MR CLEAN Appears to Redeem Endovascular Therapy for Acute Stroke

Catheter-based treatment of acute ischemic stroke caused by a large proximal intracranial occlusion achieves better reperfusion and functional outcomes than IV thrombolysis alone, according to the randomized MR CLEAN trial published online December 17, 2014, ahead of print in the New England Journal of Medicine.
MR CLEAN Appears to Redeem Endovascular Therapy for Acute Stroke

In a telephone interview with TCTMD, Philip M. Meyers, MD, of Columbia University Medical Center (New York, NY), called the results “a watershed moment” in stroke therapy. “It’s a big turnaround from February 2013 when the New England Journal published 3 large trials of stroke intervention—IMS III, MR RESCUE, and SYNTHESIS Expansion—that turned out to be either inconclusive or negative,” he said.

For the MR CLEAN trial, investigators led by Diederik W.J. Dippel, MD, PhD, of Erasmus Medical Center (Rotterdam, the Netherlands), enrolled 500 patients with proximal arterial occlusion in the anterior cerebral circulation that was confirmed on imaging and could be treated intraarterially within 6 hours of symptom onset at 16 Dutch centers between December 2010 and March 2014. Participants (mean age 65 years; 58.4% men) received usual care, which could include IV alteplase, and were randomized to intraarterial intervention (n = 233) or no additional treatment (n = 267).

Intraarterial intervention consisted of catheter-based thrombolysis, mechanical treatment, or both. Risk factors for a poor outcome, clinical risk factors for stroke, and aspects of prerandomization treatment were evenly distributed between the 2 groups.

In the intervention group, 84.1% of patients actually received intraarterial therapy. Among the 83.7% of patients who received mechanical treatment, retrievable stents were used in 81.5%. Additional intraarterial thrombolytic agents were given to 10.3%. Thirty patients (12.9%) in the endovascular arm also underwent simultaneous acute cervical carotid stenting.

Intervention Improves Functional Outcomes

Intraarterial treatment shifted the distribution of modified Rankin scale (mRS) scores at 90 days (primary outcome; ranging from 0 for no symptoms to 6 for death) toward better functional outcomes. After multivariate adjustment, the likelihood of improved neurologic outcomes was substantially increased by intraarterial treatment in the intention-to-treat analysis (adjusted OR 1.67; 95% CI 1.21-2.30). The absolute between-group difference in the proportion of patients who were functionally independent (mRS score 0-2) was 13.5% in favor of intervention (adjusted OR 2.16; 95% CI 1.39-3.38).

The treatment effect was consistent across various subgroups, including those based on NIHSS score and Alberta Stroke Program Early CT Score (ASPECTS).

Several other imaging and clinical measures also favored intraarterial treatment, including:

  • NIHSS score after 5 to 7 days: average reduction of 2.9 points (95% CI 1.5-4.3 points)
  • Successful recanalization at 24 hours: rate of 75.4% vs 32.9% (adjusted OR 6.88; 95% CI 4.34-10.94)
  • Infarct volume: decrease in median of 19 mL (95% CI 3-34 mL)

Over 90 days, no differences were seen between the intervention and control groups in rates of serious adverse events (47.2% and 42.3%; P = .31), although patients in the intervention arm were more likely to have clinical signs of a new ischemic stroke in a different vascular territory (5.6% vs 0.4%; P < .001). Rates of symptomatic intracerebral hemorrhage (7.7% and 6.4%) and 30-day mortality (18.9% and 18.4%) were also similar between intervention and control patients.

Procedure-related complications in the intervention group included embolization into new territories in 20 patients, vessel dissection in 4, and vessel perforation in 2.

Lessons Learned

In an accompanying editorial, Werner Hacke, MD, PhD, of University Hospital Heidelberg (Heidelberg, Germany), deems MR CLEAN a “step in the right direction.” He observes that it is the first study to have learned lessons from the previous trio of negative or ambiguous randomized trials by:

  • enrolling patients with severe strokes
  • requiring proof of proximal vessel occlusion
  • initiating treatment as early as possible
  • using modern thrombectomy devices    

Strengthening the case for intervention, Dr. Meyers noted, is the fact that enrollment in MR CLEAN included a relatively broad spectrum of patients with large cerebral artery occlusions.

He predicted that MR CLEAN will have a dramatic impact on stroke treatment. One of the most immediate effects, he said, has been that following initial presentation of the positive findings at the World Stroke Congress in October 2014, researchers performed interim analyses of several ongoing randomized trials of endovascular therapy and found that their primary endpoints had been met. “Perhaps 4 additional trials reportedly show the benefit of endovascular intervention,” Dr. Meyers commented.

Joseph P. Broderick, MD, of the University of Cincinnati (Cincinnati, OH), largely agreed. “There’s a good shot that we will have 3 other trials that will help inform the role of endovascular therapy,” he told TCTMD in a telephone interview. “But all are using different selection criteria, so it’s not like we can bundle them together and get an answer. We’re going to have to interpret each trial in the context of the population studied.

“The very good news [from MR CLEAN] is that reperfusion is key, and we can do better than IV tPA alone in patients who have big clots,” he said. Still, perhaps only one-third of stroke patients may qualify for endovascular therapy, he noted, and in the trial only one-third of those who received catheter-based therapy had a favorable functional outcome.

“So this is a step forward for patients and for the field,” he said, “but we’ve got a lot of work to do.”

Has Treatment Equipoise Been Lost?

Another concern, Dr. Meyers noted, is that if intervention becomes standard practice, treatment equipoise will be lost and it will become more difficult to perform future randomized trials in which some patients do not undergo intervention for large artery occlusion. “We must still address some important questions, such as when stroke damage becomes irreversible and thus is no longer treatable with endovascular revascularization, and how patients with irreversible stroke damage can be protected against potential further damage after revascularization,” he commented.

More cautious in his assessment of the impact of MR CLEAN, Dr. Hacke writes that “it is premature to conclude that there is no longer equipoise regarding thrombectomy. We need and will get results from other well-designed trials, not only to confirm or refute the results of MR CLEAN but also to look at effects in subgroups (according to stroke severity, occlusion site, or time to treatment initiation), for which most single trials are underpowered.”


1. Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2014;Epub ahead of print.
2. Hacke W. Interventional thrombectomy for major stroke—a step in the right direction [editorial]. N Engl J Med. 2014;Epub ahead of print.

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MR CLEAN Appears to Redeem Endovascular Therapy for Acute Stroke

  • The study was supported by the Dutch Heart Foundation and unrestricted grants from AngioCare, Covidien/ev3, Medac/Lamepro, and Penumbra.
  • Dr. Dippel reports no relevant conflicts of interest.
  • Dr. Hacke reports receiving grant support from Boehringer Ingelheim and consulting fees from Bayer, Covidien, and Daiichi Sankyo.
  • Dr. Meyers reports no relevant conflicts of interest.
  • Dr. Broderick reports serving as principal investigator for IMS III and receiving research support from Genentech.