Endovascular Stroke Therapy Proven at Last: MR CLEAN Published

December 17, 2014

The first trial to have shown a benefit on functional outcomes of an intra-arterial interventional approach for treating stroke vs the current standard of care has been published to widespread acclaim from experts in the field.

MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), published online in the New England Journal of Medicine on December 17, showed a clinically significant increase in functional independence in daily life by 3 months in patients with an occluded major cerebral artery who underwent endovascular intervention, most of whom had already received thrombolysis.

"Our study shows that intra-arterial treatment works. Patients are left with less handicap if they are treated with the endovascular approach," senior author, Diederik Dippel, MD, Erasmus MC University Medical Center, Rotterdam, the Netherlands, commented to Medscape Medical News.

Other stroke experts involved in this area were excited by the results.

"A Real Watershed Moment"

"This is great news — a real watershed moment," said Joseph Broderick, MD, professor of neurology at the University of Cincinnati Neuroscience Institute in Ohio and lead investigator of the previous IMS-III [Interventional Management of Stroke III] trial, which showed a neutral result with endovascular therapy. "The key thing is now we have the data to support the place of endovascular therapy. It will now be used for patients with occlusion of the major cerebral artery who present within in 6 hrs. How best to use these tools and the time window will be refined after further studies report."

The MR CLEAN results were first presented (and reported by Medscape Medical News) at the World Stroke Congress in Istanbul in October. Referring to that presentation, Dr Broderick commented: "This was one of the few times I've seen the whole audience stand up and give applause at a scientific meeting."

Werner Hacke, MD, University Hospital, Heidelberg, Germany, author of an accompanying editorial, told Medscape Medical News that this represents "a long awaited-breakthrough.

"We have been trying to show benefit of mechanical recanalization in ischemic stroke patients for years without success. Stroke is one of the most frequent major medical episodes in the world, and we have only ever had two positive trials in the hyperacute setting — both showing benefit of tPA (tissue plasminogen activator). Now we have a third."

In addition, four other similar studies have recently been stopped early, at least two because of benefit in the endovascular group. Results from some of these studies will be presented at the International Stroke Conference in February 2015.

Keith Muir, MD, Glasgow University, United Kingdom, who is heading up a similar British trial (PISTE [Pragmatic Ischaemic Stroke Thrombectomy Evaluation]), added: "It is fantastic to be a position to have finally got some positive results. Massive congratulations need to go to the investigators and the Dutch government who made it happen by doing the trial properly."

MR CLEAN has succeeded where several others have failed. Three recently published studies showed no benefit of an interventional approach after thrombolysis.

Dr Dippel said the keys to the success of MR CLEAN were "selecting the right patients to target, using the latest devices, and doing the intervention quickly."

Evidence for Occlusion Key

He explained that a crucial factor in the study design was the requirement for radiological evidence of occlusion of a major cerebral artery. "These patients have very large clots and [intravenous] tPA alone is often inadequate to clear them. Thrombolysis dissolves the clot in only about one third of these patients. That leaves a lot of room for improvement. In our study the intra-arterial intervention removed the clot in 60% to 80% of cases."

He added: "Standard treatment of stroke, including tPA if indicated, leads to one in five of these patients having a good outcome. With intra-arterial intervention as in our study one in three patients had a good outcome. That is a huge improvement."

Dr Dippel noted that this was one of the major differences between MR CLEAN and IMS-III. "When IMS-III was done, CT [computed tomographic] angiography wasn't routinely available so in many cases it wasn't known if the patient had an occlusion or not. It is unlikely that intra-arterial treatment will alter the natural history of acute ischemic stroke in the absence of a proximal arterial occlusion, so they probably included many patients who didn't need the therapy," he said. "And in a post hoc analysis they showed a benefit of endovascular treatment in the patients who did have proven occlusion, very consistent with our results."

Dr Hacke agreed on this point. "Use of CT angiography is a 'no brainer'," he said. "If you want to perform a trial to remove a clot then you have to make sure there is a clot in the artery to be removed."

