For those whose beliefs are already firmly in favor of endovascular therapy for acute ischemic stroke, the publication of the MR CLEAN trial earlier this year and more recently the EXTEND-IA and ESCAPE trials only serve as a big fat, “I TOLD YOU SO!” For the perpetual disbelievers, each of these trials possesses enough flaws to discredit their findings. For the appropriately skeptical among us, though these trials initially appear to discredit our well meaning rants, on closer examination they are far more validating.
Earlier this year the publication of a large, well done, RCT examining the use of endovascular treatment for acute ischemic stroke threatened to drastically change the acute management of CVA as we know it. And though this trial was given a most unfortunate name (MR CLEAN), it marked the first time endovascular therapy has demonstrated any clinically relevant benefit (1). We have discussed this trial in depth in two previous posts. While MR CLEAN’s results were promising, there are many reasons why they should be viewed with a healthy dose of skepticism. Before we commit to a resource heavy intervention like that of endovascular therapy, more studies validating these findings are required. Since the publication of MR CLEAN, two active trials were stopped early for benefit, seeming to be the very validation for which we asked. The results of both of these studies, EXTEND-IA and ESCAPE, were recently published in the NEJM (2,3).
The first trial, Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra-Arterial (EXTEND-IA) trial, by Campbell et al, is a multi-center RCT that examined the efficacy of endovascular treatment in patients with CVA whose symptoms began within 4.5 hours of randomization. Like MR CLEAN this trial was a stunning success. In fact its results far outpaced the, by comparison, paltry benefits found in MR CLEAN. EXTEND-IA was stopped early after enrolling 70 patients for overwhelming benefit. The rate of significant improvement after 3 days (reduction in NIHSS > 8) was 80% vs 37% in the endovascular group and control group respectively. Likewise the rate of favorable outcome at 90-days (mRS of 0-2) was 71% vs 40% respectively, boasting an absolute difference of 31% (2).
The second and far more statistically robust trial is the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial, published by Goyal et al. In this trial, authors examined patients up to 12-hours after symptom onset, (though the large majority of the patients enrolled were evaluated within 3-hours of symptom onset). Like EXTEND-IA, the ESCAPE trial was an overwhelming success. Authors randomized 316 patients to either standard care or standard care plus endovascular therapy. Like EXTEND-IA, the authors found overwhelming benefits of the endovascular therapy. The rate of functional independence at 90-days (mRS of 0-2) was 53.0% vs 29.3% in favor of the endovascular arm. With authors noting a 33.7% absolute increase in positive outcomes in patients who received endovascular therapy. For the first time in the history of reperfusion therapies for acute ischemic stroke, a clinically significant mortality benefit was demonstrated. 90-day mortality was 10.4% in the endovascular group compared to 19.0% in the control group. Not to mention the surprisingly low rate of intracranial hemorrhage, (3.6% vs 2.7%) (3).
Neither trial is definitive in its own right. The EXTEND-IA cohort only examined the efficacy of endovascular therapy in 70 patients. Originally intending to enroll 100 patients, this trial was stopped prematurely after an interim analysis demonstrated such impressive results. This premature investigation of the sealed data was not performed because of a pre-planned interim analysis, but rather because of the publication of MR CLEAN (2). Though the remaining 30 patients would have most likely not have altered the results, we cannot view this poorly powered trial as anything more than hypothesis building. In isolation, EXTEND-IA can only offer a guideline for the future of endovascular management in acute ischemic stroke. Even the authors themselves conceded this point in the statistical analysis plan they published in January 2014, in which they clearly defined EXTEND-IA as a phase II trial (4). A definition that is conveniently left out of the formal publication in the NEJM, an oversight possibly induced by the unexpected magnitude of their success causing well deserved delusions of grandeur.
ESCAPE, though far more statistically hardy than EXTEND-IA, is still a rather small cohort suffering from the same unfortunate biases. Originally intending to enroll 500 patients, the authors called for an early stoppage, prior to their planned interim analysis, again because of the results of MR CLEAN. Although the sample size of 316 patients lends a stronger validity than the 70 patients examined in EXTEND-IA, the early stoppage prevents us from confidently assessing the true effect size this treatment may provide. Interestingly when implementing this unplanned analysis, the authors utilized a dichotomous outcome comparing the mRS scale of patients alive and independent (mRS of 0-2) at 90-days rather than the ordinal analysis they had originally chosen and utilized as their primary outcome when performing the power calculation. The ordinal scale has recently gained favor as an outcome measure in stroke trials because of its ability to augment the p-value and turn otherwise negative trials into statistical successes. Conversely it is almost impossible to determine the clinical relevance of the odds ratio it produces. Given the impressive benefits of both trials, the small statistical augmentations offered by ordinal analysis are irrelevant. As such the authors of both trials favored the more traditional dichotomous outcome. The 33.7% absolute difference measured by the dichotomous scale in the ESCAPE trial, appears far more impressive than an odds ratio of 2.6 offered by ordinal analysis (3).
