Imaging, Endovascular Therapy No Benefit Late After Stroke

Honolulu, Hawaii — Final results of a new trial are doubly negative, showing that identifying a favorable penumbral pattern on imaging did not identify stroke patients who would benefit preferentially from endovascular treatment out to 8 hours after symptom onset, nor did endovascular therapy prove to be superior to standard medical care in these patients.

The results, from the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial were presented here at the International Stroke Conference (ISC) 2013 and published online February 8 in the New England Journal of Medicine.

"The first goal was to show that advanced multimodal penumbral imaging can select patients most likely to benefit from late endovascular therapy," lead author Chelsea Kidwell, MD, professor of neurology and director of the Stroke Center at Georgetown University in Washington, DC, told Medscape Medical News. "As an important secondary goal," she said, they hoped to demonstrate that endovascular therapy improves clinical outcomes in these patients.

In the end, they were not able to show that penumbral imaging identified patients likely to benefit or that there was any significant difference in clinical outcomes between patients receiving endovascular therapy, at least with use of first-generation clot retrievers, and those receiving standard care, Dr. Kidwell said.

Still, they did find that patients with a favorable penumbral pattern on MRI or computed tomography (CT) — that is, a small infarct core surrounded by substantial salvageable tissue — based on their imaging models "had significantly better outcomes than nonpenumbral patients, so the penumbra pattern is a good marker of good clinical outcome."

MR RESCUE

In this phase 2b, multicenter, controlled, blinded outcome study, the researchers randomly assigned 118 eligible patients within 8 hours of the onset of large-vessel, anterior circulation strokes to undergo mechanical embolectomy with the Merci Retriever or the Penumbra System or to receive standard care. All patients underwent multimodal CT or MRI before treatment, and randomization was stratified by whether they had a favorable penumbral pattern or a nonpenumbral pattern (a large infarct core with a small or no penumbra). Patients who had received intravenous thrombolysis were allowed into the trial if vessel imaging after treatment showed a persistent target occlusion, Dr. Kidwell noted.

Clinical outcomes were assessed by using the modified Rankin Scale (mRS). The mean age of patients was 65.5 years, mean time to enrollment was 5.5 hours, and 58% of patients had a favorable penumbral pattern. Revascularization in the embolectomy group was achieved in 67% of patients.

At 90 days, mortality was 21% in the overall group, the rate of symptomatic intracranial hemorrhage was 4%, and neither outcome differed between groups, the authors note.

"For the primary hypothesis, there was no significant interaction between treatment assignment and penumbral pattern by shift analysis of the day 90 modified Rankin score," Dr. Kidwell told attendees here. "As such, MR RESCUE failed to demonstrate that penumbral imaging identifies patients who will differentially benefit from endovascular therapy for acute ischemic stroke."

Table 1. MR RESCUE: Primary Outome

Endpoint	Endovascular/ Penumbra	Standard/ Penumbra	Endovascular/ Nonpenumbral	Standard/ Nonpenumbral	P Value
Mean 90-day mRS (95% confidence interval)	3.9 (3.3 - 4.4)	3.4 (3.3 - 4.4)	4.0 (3.4 - 4.6)	4.4 (3.6 - 5.2)	.14

"Similarly, in the penumbral arm, there was no significant difference between embolectomy and standard care, nor is there a difference in nonpenumbral patients," she added. "Finally, regardless of imaging pattern, there is no difference in outcomes between embolectomy and standard care." Results did not change after adjustment for age, the only significant univariate predictor, she added.

Table 2. Mean mRS Scores at 90 Days

Comparison	Embolectomy	Standard Care	P Value
All patients	3.9	3.9	.99
Favorable penumbral pattern	3.9	3.4	.23
Nonpenumbral pattern	4.0	4.4	.32

The investigators did see that penumbral patients overall had significantly better outcomes than nonpenumbral patients regardless of treatment assignment, she said.

Penumbral patients receiving standard care tended to have better outcomes, defined as an mRS of 0 to 2, than the other 3 groups, although the difference wasn't statistically significant. Patients with substantial reperfusion on the Tmax images, as well as those with partial or complete recanalization, had improved clinical outcomes and attenuated infarct growth, Dr. Kidwell said, regardless of treatment assignment or penumbral pattern.