Dr Dippel explained that CT angiography was performed in the emergency department of the interventional hospitals. "About half the patients had come straight to these hospitals, so the CT angiography was done soon after thrombolysis was started. The other half were transferred from other hospitals where they had already been given tPA. So by the time they had the CT angiography the clot might have been lysed and then they wouldn't be randomized. But in those that were randomized, the interventional approach benefited both those treated early after thrombolysis and those treated later."

Latest Generation Stent Retrievers

The other main difference in MR CLEAN was that the latest-generation stent retrievers were used in most patients given endovascular treatment. The trial allowed several different options for intervention, but the majority of procedures used one of the latest-generation stent retrievers.

At time of treatment, all patients in MR CLEAN were given endovascular therapy within 6 hours of symptom onset. Dr Muir noted that this is very fast and reflects the good set-up for stroke care in the Netherlands. Some of the other trials reporting in February have treatment out to 12 hours.

Dr Dippel added: "Some patients had no tPA — they arrived too late or had contraindications. But they still responded just as favorably."

He noted another factor that helped the trial be successful: Endovascular therapy was not reimbursed in the Netherlands outside the trial, so that patients with the greatest likelihood of benefiting from this approach were entered into the study.

"The trial recruited fast as we involved all centers in the Netherlands capable of conducting intra-arterial treatment," he commented. "This procedure was being done experimentally but it was not being reimbursed. Then the government agreed to reimburse the procedure but only if the patient was enrolled in our trial. That meant we took all the eligible patients, which had the added benefit of no bias."

In his editorial, Dr Hacke says this process should be the norm for medical devices. He writes: "This policy may be difficult to implement in other health care systems but imagine what progress the medical-device field would see if this strategy were the rule."

Dramatic Effect on Clinical Practice

The MR CLEAN results, along with the other trials to be presented in February, are expected to have a dramatic effect on clinical practice. Dr Hacke commented: "Endovascular therapy was popular even though unproven until the three neutral trials were reported recently. It has diminished somewhat since then, but now it will skyrocket."

He added that certain countries, such as the United States and parts of Europe, were already set up to deliver this type of care. But other countries lack the systems to facilitate timely endovascular intervention; in these places, very few patients will be treated this way unless major restructuring takes place.

Another achievement of Mr CLEAN was the inclusion of elderly patients. "We had no upper age limit," Dr Dippel said. "The eldest patient was 96 years old. The effect was just as good in the elderly. These patients aren't normally included in such trials as they have a poor prognosis and it has been felt they have a low chance of a good outcome even with the new treatment. But our feeling was that patients with a poor prognosis give more opportunity show benefit, and this is what happened."

The trial also demonstrated benefit of endovascular therapy in patients with mild strokes, Dr Dippel added. "The patients with NIHSS [National Institutes of Health Stroke Scale] scores of 2 to 10 also showed a benefit. It is worth doing in smaller strokes."

The MR CLEAN Data

For the study, 500 patients at 16 medical centers in the Netherlands were assigned to intra-arterial treatment or to usual care alone, with 89% receiving tPA before randomization. The primary outcome was the odds ratio of achieving a lower score on the modified Rankin scale (shift analysis) at 90 days with endovascular therapy. This was achieved with an odds ratio of 1.67 (95% confidence interval, 1.21 - 2.30).

The absolute difference in the rate of functional independence was 13.5 percentage points (modified Rankin scale score, 0 to 2) in favor of the intervention (32.6% vs 19.1%).

All clinical and imaging secondary outcomes favored the intervention. The NIHSS score after 5 to 7 days was, on average, 2.9 points lower in the intervention group than in the control group.

In terms of safety, mortality, symptomatic intracerebral hemorrhage, and serious adverse events did not significantly differ between the two groups.

However, 13 patients (5.6%) in the intervention group vs only 1 patient (0.4%) in the control group had clinical signs of a new ischemic stroke in a different vascular territory.

