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FigureIf the latest research news about acute interventions for ischemic stroke has given you a sense of whiplash, you're probably not alone. The 2012 IMS III trial comparing endovascular therapy after tPA with tPA alone was stopped early for futility. The combination therapy demonstrated similar safety to tPA alone, but on the primary endpoint — improved functional independence according to the modified Rankin scale — endovascular therapy after tPA was not significantly better than tPA alone. An entire session of the Stroke Conference was even dedicated to IMS III in April 2013. But over the past eight months, no fewer than four major trials have released results showing precisely the opposite: endovascular therapy (usually following tPA) improves function and, in at least one study, even decreases mortality compared with usual care (most often tPA alone). The first of the studies, the Dutch MR CLEAN trial reported in the New England Journal of Medicine, found that patients undergoing clot removal by stents in combination with tPA were functioning better 90 days after the stroke than patients who received tPA alone. (2015;372[1]:11; http://bit.ly/1aLInwZ.) Those who received endovascular therapy in that 500-patient trial showed a significant shift toward better outcomes consistently across all categories on the modified Rankin scale, except for death. The trial was supported by unrestricted grants from AngioCare Covidien/ev3, Medac/Lamepro, and Penumbra, and five investigators received fees from Covidien, Stryker Neurovascular, or Penumbra. Nearly twice as many patients in the interventional arm had an mRS score of 0 to 2 compared with the control arm. A total of 32.6 percent achieved a clinically defined positive stroke outcome compared with 19.1 percent of those who received medical management. Intra-arterial treatment was even beneficial for the elderly (80+), a population for whom intervention was previously thought to be risky. Several explanations likely account for this 180-turnaround in results compared with IMS III, the authors noted. IMS III only used the first-generation Merci retrieval device while MR CLEAN used newer-generation retrieval devices that have demonstrated superiority. And unlike IMS III, MR CLEAN required a radiologically proven intracranial occlusion, something that was challenging to do in IMS III given the then-limited availability of CT angiography. A virtual blizzard of positive results for endovascular stroke treatment echoed MR CLEAN's findings at the 2015 International Stroke Conference in February. The ongoing SWIFT-PRIME, ESCAPE, and EXTEND 1A trials all reported positive results for endovascular thrombectomy in their interim analyses.Figure: The clot in this patient was successfully retrieved eight hours after symptom onset in a patient with basilar artery occlusion and very poor initial neurologic exam, left. The digital subtraction angiography image, center, shows the complete occlusion (arrow) in the left vertebral artery distal to the origin of the left posterior inferior cerebellar artery (black arrowheads), with nonvisualization of the basilar artery. The clot was removed by the distal coiled nitinol loops of a MERCI retriever, right. The patient had mild neurologic deficits the day following the procedure, and made a full clinical recovery in the subsequent three months.The Canadian ESCAPE trial, which randomized 316 patients before the trial was stopped because of positive results, found the adjusted risk ratio for a mRS shift with thrombectomy at 90 days was 3.1. A total of 53 percent of thrombectomy patients achieved a mRS of 0-2 at 90 days compared with 29.3 percent in controls (p<0.001). In contrast with MR CLEAN, mortality was also significantly lower in the intervention group: 10.4 percent compared with 19 percent in the control group. The trial was also supported by Covidien, and 13 researchers received fees from Covidien, Stryker Neurovascular, Penumbra, or Edoxaban. (New Engl J Med 2015;372[11]:1019; http://bit.ly/1yLP3Xx.) EXTEND-1A, which was supported by an unrestricted grant from Covidien, which makes the stent retriever used in the study, randomized just 70 patients before interruption. Early neurologic improvement — NIHSS reduction of 8 points higher or NIHSS 0-1 at three days — was 80 percent in the intervention group vs. 37 percent in the control group (p<0.001). A total of 71 percent of the thrombectomy patients achieved mRS 0-2 at 90 days vs. 40 percent of controls (p<0.01). Mortality was lower in the intervention group (9% vs 20%), although it did not achieve statistical significance, possibly because of the relatively small number of patients accrued before interruption. (New Engl J Med 2015;372[11]:1009; http://bit.ly/1G17rZx.) One of the authors in the EXTEND-1A trial received fees from Covidien. Finally, SWIFT PRIME, also supported by Covidien, accrued 196 patients before interruption after its positive interim analysis. The odds ratio for a mRS shift at 90 days with thrombectomy was highly significant (p=0.0002), and 60.2 percent of thrombectomy patients achieved mRS 0-2 at 90 days compared with 35.5 percent in the control group (p<0.0001). As with EXTEND-1A, mortality was lower in the intervention group at 90 days (9.2% vs. 12.4%), but did not achieve statistical significance. (New Engl J Med 17 April 2015; http://bit.ly/1P6sDUI.) Nineteen of the researchers in the SWIFT PRIME study received feeds from Covidien, Penumbra, or Stryker Neurovascular. “I think the biggest difference between