Subscribe to eTOC

MRI May Help Identify Patients Who Can Benefit from Late Thrombolysis

ARTICLE IN BRIEF

Figure

No caption available.

Strong trends, but not statistically significant results, suggest some limitation in the extent of the infarct in patients with a mismatch on perfusion-weighted imaging and diffusion-weighted magnetic resonance imaging who were given tPA outside the three-hour window.

NEW ORLEANS—Results of a phase 2 study hint that MRI may someday help to identify ischemic stroke patients who will benefit from thrombolysis outside the three-hour window from symptom-onset for which it is currently approved, investigators said here at the American Stroke Association International Stroke Conference.

The trial tested the use of intravenous tissue plasminogen activator (tPA) three to six hours after symptom-onset and did not meet the primary endpoint of significantly limiting enlargement of the infarct in patients who theoretically would have benefited because imaging showed large regions of potentially viable brain tissue.

But strong trends suggested some limitation in the extent of the infarct in patients with a mismatch on perfusion-weighted imaging (PWI) and diffusion-weighted magnetic resonance imaging (DWI) who were given tPA outside the three-hour window, said study co-chair Stephen M. Davis, MD, director of neurology at the Royal Melbourne Hospital of the University of Melbourne in Victoria, Australia.

Additionally, patients with a mismatch on PWI and DWI had significantly better reperfusion, compared to patients randomized to placebo. Also, reperfusion significantly correlated with attenuation of infarct growth as well as better clinical outcome, he said.

“Given the strong link between reperfusion and improved clinical outcome, phase 3 trials in this time window are warranted,” Dr. Davis said.

Dr. Davis discussed the results of the randomized, double-blind, placebo-controlled trial Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) at a late-breaking session. The results were published simultaneously online on Feb. 22 by Lancet Neurology and in April, in the print edition.

‘RATIONALE FOR THE APPROACH’

There is a strong biological rationale for the approach, according to Harold P. Adams Jr., MD, professor and director of the Division of Cerebrovascular Disorders in the department of neurology at the University of Iowa Hospitals and Clinics in Iowa City. Dr. Adams was not involved with the research.

The possible clinical benefit of thrombolytic therapy depends in part on the presence and extent of the ischemic penumbra, a region of critically hypoperfused but potentially viable tissue around the irreversibly damaged infarct core.

A mismatch between a larger PWI and a smaller DWI lesion is thought to be the signature of the ischemic penumbra, he explained.

“Diffusion-weighted MRI identifies the area of primary brain injury that may or may not be salvageable, while perfusion-weighted MRI identifies an area that might be saved,” Dr. Adams said.

Therefore a mismatch between a larger perfusion-weighted and a smaller diffusion-weighted MRIs should theoretically identify patients with a relatively large area of injured brain tissue in the ischemic penumbra that might still be salvageable with late thrombolysis, he said.

STUDY METHODS, FINDINGS

The study involved 101 patients with confirmed ischemic stroke who were randomized to intravenous tPA or placebo three to six hours after symptom onset. Their mean age was 71.6 years, and they had a median score of 13 points on the 42-point NIH Stroke Scale (NIHSS), where higher scores indicate worse severity.

Figure

DR. STEPHEN M. DAVIS: “Given the strong link between reperfusion and improved clinical outcome, phase 3 trials in this time window are warranted.”

The primary hypothesis was that tPA would attenuate infarct growth in patients with a mismatch between DWI and PWI lesions. However, MRI mismatch was not used in the selection of patients, “because rapid online detection of mismatch was not feasible,” Dr. Davis said.

Instead, the patients were screened with noncontrast CT to rule out hemorrhage, and “all other comers were accepted.”

PWI and DWI were done before and after three to five days after therapy, and T2-weighted MRI was performed at about day 90. In some patients lost to follow-up who did not have a 90-day MRI, the DWI lesion volume at days three to five was used as a surrogate for the final lesion.

The final analysis included 37 patients with mismatch who got tPA and 43 patients with mismatch who got placebo. Mean infarct growth was 1.23 in tPA arm and 1.78 in the placebo group. The difference was not significant, but this was a 30-percent reduction in infract growth in the tPA arm, said Dr. Davis.

The median relative infarct growth, a secondary endpoint, was 1.18 in the tPA group and 1.79 in the placebo group. “This strong trend approached significance, with a 61 percent reduction seen with tPA and a p value of 0.054,” he said.

Reperfusion rates at days three through five were 56 percent in the tPA arm and 26 percent in the placebo arm, a significant difference.

Reperfusion was significantly associated with less infarct growth, better neurological outcome, and better functional outcome, Dr. Davis reported.

He said there was also a strong trend toward improved clinical outcomes in the tPA group: Fifty percent had a good neurological outcome — defined as an improvement of 8 points or more, or a score of 0–1, on the NIHSS — versus 37 percent in the placebo group. Forty-five percent had a good functional outcome, defined as score of 0 to 2 on the 6-point modified Rankin scale, versus 40 percent in the placebo arm.

There were no unforeseen safety issues, said EPITHET co-chair Geoffrey A. Donnan, MD, director of the National Stroke Research Institute and professor of neurology at the University of Melbourne, both in Australia.

“With tPA you usually see a symptomatic hemorrhage rate of 6–8 percent and ours was 7.7 percent. So beyond three hours, it was not less safe than under three hours,” he said.

FINDINGS ARE ‘ENCOURAGING’

Asked to put the findings into perspective, both the researchers and neurologists not involved with the trial echoed the term “encouraging.”

Philip B. Gorelick, MD, John S. Garvin Professor and head of the Department of Neurology and Rehabilitation and director of the Center for Stroke Research at the University of Illinois College of Medicine in Chicago, said: “This should be viewed in a positive way, as an intermediate step leading to a larger trial that could be more definitive and that could alter guidelines for the treatment of ischemic stroke. This would be a great thing, if we could extend the window of tPA,” he said.

Said Dr. Adams: “This is a test not so much of outcomes, but to see if we can identify patients who will benefit from late thrombolysis and intervene.

“The study is not definitive and not practice-changing. But the approach shows promise and should be tested in a larger trial,” Dr. Adams said.

Figure

DR. HAROLD P. ADAMS JR. “The study is not definitive and not practice-changing. But the approach shows promise and should be tested in a larger trial.”

In an editorial accompanying the publication of EPITHET in Lancet Neurology online, Peter D. Shellinger, MD, professor and vice chairman of the department of neurology at the University of Erlangen in Erlangen, Germany, criticized the researchers for not using MRI to select patients.

“A more rigorous randomized controlled trial of intravenous thrombolytic therapy on the basis of PWI-DWI mismatch would have used MRI to select patients and randomize them between [tPA] and placebo,” he said. Nevertheless, he considered the mismatch hypothesis worthy of further study.

Dr. Davis said the EPITHET investigators “believe the next step is to do a clinical phase 3 trial i patients with mismatch in the three to six hour window, which would require only about 400 patients,” he said.

REFERENCE

• Davis SM, Donnan GA, Demond PM, et al., for the EPITHET Investigators. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008;7(4):299–309.