MRI Mismatch After Stroke Predicts Better Outcome With tPA

Daniel M. Keller, PhD

June 07, 2012

June 6, 2012 (Lisbon, Portugal) — Baseline magnetic resonance imaging (MRI) characteristics, specifically, an MRI mismatch in lesion volumes between the perfusion-weighted image (PWI) and the diffusion-weighted image (DWI), can predict the response of ischemic stroke patients after endovascular (intra-arterial) tissue plasminogen activator (tPA) therapy at the site of the lesion.

Maarten Lansberg, MD, PhD, from the Stanford Stroke Center of Stanford University in Palo Alto, California, told delegates here at the XXI European Stroke Conference that patients with an MRI mismatch have a better chance of favorable clinical and radiographic outcomes with early reperfusion. But there was no association between reperfusion and favorable outcomes for patients in the absence of MRI mismatch.

Dr. Lansberg concluded that the response to endovascular reperfusion therapy differs among patients, depending on the presence of MRI mismatch at baseline. "Target mismatch patients have an increased chance of favorable clinical and radiographic outcomes with early reperfusion," he said, "whereas no association between reperfusion and favorable outcomes was apparent in the nontarget mismatch group." The results support a randomized, controlled trial of endovascular therapy with MRI selection, he suggested.

Imaging modalities are now sufficient to select patients in the acute setting, he said, and the software processing of images to determine mismatch "is fast enough to make those selections in real time, and our endovascular therapies are continuing to improve with higher recanalization rates."

Mismatch a Marker of Favorable Outcome?

Soon after an ischemic stroke, the DWI lesion volume is typically smaller than the region with abnormal perfusion (PWI), which represents the potential infarct size. This mismatch region has been suggested to be "tissue at risk."

In the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study–2 (DEFUSE-2), the investigators hypothesized that reperfusion would be associated with reduced infarct growth in patients with mismatch compared with patients with other imaging profiles, ie, that reperfusion could limit growth of the infarct area from reaching its full potential size if they intervened while the DWI volume was still smaller than the region with abnormal perfusion, as seen in the PWI.

In other words, the mismatched volume represented potentially salvageable brain tissue. The investigators considered a PWI-to-DWI ratio of 1.8 or greater to constitute a mismatch.

DEFUSE-2 was a multicenter prospective cohort study at 9 sites; enrollment occurred between 2009 and 2011. Patients aged 18 years or older with a National Institutes of Health Stroke Scale (NIHSS) score of 5 or greater were eligible if they were scheduled to undergo intra-arterial acute stroke therapy (groin puncture less than 12 hours after symptom onset) and were able to undergo an MRI stroke study less than 90 minutes prior to the start of the intra-arterial procedure.

Follow-up MRIs were performed 12 hours after the endovascular therapy and at 5 days. A greater than 8-point improvement on the NIHSS or a score of 0-1 at 30 days was considered a favorable clinical response.

The median age of the patients was 66 years, and their median NIHSS score was 16; 53% had been pretreated with intravenous tPA. The median time from the onset of stroke to intra-arterial therapy was 5.9 hours.

Of the 110 patients who received direct endovascular therapy, 6 had inadequate MRIs, leaving in the study 78 treated patients with MRI mismatch and 26 without.

Early reperfusion was achieved in 59% of the mismatch group and in 57% of the patients without mismatch. The investigators defined reperfusion as a 50% or greater reduction in the PWI lesion volume on MRI at 5 days compared with baseline.

Infarct growth at 5 days poststroke was attenuated in patients with MRI mismatch who achieved reperfusion (median, 30 mL vs 73 mL if no reperfusion; P = .005), but there was no significant difference in patients without MRI mismatch (96 mL with reperfusion vs 34 mL without, P = .21).

Patients with a mismatch who achieved reperfusion had a 5-fold higher likelihood of a favorable clinical outcome at 30 days after stroke onset (unadjusted odds ratio [OR], 5.0; 95% confidence interval [CI], 1.9 - 13) compared with reperfused patients without a mismatch (OR, 0.2; 95% CI, .0 - 1.4; P = .004 for the difference between odds ratios).

Among patients with mismatch, 70% who underwent reperfusion had a favorable clinical response at 30 days vs 31% with a favorable response without successful reperfusion (P = .001). However, for patients without an MRI mismatch, reperfusion did not yield a significant difference in favorable outcomes (42% favorable clinical response with reperfusion vs 78% without reperfusion, P = .2).

At 90 days, 57% of patients with a mismatch who underwent reperfusion had a modified Rankin Scale (mRS) score of 0-2 vs 31% with no reperfusion. Among patients with no mismatch at baseline, only about one quarter of the patients had an mRS score of 0-2, whether reperfusion was achieved or not.

Bridging Therapy

Michael Hennerici, MD, professor and head of the Department of Neurology at the University of Heidelberg and at Mannheim Hospital in Mannheim, Germany, and chairman of the European Stoke Conference, commented to Medscape Medical News that he thinks the study was conducted well. However, it is relatively small, so "it needs to be confirmed by a larger study, and we need to know more about the details."

He said stroke patients are a very heterogeneous population, and he wondered whether the patients in the study were sufficiently representative of most stroke patients.

Dr. Hennerici noted that it is not easy to decide whether to use intravenous or local intra-arterial tPA. Intravenous administration resolves only about 30% of blockages within 90 minutes. But it can be done sooner, whereas it may take quite some time to get a patient to an angiography suite, assemble the necessary staff, and do the procedure. However, endovascular therapy is more likely to open the occluded vessel and prevent infarction of the whole territory. He noted that tPA is currently approved only for intravenous use.

He said the investigators tried to see whether MRI could select the patients with the best chance of a favorable radiographic and clinical outcome if they were offered intra-arterial therapy.

"They showed that those patients who came into the hospital with the mismatch and an occlusion of a large vessel, that those who recanalized really had a better outcome," Dr. Hennerici said. "Now, I'm not sure that things are that simple.... The numbers were small."

He also pointed out that tPA may have beneficial effects besides opening just the target vessel. When injected intravenously into the systemic circulation, it may also affect collateral vessels and the stroke penumbra.

"And this tPA can also support [limiting] the development of the ischemic events in the ischemic territory so that the infarct doesn't become that big, as in the worst case scenario," he explained, and he noted that several groups have shown that intravenous tPA improves the brain image in the case of MRI mismatches. Intra-arterial tPA is a much smaller dose, is injected locally, and does not circulate, "so you have no effect whatsoever on the collateral perfusion," he said.

He also suggested the possibility of a bridging concept — using intravenous tPA immediately, watching for a response while preparing for angiography and intra-arterial tPA infusion, and then going that route if there is no improvement within 60 to 90 minutes "to have it from both sides," he suggested.

Dr. Hennerici said he personally prefers this strategy — preparing for intra-arterial therapy while giving intravenous tPA some time to work on a clot.

"If it is from the heart and it is a fresh thrombus, then it dissolves like butter in the sun," he said. "If it's a calcified part of the carotid lesion, you can do what you wish — whether you put it intra-arterially or intravenously," nothing will resolve the occlusion short of mechanical removal.

Dr. Lansberg and Dr. Hennerici have disclosed no relevant financial relationships.

XXI European Stroke Conference. Presented May 23, 012.

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