A large new trial provides the first substantial evidence that new devices can improve the outcome of patients who have acute ischemic stroke. Earlier, less sophisticated versions of the devices had produced disappointing results in clinical trials. The previous trials may also have been hindered by long treatment delays and difficulties in recruiting suitable patients. The new devices are retrievable stents that extract blood clots from inside vessels.
MR CLEAN (The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), published in the New England Journal of Medicine today, was designed to address the limitations of these previous trials. 500 patients with ischemic stroke were randomized to usual care or the addition of intraarterial treatment within 6 hours of symptom onset. 90% of patients in both groups received intravenous alteplase, considered the current standard of therapy. More than 80% of patients in the intraarterial treatment group were treated with a contemporary retrievable stent. Treatment was open label but the endpoint evaluation was blinded.
There was a significant difference between the groups in outcomes. For the primary outcome measure, there was a one point reduction in the modified Rankin scale at 90 days, from 4 in the control group to 3 in the treatment group. 32% of patients in the treatment group and 19% of patients in the control group were functionally independent (modified Rankin score 0-2). The results were consistent across all prespecified subgroups.
There was no difference in mortality between the groups. More patients in the treatment group had clinical signs of a second ischemic stroke in a different vascular territory (5.6% versus 0.4%).
In addition to the use of retrievable stents, the authors speculated that a key factor in the success of intraarterial therapy in their trial was that all patients had a radiologically proven intracranial occlusion.
In an accompanying editorial, Werner Hacke praises the trial as a "first step in the right direction" but believes that it is too early to proclaim thrombectomy "the new standard treatment for severe stroke with proximal large-vessel occlusion up to 6 hours after stroke onset." Several ongoing trials are still needed, he writes.
A Word of Caution
It would be wise to view this trial with some caution. In his editorial 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." Don't expect similar caution from other corners, though. The pressure from industry and KOLs (key opinion leaders) supported by industry will be quite intense. Indeed, even before the trial was published in the New England Journal of Medicine PR companies were offering up embargoed interview opportunities to journalists with trial investigators and other leading figures in the field. Writing in Mass Device, Brad Perriello notes that "medical device makers are jumping on the bandwagon of the Mr. Clean trial" and "wasted no time in touting the results." Device makers whose thrombectomy devices were used in the trial include Penumbra, Covidien, and Stryker.
Several ongoing trials are now underway that may confirm the findings of MR CLEAN. But it would be a mistake to think these trials are now a slam dunk. Ischemic stroke has proved a notoriously difficult target. With the exception of a few trials of thrombolysis, all the trials have been negative. One Emergency Medicine physician, Ryan Radecki, expressing skepticism about MR CLEAN in a blog, wrote about these trials:
As has been well-documented, a few trials were positive, many were neutral, and a few were stopped early for harm or futility. To most of us, this indicates a therapy for whom only a small subset of those treated are ideal candidates for benefit, and the margin between benefit and harm is razor thin.
Radecki's analysis suggests that a similar situation will emerge with thromboectomy devices. It is unclear whether the new generation of thrombectomy devices is truly superior to the earlier generation devices that yielded negative results. Thrombectomy may prove beneficial, in some patients and in some clinical situations, but it may well not be widely beneficial in a broad spectrum of stroke patients.
See also this analysis of an earlier presentation of the MR CLEAN trial by another emergency medicine resident, Rory Spiegel.