"Had we not had a control arm, we would not have been able to show that the benefit from revascularization was not an acute embolectomy treatment effect," she noted.

Limitations include the long time to complete the trial (8 years), use of only first-generation devices that have lower recanalization rates, and relatively late time to enrollment for the cohort as a whole and late time to groin puncture for the embolectomy group.

"MR RESCUE underscores the importance of confirming hypotheses in randomized, controlled trials prior to implementing treatment approaches in clinical practice," she concluded. "Further randomized, controlled trials with new-generation devices are needed to test the full spectrum of the penumbral imaging selection hypothesis, and to test the clinical efficacy of new-generation stent-retriever devices."

During the question period, 1 audience member interpreted these data slightly differently for those who treat stroke at smaller centers. "In my mind, this is good news," she said. "The vast majority of the people in the United States and the world probably have better access to primary care facilities rather than having access to academic centers, so to my patient population, and to people I think in the vast majority, when we see that IV tPA is perhaps equivalent to more aggressive treatments…it's kind of good news," she concluded, drawing applause from the audience.

Dr. Kidwell thanked her for the comment. However, she said, "I think there still are those among us who do believe that advanced neuroimaging as well as endovascular therapy will have a role down the line. I think we just need more trials with the new stent retriever devices to really sort this out."

More Effective Therapies "Imperative"

In an accompanying editorial, Marc I. Chimowitz, MB, ChB, from the Department of Neurosciences, Medical University of South Carolina, Charleston, reviewed findings from the MR RESCUE trial, as well as those from the SYNTHESIS Expansion and the Interventional Management of Stroke III (IMS-III), trials of endovascular therapy for stroke also presented at the International Stroke Conference here, published in the New England Journal of Medicine, and reported by Medscape Medical News.

"What are the implications of these results for clinical practice?" Dr. Chimowitz writes. "The IMS III and SYNTHESIS Expansion studies show that intravenous thrombolysis should continue to be the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset, even if imaging shows an occluded major intracranial artery," he writes. "Beyond 4.5 hours, the MR RESCUE trial does not provide data supporting the use of endovascular treatment in patients with an ischemic penumbra of any size."

The development of more effective intravenous lytics and endovascular devices, he adds, "is imperative, since the majority of such patients still have substantial disability after treatment, as these trials show."

But progress is being made on these fronts, Dr. Chimowitz notes, including the ongoing development of tenecteplase for use in stroke, and newer stent retriever devices recently approved by the US Food and Drug Administration (FDA). The IMS-III trial provides preliminary data for a randomized trial to test whether the newer endovascular devices add benefit to intravenous thrombolysis if both therapies can be initiated very early, although rapid treatment is "challenging."

Because of its small sample size and use of older devices, the ischemic penumbra hypothesis tested in MR RESCUE should be retested in a larger randomized trial, he said.

He points out, however, that both the IMS-III and MR RESCUE trials had difficulty with enrollment once the FDA approved these devices and Medicare provided reimbursement. Endovascular treatment became widespread, and many doctors felt the "answer was in," he writes. "Therefore, treatment equipoise was lost. It is hoped that equipoise will return on the basis of the results of these three trials."

Still, he anticipates that recruitment will nevertheless be challenging given the number of new retrievers and the pressure from patients' families to take all measures, particularly when the stroke is large and disabling.

"A decision by Medicare to place a moratorium on reimbursement for endovascular treatment of acute ischemic stroke outside of randomized trials would facilitate recruitment in these urgently needed trials," Dr. Chimowitz concludes. "Once the new trials are completed, endovascular treatment will have been given ample opportunity to prove itself."

The trial was supported by a grant from the National Institute of Neurological Disorders and Stroke. Disclosures for Dr. Kidwell and colleagues, as well as Dr. Chimowitz, are available at www.nejm.org.

International Stroke Conference (ISC) 2013. Abstract LB12. Presented February 8, 2013.

N Engl J Med. 2013; Published online February 8, 2013. Abstract