ISTANBUL, Turkey — For patients with acute ischemic stroke caused by an intracranial arterial anterior-circulation occlusion, intra-arterial treatment is effective and safe when given within 6 hours of stroke onset, a recent study shows.
These results from MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands) conflict with those from other recent randomized controlled trials of intra-arterial treatment, which showed no effect of intra-arterial treatment on functional outcomes.
Back-to-back results of the SYNTHESIS Expansion trial, the IMS-III (Interventional Management of Stroke III) trial, and the MR RESCUE (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy) trial showing no benefit with endovascular therapy in addition to or instead of tissue plasminogen activator (tPA) stunned the stroke community when they were presented in February 2013 at the International Stroke Conference.
Presenting these new trial results here at the 9th World Stroke Congress (WSC), Diederik Dippel, MD, PhD, senior consultant in the Department of Neurology at the Erasmus Medical Center in Rotterdam, the Netherlands, explained that for the more than one third of patients with acute stroke who have a proximal intracranial arterial occlusion, intravenous (IV) alteplase within 4.5 hours of stoke onset clears the blockage in only about one third and leads to recovery in only 10%.
But now, with improved patient selection from widespread use of computed tomography (CT), quick access to treatment in the Netherlands through stroke units, and new endovascular treatment modalities, it was time to again assess intra-arterial treatment on a background of best medical management.
Beginning in December 2010, "patient accrual was faster than expected" for this 500-patient trial, Dr Dippel reported. He attributed it to the fact that the investigators worked out a strategy with the Dutch government healthcare system that reimbursement would apply to endovascular therapy only if a patient was in the study.
Open-Label but Blinded Assessment
Patients (age 18 years or older) had acute ischemic stroke of the anterior circulation. Those in the intervention group received intra-arterial treatment within 6 hours from symptom onset. National Institutes of Health Stroke Scale (NIHSS) scores were 2 or greater. The trial was open label but used blinded assessment of functional outcome at 90 days as well as blinded neuroimaging at baseline and 90 days.
Functional outcome at 90 days was assessed by a structured telephone interview and masked report for modified Rankin Scale (mRS) and Barthel Index for the level of disability and the EQ-5D as a measure of health outcome. A central committee comprising two blinded assessors (with a third if there was a disagreement) rated the outcomes.
The endovascular intervention consisted of arterial catheterization with a microcatheter to the level of occlusion for delivery of mechanical treatment or a thrombolytic agent, or both. Mechanical treatment could use a retrievable stent, thrombus retraction, aspiration, or wire manipulation. All effect analyses were adjusted for age, time from stroke onset to randomization, previous stroke, atrial fibrillation, diabetes, and carotid terminus occlusion.
After baseline CT and CT angiography, 233 patients were randomly assigned to endovascular therapy; of these, 196 received the treatment. All 233 were assessed for mRS score at 90 days. Of 267 patients randomly assigned to the control group, 1 received intra-arterial therapy. All patients in the study received standard stroke therapy.
The intervention and control groups were well balanced: Average ages were 65 and 66 years, 58% and 59% of patients were male, average NIHSS scores were 17 and 18, and 87% and 91% of patients were treated with IV alteplase, respectively. They were also approximately equivalent in terms of location of the occlusion: about 25% to 30% in the internal carotid artery terminus, about 61% to 66% in the M1 segment of the middle cerebral artery, just under 10% in the M2 segment, and under 1% in the A1/A2 segments of the anterior cerebral arteries. The groups were also well matched for the time of onset to the start of IV alteplase (85 to 87 minutes) and time to randomization (196 to 204 minutes).
Endovascular treatment involved retrievable stents in 97% of the cases. The remaining patients underwent other mechanical interventions or, in one case, alteplase alone. The time from onset to groin puncture was 260 minutes.
The endovascular procedure was associated with a shift to improved function at 90 days, as reflected in more patients who shifted to lower mRS categories, with an adjusted odds ratio of 1.67 (95% confidence interval [CI], 1.21 - 2.30).
Table 1. Proportion of Patients in Each mRS Category at 90 Days
|mRS Score||Endovascular Intervention (n = 233) (%)||Controls (n = 267) (%)|
Whereas 92% of patients in the endovascular treatment group had a complete occlusion at presentation (modified Thrombolysis in Cerebral Infarction [mTICI] score, 0), half had good flow after the intervention. On CT angiography, the control group exhibited about 32% recanalization compared with about 80% for the endovascular treatment group at 24 hours (adjusted odds ratio, 6.9; 95% CI, 4.3 - 10.9).
Table 2. Postintervention mTICI Score
|mTICI Score||Patients (%)|
|0 - 1 (no or limited perfusion)||20|
|2a (less than half perfusion)||21|
|2b (half or greater perfusion)||35|
|3 (full perfusion)||24|
The intervention group had slightly more patients with at least one serious adverse effect than did the control group (47% vs 42%, respectively). Parenchymal hemorrhage type 2 (hematomas involving greater than 30% of the infarct with mass effect) occurred in 6.0% vs 5.2%, a new ischemic stroke in a different vascular territory in 5.6% vs 0.4%, and hemicraniectomy in 6.0% vs 4.9%, respectively.
