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Pooled Data From IMS III, MR CLEAN Further Support Endovascular Therapy for Severe Stroke

By L.A. McKeown

In what appears to be a reversal of fortune for endovascular stroke therapy, a pooled analysis from 2 major trials—1 of which was negative overall—points to improvements in functional outcome at 90 days for patients with the most severe strokes, according to data presented February 12, 2015, at the International Stroke Conference in Nashville, TN.

The analysis comes on the heels of 3 other trials presented at the meeting—ESCAPE, EXTEND-IA, and SWIFT PRIME—which all demonstrated benefit of endovascular therapy in large strokes.Take Home: Pooled Data From IMS III, MR CLEAN Further Support Endovascular Therapy for Severe Stroke

The therapy has had a bumpy road. In May 2012, the IMS III trial was halted after interim analysis indicated that endovascular therapy was unlikely to show additional benefit over IV tissue plasminogen activator (tPA) alone even if the study completed enrollment of its projected 900 patients. By then it had already enrolled 656 patients at 58 centers in North America, Europe, and Australia.

Still, analyses of IMS III suggested a strong trend for certain subgroups, including those with severe stroke at baseline (score of 20 or greater on the NIH Stroke Scale [NIHSS]), major arterial occlusions on pretreatment CT angiography, and internal carotid artery occlusions.

More negative trials followed. Then, in December 2014, MR CLEAN was published in the New England Journal of Medicine and everything changed.

The study enrolled 500 patients at 16 Dutch centers. All had proximal arterial occlusion in the anterior cerebral circulation confirmed on imaging and could be treated intraarterially within 6 hours of symptom onset. Intraarterial intervention consisted of catheter-based thrombolysis, mechanical treatment, or both. Overall, there was an absolute difference of 13.5% in the rate of functional independence (modified Rankin score [mRS] 0-2) at 90 days in favor of the intervention (adjusted OR 2.16; 95% CI 1.39-3.38), with no differences in mortality or symptomatic intracerebral hemorrhage rates.

The new pooled analysis, presented by IMS III’s principal investigator Joseph P. Broderick, MD, of the University of Cincinnati Medical Center (Cincinnati, OH), was planned prior to the unblinding and after the publication of MR CLEAN. It included a total of 343 patients from both trials (IMS III, n = 194; MR CLEAN, n = 148), all of whom had a pretreatment NIHSS ≥ 20 and received tPA within 3 hours of symptom onset.

Functional Improvements

Compared with IV tPA alone, more patients who received additional endovascular therapy were designated as mRS 0-2 at 90 days (24.1% vs 13.9%; adjusted OR 1.85; 95% CI 1.03-3.33), with no increase in mortality. This in contrast to the overall results of IMS III, which showed no difference in functional independence with endovascular therapy compared with tPA alone.

Within the IMS III cohort, 35% of patients had reductions in stroke severity during the first 40 minutes after IV tPA administration.

In an article published on the University of Cincinnati Academic Health Center website, Dr. Broderick said, “Our pooled data, as well as other reported trials, call for thoughtful consideration of current triage for patients who present with severe stroke and who are candidates for endovascular therapy within a given region of the brain.”

No Time to Waste

Philip M. Meyers, MD, of Columbia University Medical Center (New York, NY), concurred that the influx of new data counteracts the disappointment seen in February 2013 when IMS III, MR RESCUE, and SYNTHESIS Expansion all reported unfavorable results for endovascular stroke therapy.

“That was a major blow because it didn’t meet with the experience of many neuro-interventionalists, yet the best scientific data did not support stroke intervention,” he told TCTMD in a telephone interview.

“Previously, only subgroup analyses had shown the benefits of endovascular treatment, especially in IMS III,” Dr. Meyers said. He added that the results of MR CLEAN spurred investigators to perform interim analyses of ongoing trials that were not already scheduled.

Taken together with ESCAPE, EXTEND-IA, and SWIFT PRIME, the pooled analysis presented by Dr. Broderick clarifies the benefit of endovascular therapy in severe strokes due to large artery occlusions, he said.

“These data tell clinicians that we need to avoid wasting any time identifying stroke patients for endovascular treatment of large vessel occlusions,” Dr. Meyers commented. “Once the emergency physician or stroke neurologist obtains a noncontrast CT scan to deliver intravenous [recombinant] tPA, then they should strongly consider another scan—namely, CT [angiography]—to confirm that there is a large artery blocked. It is now clear that there is importance to get the clot out and restore cerebral circulation in appropriately selected stroke victims.”

Still, unanswered questions remain, including how to tell when it is too late to intervene. “We’ve learned a lot about patients with severe stroke,” he said. “The combination of rapid triage, new techniques, new tools, and some ongoing trials looking at the influence of collaterals in this population is going to be important going forward.”

In just a short period of time, “we have gone from having no conclusive [evidence] of benefit to having 4 trials that are all pointing in the same direction. I believe that this puts the issue to rest in terms of whether endovascular therapy works,” Dr. Meyers concluded.

 

Source:
Broderick J. Pooled analysis of IMS III and MR CLEAN trials for patients with NIHSS ≥ 20. Presented at: International Stroke Conference; February 12, 2015; Nashville, TN.

Disclosures:

Dr. Broderick reports serving as principal investigator for the IMS III trial, receiving research support from Genentech, and serving as a consultant/advisory board member for Pfizer.

  • Dr. Meyers reports no relevant conflicts of interest.

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