With the overwhelming success of both EXTEND-IA and ESCAPE, the MR CLEAN data appears almost lacking. In the MR CLEAN cohort, patients randomized to receive endovascular therapy had a 14% absolute benefit over those in the controls. It is safe to say neither group did all that well, with the amount of patients alive and independent at 90-days reported as 33% and 19% respectively(1). The EXTEND-IA and ESCAPE cohorts however did exponentially better (71% vs 41% and 53.0% vs 29.3% respectively) (2,3). Are we truly looking at the same patients as were examined in MR CLEAN, or do the EXTEND-IA and ESCAPE cohorts represent a completely different population?
It should come as no surprise that both the EXTEND-IA and ESCAPE cohorts included vastly different patients than those enrolled in MR CLEAN. In MR CLEAN, to be eligible for inclusion patients were required to have an occlusion of distal intracranial carotid artery or middle cerebral artery (M1, M2) or anterior cerebral artery (A1) as identified by CT angiography (CTA), magnetic resonance angiography (MRA) or digital subtraction angiography (DSA)(1). Both EXTEND-IA and ESCAPE had far stricter inclusion restrictions. Patients who were enrolled in the EXTEND-IA cohort needed to demonstrate an ischemic penumbra on perfusion imaging with a small infarcted core(2). Though slightly different criteria were utilized, like EXTEND-IA, the ESCAPE cohort used CT angiographic imaging to identify patients with small infarcted cores and large areas of salvageable tissue (3). These inclusion criteria significantly narrowed the subset of stroke patients examined. These differences in patient selection are not only responsible for the almost unbelievable efficacy demonstrated in both of the EXTEND-IA and ESCAPE trials, they mark the first time that imaging criteria was successfully used to identify a cohort of stoke patients who may benefit from reperfusion therapy.
There has been a long history of failure in the use of perfusion imaging for the management of acute ischemic stroke. Early studies investigating the use of diffusion weighted MRI to identify potentially salvageable ischemic brain failed to show benefit (5,6,7,8,9). These failures may be due in part to the industry bias of only enrolling patients presenting > 3 hours after onset, in the hopes of extending FDA approved treatment windows and more importantly their profit margins. Though these trials showed promising rates of reperfusion, the consistently high incidence of intracranial hemorrhage overshadowed the minimal benefits. The MR RESCUE trial, published in NEJM in February 2013 was the first to utilize this technology to identify potential candidates for endovascular therapy (10). Again this trial failed to demonstrate that patients with ischemic penumbrae benefitted from revascularization. However this may have been due more to the trial’s flawed design than the technology’s deficiencies. The authors of MR RESCUE only enrolled patients after initial IV tPA failure. In contrast to these historical failures both the EXTEND-IA and ESCAPE cohorts, unencumbered by fears of disproving tPAs early successes, aggressively pursued reperfusion therapy after salvageable tissue was identified on CT imaging. In doing so, these trials have, for the first time, identified the population that will most likely benefit from reperfusion therapy.
At the risk of sounding optimistic, both EXTEND-IA and ESCAPE are impressively positive trials. Although small and methodologically flawed, with likely exaggerated effect sizes, when viewed in concert with MR CLEAN, these trials present endovascular therapy in a promising light. For some time now legitimate cries for more data regarding tPA’s safety and efficacy in acute ischemic stroke management have been disregarded and marginalized. This almost fanatical acceptance based around the success of the NINDS trial, a single poorly powered study which treated patients with IV tPA within 3-hours of symptoms onset. Despite the many methodogical flaws of NINDS, its results were never duplicated because of the pharmaceutical industry’s fear of losing the tenuous ground they had gained. Although there are significant harms associated with the administration of tPA, the literature has consistently suggested that there is a subset of patients who will benefit from its administration. Rather than working to identify this narrow population, we have witnessed an industry driven effort to expand the indications for reperfusion therapy. EXTEND-IA and ESCAPE have identified potential cohorts of patients who will likely benefit from reperfusion therapy. If these results can be confirmed, no longer will we be forced to use the blunt tool of perceived time from symptom onset to determine which patients are eligible for treatment. These trials should inspire us to not only explore the successful utilization of endovascular therapy, but also reexamine the harmful practice of thrombolytic therapy we currently employ.
- Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:(1)11-20.
- Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection. N Engl J Med. 2015.
- Goyal M, Demchuk AM, Menon BK, et al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. N Engl J Med. 2015.
- Campbell BC, Mitchell PJ, Yan B, et al. A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA). Int J Stroke 2014;9:126-132
- Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h after stroke in the echoplanar imaging thrombolytic evaluation trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7:299–309.
- Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. 2006;60:508–517
- Hacke W, Albers G, Al-Rawi Y, et al. The desmoteplase in acute ischemic stroke trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66–73.
- Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37:1227–1231.
- Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8:(2)141-50.
- Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J 2013;368:(10)914-23.
University of Maryland
Resuscitation Fellowship Graduate