February 2015

Endovascular Stroke Treatment: 'MR CLEAN' Data Supports Within-the-Artery Approach to Treating Ischemic Stroke
A Radiology Today staff report
Radiology Today
Vol. 16 No. 2 P. 26

Combining an endovascular thrombectomy procedure with tissue plasminogen activator (tPA) application to the clot produced better outcomes than standard intravenous tPA treatment in a study done in the Netherlands. Several previous studies had not shown such a benefit, so the results are sparking new enthusiasm among proponents of the endovascular intervention.

Intravenous tPA has become the standard of care for acute ischemic stroke after being shown effective in numerous well-controlled, randomized clinical trials if administered within 4.5 hours of the onset of stroke symptoms.1 But TPA therapy's use has been limited by that time constraint. As the time from stroke symptom onset to treatment increases, the therapy is less effective and the risk of hemorrhagic stroke increases. Consequently, researchers have been investigating ways to lengthen that treatment time window, including using endovascular approaches to removing clots. Some physicians report success with endovascular approaches outside those time limits, but until the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands study, widely known as the MR CLEAN study, announced results at a stroke conference late last year, no controlled trial has shown improved outcomes. Published in the January 1, 2015, issue of The New England Journal of Medicine, the MR CLEAN study reports that "Intra-arterial treatment improved the rate of good functional outcome by 71% over treatment with medical management with tPA alone," according to a press release announcing the study. "Of patients who received intra-arterial treatment, 32.6% achieved a clinically defined positive stroke outcome compared with 19.1% of those who received medical management. Intra-arterial treatment was beneficial for all ages (18-plus), including the elderly (80-plus)—a population for whom intervention was previously thought to be risky."1

While one study does not change the standard of care, the results encourage researchers to further investigate the interventional approach as a possible advancement in treating acute ischemic stroke.

"The MR CLEAN Study confirms what we are seeing in everyday practice," Peter Rasmussen, MD, director of the Cleveland Clinic Cerebrovascular Center and president of Society of NeuroInterventional Surgery, said via a press statement on the study. "Within-the-artery procedures, which are performed by neurointerventional surgeons, are not the appropriate treatment for every patient suffering from stroke, but for many patients they are life-saving, viable, and effective therapies that offer many benefits over traditional treatments, including shorter recovery times and a better chance to return to normal activities."

The published conclusion of the study: "In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intra-arterial treatment administered within 6 hours after stroke onset was effective and safe."1

Other findings from the study, according to Penumbra, Inc, which funded the study with an unrestricted grant and developed the clot-removal system used in the study, include:

• The treatment was effective for patients with large vessel occlusion strokes. In such cases, tPA is considered less effective.

• The treatment is effective up to 6 hours after stroke onset, compared to 3 to 4.5 hours for tPA.

• Both the treatment using endovascular clot removal and standard tPA treatment were safe, with no significant differences between them relating to hemorrhage or mortality.

"With the results of MR CLEAN, we have the needed evidence to support endovascular treatment in the fight against stroke, and the results are truly astounding. [The results] show that endovascular treatment can benefit a broad population of patients—not just younger patients as previously thought but older patients as well if treated early," Michael J. Alexander, MD, FACS, said via a statement on the study. Alexander is the director of the neurovascular center and a professor of neurosurgery at Cedars-Sinai Medical Center in Los Angeles and past president of the Society of NeuroInterventional Surgery.

The MR CLEAN trial began enrolling in 2010 and used an earlier generation of endovascular thrombectomy technology. The current system, ACE, uses aspiration alone to engage and remove the blood clots that cause acute ischemic stroke and is improving results from the baseline set by the MR CLEAN study, according to the company.

The study enrolled 500 patients and specified that large vessel occlusion had to be confirmed by CT angiography for the patient to be enrolled in the trial. Once confirmed, all patients were first administered tPA if eligible; 233 were then assigned to the intra-arterial treatment arm and 267 to the control arm receiving only tPA. All the stroke centers in the Netherlands participated in the study and the intervention and control groups were well balanced. Intra-arterial devices were used at the discretion of the treating physician to include stent retrievers, direct aspiration, or combination therapy. The primary endpoint was measurement of blinded modified Rankin Scale (mRS) scores at 90 days. The mRS is the most widely used clinical outcome measure for stroke clinical trials; an mRS score of 2 or less is considered to be the threshold for positive stroke outcome, according to Penumbra's release about the study.

Earlier Research
The Interventional Management of Stroke III Trial (IMS-3) found no overall functional benefit of endovascular therapy after thrombolysis. The study was halted due to futility in 2012, when the researchers agreed there was almost no likelihood the combined treatment would show benefit. The IMS-3 researchers did note that there might be some benefit to adding thrombectomy in some patients with large artery strokes.2

A study known as the MR RESCUE trial sought to use brain imaging to identify patients who were more likely to benefit from treatments for acute ischemic stroke. The study also sought to learn whether endovascular thrombectomy improves clinical outcomes for some stroke patients compared to outcomes using tPA alone. Researchers examined whether neuroimaging could identify a penumbral pattern that would identify patients who would benefit from the endovascular approach. The authors concluded: "A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care."3

The SYNTHESIS Expansion trial directly compared outcomes using endovascular thrombectomy to those achieved with intravenous thrombolysis using tPA. Italian researchers reported in 2013 that at three months, there was no significant difference between the two treatment groups on the study's primary endpoint of survival free of disability.4

Since the MR CLEAN results differed from these previous studies, there was speculation as to why. In addition to the possibility of chance results, researchers have offered possible reasons for the different outcome in MR CLEAN and the previous research. In a review of the study on Medscape.com, Rory Spiegel, MD, the chief emergency medicine resident at Newark Beth Israel Medical Center in New Jersey offered several possibilities to consider:

• Patient selection: The MR CLEAN study was more selective in the patients they included. They required patients "to have an occlusion of distal intracranial carotid artery or middle cerebral artery (M1, M2) or anterior cerebral artery (A1) demonstrated with CT angiography (CTA), magnetic resonance angiography (MRA) or digital subtraction angiography (DSA)" to participate in the study.5

• Time: Patients were treated sooner that those in the IMS-3, MR RESCUE, and SYNTHESIS trial. Intravenous tPA therapy was started on average in less than 90 minutes from symptom onset. Endovascular treatments were begun on average less than 3½ hours after onset.5

• Device used: Almost all (97%) of the endovascular interventions performed utilized a modern retrievable stent device.5
Donald Frei, MD, a neurointerventional surgeon at Radiology Imaging Associates in Denver, offered this perspective on the study.

"MR CLEAN is an important milestone in the transformation of care for stroke patients, but it is not the end of the story," Frei said via a release on the study. "Neurointerventional surgery is a relatively young and rapidly changing field that typically outpaces clinical research, and we need to ensure that these treatments—their success evident in thousands of lives saved—continue to be evaluated in clinical trials. We are confident that when designed and implemented correctly, clinical studies will continue to show positive results."

— A Radiology Today staff report

1. Berkhemer OA, Fransen PSS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20.

2. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903.

3. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914–923.

4. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(10):904-913.

5. Spiegel R. MR 'not so' CLEAN: more questions than answers. Medpage Today website. http://www.medpagetoday.com/Neurology/Strokes/48560. Updated November 13, 2014. Accessed January 21, 2015.