these studies and previous studies that were unable to show benefit is that these new devices are a lot more effective at opening the targeted vessel than previous devices,” said Ryan Radecki, MD, an assistant professor of emergency medicine at the University of Texas Health Sciences Center at Houston. “A 50-70 percent recanalization rate compared with a 90 percent recanalization rate will significantly affect outcomes.” (The trials primarily or exclusively used Covidien's Solitaire stent retrieval device.) The trial designs in general also carefully selected patients based on substantial collateral flow to the ischemic penumbra. “Patients with big lesions, but a lot of collateral circulation behind the infarct core have significant salvageable tissue,” Dr. Radecki said. “What's interesting is that in some of these studies, time didn't seem to matter as much as the presence of viable brain. If there isn't salvageable tissue, you could get to the clot in 90 minutes and it might not help, but if there is, you could probably start much later. This tells us that we should probably be making a lot more triage decisions based on perfusion.” Dr. Radecki said he would have liked to have seen the studies run to completion. “Yes, they met the criteria for stopping early for benefit, but more patients means more safety information and a better idea of who to exclude or target,” he said. “It will be important to have an ongoing registry and monitoring to better identify who this does and does not work for.” Brian Alper, MD, a clinical research assistant professor in family and community medicine at the University of Missouri School of Medicine and the founder of the clinical reference tool DynaMed, is cautiously optimistic. “Stent retrieval looks like an effective therapy in an area where we don't have a lot of effective therapy,” he said. “We could still use more information and more experience to know which patients it is best suited for and exactly when to apply it, but stent retrieval-based therapy looks significantly better than thrombectomy approaches that did not include stent retrieval as well as other approaches. As many of these well-done trials showing this benefit just came out literally in the past few weeks, we may start to see some more insights and nuances as people have time to give more commentary.” With all the discussion about stent retrieval, however, questions about the appropriate use of tPA seems to have shifted to the background. Most although not all of the patients in the four stent retrieval trials received IV tPA prior to endovascular therapy, although the windows for tPA differed substantially among the trials. The window for initiation of tPA (without addressing whether the patient might subsequently undergo thrombectomy) has recently been expanded from three hours to 4.5 hours in the United States and Europe based in large part on the European Cooperative Acute Stroke Study (ECASS-3). But the “stentrieval” trials went a step further: MR CLEAN randomized patients if intra-arterial therapy could begin within six hours of symptom onset; ESCAPE randomized patients if they arrived within 12 hours of symptom onset and were otherwise eligible. But Dr. Alper and his DynaMed colleagues suggested that the data on safety and efficacy of tPA outside the three-hour window remain inconsistent at best in a comprehensive evidence analysis published in the British Medical Journal. (2015 Mar 17;350:h1075.) “For example, some data support an increase in good functional outcome at three months, and others show a worse functional outcome at six months. As such, any single estimate of effect from currently available data is therefore likely to be unreliable,” they wrote. They also note that use of tPA outside the three-hour window is associated with a significantly increased risk of fatal intracranial hemorrhage. DynaMed provides open access to its continuously updated evidence page on thrombolytics for acute stroke at http://bit.ly/1H9j06F. Dr. Alper also noted that no real data are yet available on stent retrieval in patients who did not first receive tPA. “The most robust trials supporting endovascular therapy were done in populations that had mostly received IV tPA,” he said. “We don't have the same robust data on people who didn't get tPA. My personal take is that if a patient is seen within three hours where tPA is a good option, then endovascular therapy should be considered in addition, especially if the imaging shows a treatable lesion where you may get further benefit. And if the patient is not eligible for tPA for a reason that does not contraindicate a stent, such as presenting more than three hours after stroke onset, endovascular therapy could be an optimal treatment without tPA.” Dr. Radecki said he hopes patient selection for endovascular therapy will remain conservative. “It looks like you have to narrowly select patients to be successful,” he said. “I hope we don't see ‘indication creep’ like we have with tPA.” Probably one of the biggest impacts on emergency medicine will be changes in the EMS triage model, he predicted. “The best possible care calls for cerebral angiography and perfusion, and most ERs aren't set up to do that on a routine basis. I think we will see more diversion from certified to comprehensive stroke centers with the ability to do these kinds of studies 24/7.” Share this article on Twitter and Facebook. Access the links in EMN by reading this on our website or in our free iPad app, both available at www.EM-News.com. 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