Procedure-related complications in the intervention group included embolization into new territories outside the target downstream territory of the occluded vessel in 20 patients (8.6%), procedure-related vessel dissections in 4 patients (1.7%), and vessel perforations in 2 patients (0.9%).

The authors write: "A total of 30 patients (13%) assigned to intraarterial treatment also underwent a simultaneous second revascularization procedure (acute cervical carotid stenting), and this complexity needs to be considered when interpreting our trial results."

Other Trials Reporting Soon

Commenting for Medscape Medical News, Dr Muir stressed the importance of evaluating the data carefully before other in-progress trials of endovascular treatment were stopped.

Noting that 17 other studies are underway, he said, "MR CLEAN is fantastic news. But it will not answer every question. The Netherlands has a particularly good set-up — a small country with lots of hospitals delivering acute stroke care, so the time to treatment is fast. In MR CLEAN they had a mean time to tPA treatment of 80 minutes. That is extraordinarily short. We now all need to look at how these results are applicable to our countries, and what else needs to be investigated. All the ongoing studies are looking at different logistical set ups and addressing slightly different questions."

 
We need to be careful not to get too carried away. MR CLEAN is tremendously exciting, but are we really going to change the whole culture of acute stroke care worldwide based on only 193 people in the Netherlands who actually got the intervention? Dr. Keith Muir
 

He added: "It is always difficult to know how the equipoise moves as trials report. We need to be careful not to get too carried away. MR CLEAN is tremendously exciting, but are we really going to change the whole culture of acute stroke care worldwide based on only 193 people in the Netherlands who actually got the intervention? I think we need more robust evidence from further studies in different settings. We might be in a better position next year after the next wave of studies have reported."

This next wave of studies will include ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke) and EXTEND IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial), both of which have been stopped for benefit, and also the SWIFT-PRIME (Solitaire FR as Primary Treatment for Acute Ischemic Stroke) and REVASCAT studies, which have also both stopped enrollment. But Dr Muir pointed out that the RACE trial in France has been advised to continue, and "this is one of the larger ongoing studies."

In his editorial, Dr Hacke agrees that it would be advisable to wait for these trials before making major changes in practice.

Dr Muir also pointed out that governments would have to look carefully at the costs involved in restructuring systems to facilitate endovascular therapy, but he believes this will be cost saving. "The patients that are benefitting here are the ones who end up very badly disabled and having to be cared for in nursing homes long term. If we can prevent that then it will be extremely cost-effective. But we will have to get the powers that be to recognize that and shift resources to the acute end of stroke care."

Bruce Campbell, MBBS, Royal Melbourne Hospital, Australia, who is involved with the EXTEND IA trial, told Medscape Medical News he believes systems will be restructured to accommodate this treatment.

"Endovascular therapy needs to be performed in a slick, high-volume system which requires careful systems design and a degree of centralization," Dr Campbell said. "Although it is applicable to a relatively small proportion of stroke patients overall — perhaps about 10% — they are the group with the greatest potential for disability and therefore a critically important subgroup."

Jeffrey Saver, MD, from UCLA Comprehensive Stroke Center, Los Angeles, California, who is principal investigator of the SWIFT PRIME trial, also commented on MR CLEAN. "This study heralds a new era of acute stroke care. There is every reason to expect that these findings will be confirmed by forthcoming results from ESCAPE, EXTEND IA, SWIFT PRIME, and REVASCAT.

"The demonstration that stent retrievers further improve outcome when added to tPA marks the start of a new paradigm in acute stroke, in which we will revise our regional systems of care to provide access to neurocath lab intervention for as many patients as possible with ischemic stroke due to large artery occlusions," Dr Saver added. "Dr Dippel and all the MR CLEAN investigators are to be congratulated on completing a well-conducted, practice-changing clinical trial."

Mr CLEAN was supported by the Dutch Heart Foundation and by unrestricted grants from AngioCare Covidien/ev3, Medac/Lamepro, and Penumbra. Dr Dippel has disclosed no relevant financial relationships.

N Engl J Med. Published online December 17, 2014. Abstract Editorial

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