However, fewer patients in the intervention group had pneumonia (11% vs 15%). The death rates at all time points out to 90 days were essentially the same in the two groups.
On the secondary outcome of NIHSS score, the intervention group started at baseline with a score of 17, compared with 18 for the controls. Both groups were improved at 24 hours and at 1 week, with the biggest improvement in the intervention group. The difference in NIHSS scores between the groups was 2.3 points at 24 hours and 2.9 points at 1 week. At 90 days, the Barthel Index scores also reflected superior improvement among the intervention group, but there was no significant difference on the EQ-5D scores.
Final infarct median volumes at 7 days were 49 mL for the intervention group and 80 mL for the control group.
In subgroup analyses, endovascular treatment was superior to controls for all age groups and, in fact, was more beneficial for the oldest elderly. The adjusted odds ratios were 1.6 (95% CI, 1.13 - 2.27) for patients younger than 80 years of age and 3.24 (1.21 - 8.62) for those 80 or older.
When broken down by NIHSS score, the intervention was not statistically better for lower scores (2 to 15 or 16 to 19) but was significantly better for the most severe strokes (20 or greater; adjusted odds ratio, 1.85; 95% CI, 1.06 - 2.31).
The intervention was also better if the time from stroke onset to randomization was 120 minutes or longer but not for shorter intervals. It was also significantly better than control treatment if IV alteplase was given but not if alteplase was withheld.
Dr Dippel concluded that intra-arterial treatment on a background of usual best stroke care was effective and safe if provided within 6 hours of stroke onset.
At the end of his talk, the audience gave him a standing ovation for carrying out such a comprehensive trial, for the clarity of his presentation, and for keeping the results a secret up to the time of the late-breaking trial presentation in the final scientific session of the WSC. But he said further confirmatory studies are still needed.
During the question-and-answer period, Joseph Broderick, MD, professor of neurology at the University of Cincinnati Neuroscience Institute in Ohio, and principal investigator of the IMS-III trial, commented, "I was impressed with the time to IV treatment, less than 90 minutes." A good part of the reason for that is that the Netherlands is a small country, and 30 Dutch centers were involved in the trial, meaning that no one is more than about a half hour from a center, he noted. Thus, these results might not be replicable in other areas with wider distances between qualified centers.
Another audience member asked whether, in light of the results of no age barrier to effective treatment seen in this trial, age limits are still ethical going forward. "They weren't, and they aren't," Dr Dippel quickly replied.
Asked to comment on the trial, session moderator Werner Hacke, MD, PhD, professor and chairman of neurology at the University of Heidelberg, Germany, said that it was important in light of the previous randomized results from the IMS-III, MR RESCUE and SYNTHESIS extension trials. Some criticisms raised at that time suggested that the devices used were of older generations.
In contrast, "many of us believe" this kind of approach "makes sense [and] has a real value, but we have to prove it," he told Medscape Medical News. "Now, in a relatively large trial we see such a clear-cut, overwhelming effect on almost all endpoints. It's reassuring."
Addressing the low numbers of patients with mRS outcomes in the 0 and 1 categories, he said this finding represents the severity of the strokes. A mean score of 16 or 17 on the NIHSS "is a pretty bad stroke with a proximal vessel occlusion. That there are even people who reach a 0, a few, and a 1, some more, this is fantastic."
He said the trial involved an ideal population for this type of study in terms of stroke severity, as well as co-treatment with a thrombolytic agent and intervention with modern endovascular technology. He noted that this was the first positive trial of this type and that there are at least 10 more running. "We need certainly two or three more positive trials, and those trials take a long time to recruit the number of patients they need," he said. The problem is that many patients are treated outside of trials.
Finally, he added, "Let's congratulate the Dutch authorities for making the wise decision only to pay for the intervention when it's done in a randomized trial. That would change the way we are doing clinical trials." He noted that, especially in the United States, "you got luxurious payments for something that was not proven," and so there is no incentive to put patients in a trial.
Dr Hacke warned that the danger inherent in the MR CLEAN results may be that people take it to be definitive, think that no more trials are necessary, and therefore do not enroll patients in ongoing trials.
The study is due to be published soon in a major medical journal.
The study was funded by the Dutch Heart Foundation with nominal support from AngioCare BV, Covidien/EV3, MEDAC GmbH/LAMEPRO, and Penumbra Inc. Dr Dippel has disclosed no relevant financial relationships. Dr Hacke is on the steering committee for SWIFT PRIME, a study to examine the adjunctive use of mechanical thrombectomy in acute stroke. Dr Broderick was a coauthor of another endovascular intervention trial, the IMS-III.
9th World Stroke Congress: Session: Main Theme 43: Late Breaking News. No abstract number. Presented October 25, 2014.
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Cite this: 'MR CLEAN' Polishes Stroke Outcome With Endovascular Therapy - Medscape - Oct 29, 2014.