patients who made it to MR were eligible,” Dr. Furlan said. “The MR criteria did not exclude a lot of patients.”

The other novel feature of both the European and U.S. studies was the thrombolytic drug used: desmoteplase, a plasminogen activator derived from vampire bat saliva. Desmoteplase has several potential advantages over tissue plasminogen activator (TPA).

In animal studies, desmoteplase showed no neurotoxicity, and it did not activate β-amyloid, a process that's been linked to an increased risk of intracranial hemorrhage. Desmoteplase also has very high specificity and selectivity for fibrin and a long serum half-life of 4 hours. This last property means that it can be given as a bolus dose and may also help prevent acute reocclusion of newly opened arteries.

Desmoteplase is being developed in the United States by Forest Laboratories and in Europe by PAION, a German drug company. Dr. Furlan is a consultant to both companies, and he received compensation from both for acting as a principal investigator in these and ongoing studies.

The U.S. study involved enrollment of 37 patients who all met the entry MR criteria. After randomization, 14 of the patients were treated with 90 mcg/kg desmoteplase, 15 received 125 mcg/kg desmoteplase, and 8 received placebo. The average time to treatment was 7 hours. Although patients could enter treatment as long as 9 hours after the onset of their stroke symptoms, the top reason for excluding patients from the study was that they had gone beyond the 9-hour window.

The U.S. study's primary end point was the rate of symptomatic, intracranial hemorrhage (sICH), which occurred in none of the patients. In the prior European study, one sICH occurred among 15 patients treated with 90 mcg/kg and none among 15 patients treated with 125 mcg/kg. Thus, the overall rate of sICH in these two studies at these two doses was one among 59 treated patients, a 1.7% rate that was lower than the 6% rate with TPA in routine practice, noted Dr. Furlan at the conference, sponsored by the American Stroke Association.

In the European study, 30 patients received substantially higher doses of desmoteplase, and they had a 27% rate of sICH. In this higher-dose group, the lowest desmoteplase dose associated with intracranial hemorrhage was 294 mcg/kg.

The new study was not powered to show significant differences in clinical outcomes.

The reperfusion rate was 38% in the control group, 18% among those who received 90 mcg/kg, and 53% among those who received 125 mcg/kg. Improved clinical outcomes at 90 days were seen in 25% of those in the placebo group, 29% of those in the low-dose arm, and 60% of those in the high-dose arm. There was no reduction of safety or efficacy in the patients treated 6–9 hours after their stroke onset, compared with those treated 3–6 hours after onset, Dr. Furlan reported.

The results were promising enough for a phase III study to start this spring, retesting both desmoteplase doses against placebo in a total of 186 patients, Dr. Furlan said. The next study will also test perfusion CT imaging as well as MR imaging because some centers have easier access to CT scanners.

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