Critical Care Update
David J. Dries, MSE, MD, and Haitham M. Hussein, MD, MSc
Stroke: Part 2 The game has changed! After decades of skepticism, lack of evidence, and negative trials, endovascular intervention has made it to the national guidelines for the treatment of acute stroke. Over the past several months, 5 clinical trials showed benefit of mechanical thrombectomy for the treatment of ischemic stroke secondary to anterior circulation occlusion. In this column, we review the history of endovascular therapy and the recent major studies with their impact on practice.
Intravenous Thrombolysis Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587. Hacke W, Kaste M, Bluhmki E, ECASS Investigators, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329. Schwamm LH, Ali SF, Reeves MJ, et al. Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With The Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;6:543-549. Marshall RS. Progress in intravenous thrombolytic therapy for acute stroke. JAMA Neurol. 2015;72:928-934. In the mid-1990s, the National Institute of Neurological Disorders and Stroke (NINDS) trial was the first to show efficacy of intravenous (IV) tissue plasminogen activator (tPA) for the treatment of acute stroke provided that it is administered within 3 hours of symptom onset. The Food and Drug Administration (FDA) subsequently approved the medication with the patient selection criteria of the NINDS trial. A little over a decade later, the time window was extended to 4.5 hours from symptom onset based on the European trial ECAS (European Cooperative Acute Stroke Study) III. Other IV thrombolytic agents such as streptokinase and urokinase were studied but did not yield clinical benefit. Unfortunately, the rate of utilization of IV tPA remains very low. In a recent analysis of national data, the utilization rate increased from 4% in 2003 to 7% in 2011 for acute stroke patients presenting in the 3-hour time window. Of course, a major limitation is the short time window. Attempts to extend the time window using imaging criteria have failed. Ongoing trials are currently evaluating a relatively recent thrombolytic agent called tenecteplase as well as the combination of more than 1 306
thrombolytic agent. The article by Marshall provides an elegant history of the evolution of IV thrombolytic therapy. Parallel to the IV thrombolysis paradigm, efforts were made to incorporate endovascular interventions in acute stroke care for patients with contraindications to IV therapy or who have large artery occlusions. Endovascular clinical trials went through 3 main phases: intra-arterial (IA) administration of thrombolytic agents, mechanical thrombectomy devices compared with the historic control or other devices with a focus on radiologic outcome, and mechanical thrombectomy devices compared with the standard of care with a focus on functional outcome.
Intra-Arterial Administration of Thrombolytic Agents del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: A phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29:4-11. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282:2003-2011. Reports of IA thrombolysis using streptokinase and urokinase for the treatment of acute stroke began to emerge in the early 1980s. It was not until the late 1990s that the first randomized trial, Prolyse in Acute Cerebral Thromboembolism (PROACT) II, showed a benefit with directed IA infusion of a thrombolytic agent in acute stroke. PROACT II used the thrombolytic agent prourokinase, which, to this day, is not approved by the FDA and not commercially available. This agent has a unique characteristic of an improved effect through coadministration of heparin. PROACT showed safety of arterial intervention and helped refine the treatment regimen because the heparin dose was reduced and the prourokinase dose was increased in the subsequent trial. PROACT II was a multicenter trial that enrolled patients with middle cerebral artery (MCA) occlusion and randomized them to IA infusion prourokinase ⫹ IV heparin versus IA infusion of saline ⫹ IV heparin. IA treatment had to be initiated within 6 hours from symptom onset. No mechanical thrombectomy was allowed. The primary outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 2 or less at 90 days. The mRS is a measure of disability and functional state. It ranges from 0 to 6 with a score of 0 being completely free of symptoms, a score of 5 indiAir Medical Journal 34:6
cating maximum disability, and a score of 6 indicating death. An mRS score of 0 to 2 is a common definition of a good outcome in stroke research. PROACT II showed higher rates of recanalization in the treatment group (66%) compared with the control group (18%) with an absolute benefit of 15% in the rate of good outcome at 3 months, which was statically significant. The rate of symptomatic hemorrhage was 10% in the prourokinase group and 2% in the control group (P ⬍ .001). It is important to recognize that the rate of good outcome and the overall benefit were higher in the prourokinase group despite the higher rate of symptomatic hemorrhage. There was no difference in mortality between the 2 groups. Despite the PROACT II results, the FDA did not approve prourokinase for the treatment of acute stroke (or any other indication). Given the different pharmacologic properties of the various thrombolytic agents, the results of PROACT II cannot be generalized; however, it remains a landmark study that proved the benefit of IA therapy for acute stoke.
with the standard microcatheter. The EKOS has a small-vessel ultrasound infusion system that uses low-energy ultrasound to alter the structure of the thrombus and facilitate access of the thrombolytic agent to potentially accelerate thrombolysis. The 3month mortality in IMS II subjects (n ⫽ 81) was 16%, which compared favorably with the mortality of placebo (24%) and tPA-treated subjects (21%) in the NINDS trial. The rate of symptomatic intracerebral hemorrhage in IMS II subjects (9.9%) was not significantly different than that for tPA-treated subjects in the NINDS trial (6.6%). IMS II subjects had significantly better outcomes at 3 months than NINDS placebo-treated subjects for all end points (odds ratio ⫽ 2.7) and better outcomes than NINDS tPA-treated subjects in some end points.
Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke. Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999;30:2598-2605.
Smith WS, Sung G, Starkman S, MERCI Trial Investigators, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005;36:1432-1438.
IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: The Interventional Management of Stroke Study. Stroke. 2004;35:904-911. IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II Study. Stroke. 2007;38:2127-2135. The Emergency Management of Stroke study was a doubleblind, randomized, placebo-controlled multicenter phase I study that tested the feasibility, efficacy, and safety of combined IV and local IA tPA versus IA placebo for stroke within 3 hours of onset of symptoms. The sample size was very small (17 subjects in the treatment group and 18 in the placebo group). There was no significant difference in the efficacy or safety outcomes at 7 to 10 days or at 3 months. In the Interventional Management of Stroke (IMS) trial, a cohort of 80 subjects with acute stroke and NIHSS ⱖ 10 presenting in the 3-hour time window after the onset of symptoms were treated with IV tPA but with a dose that was lower than the standard dose (0.6 not 0.9 mg/kg) followed by another small dose of tPA given through the IA route so that the combined IV and IA tPA dose was slightly less than the total standard IV tPA dose. The outcomes of the study subjects were compared with the outcome of the placebo and the treatment arms of the NINDS IV tPA trial. The results of the trial showed that this combined IV and IA approach yielded a similar clinical benefit and safety outcome when compared with the treatment arm of the NINDS trial. The IMS II trial had a similar study design but used a new microcatheter to administer IA tPA—the EKOS (EKOS Corporation, Bothell, WA, USA) microinfusion catheter along November-December 2015
Mechanical Thrombectomy Devices Compared With a Historic Control or Other Devices with a Focus on Radiologic Outcome
The MERCI Retriever (Stryker, Kalamazoo, MI) was the first device to be approved by the FDA for revascularization cerebral arteries (note that it was not approved for the treatment of stroke). It is a corkscrew-like device, which assumes its coiled shape once deployed, that can engage and extract a clot. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial was conducted in 2 parts. MERCI Part 1 was a safety trial that enrolled 30 patients with symptom onset more than 3 hours and less than 8 hours. Concomitant use of IA tPA was allowed. The primary outcome was arterial recanalization (not neurologic recovery), which was achieved in 43% of patients with mechanical thrombectomy alone and 64% of patients when additional IA tPA was given. At 30 days, 50% of the patients who achieved recanalization had a good functional outcome. There was only 1 technical complication and 12 incidents of asymptomatic intracerebral hemorrhage. MERCI Part 2 was also a single-arm study that enrolled 151 patients with the same inclusion/exclusion criteria as Part 1. The primary outcomes were recanalization and procedure complications (again, not the functional state). The intention-to-treat analysis showed a recanalization rate of 46%, a complication rate of 7%, and a symptomatic intracranial hemorrhage rate of 8%. The rate of good functional outcome was 28%, similar to the control arm of the PROACT II trial, whereas the mortality rate was 44%, which was higher than the treatment arm of PROACT II.
Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial. Safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40:2761-2768. The Penumbra System (Penumbra, Alameda, CA) was the second device used for direct mechanical IA intervention for 307
stroke. The system provides 2 revascularization options: aspiration and extraction. The supporting clinical trials followed the same steps as MERCI. A small trial (20 patients) showed the safety of the device in patients with acute stroke treated within 8 hours of symptom onset, and a larger trial (125 patients) showed noninferiority compared with the MERCI Retriever outcomes. In fact, the rate of recanalization (82%) was higher than MERCI (48%), whereas the rate of symptomatic hemorrhage was 11% and the rate of procedure-related complications was 13%. At 3 months, the rate of good functional outcome (mRS 2 or less) was 25% (27% in MERCI), and the mortality rate was 33% (44% in MERCI).
Saver JL, Jahan R, Levy EI, SWIFT Trialists, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet. 2012;380:1241-1249. The Solitaire Flow Restoration device (Covidien/ev3, Dublin, Ireland) is a self-expanding stent that is fully retrievable and can be reapplied. The device approval was based on the Solitaire With the Intention For Thrombectomy (SWIFT) trial, which was a multicenter, randomized, noninferiority, parallel-group trial. The study enrolled patients with stroke symptoms who did not have radiologic evidence of large volume completed infarction and who could be treated within 8 hours of symptom onset. The primary end point was partial or complete recanalization without symptomatic intracranial hemorrhage. The planned sample size was 200 subjects; however, the trial was stopped after randomizing 113 subjects because a preplanned interim analysis showed the superiority of the Solitaire device over the Merci device with the efficacy end point achieved in 61% and 24%, respectively. The Solitaire patients also had a higher rate of good functional outcome (mRS 0-2) and lower mortality rate at 90 days although the trial was not powered to examine clinical outcomes.
Nogueira RG, Lutsep HL, Gupta R, TREVO 2 Trialists, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet. 2012;380:1231-1240. TREVO (Stryker, Fremont, CA) is another stent retriever device that was evaluated in 2 trials. In the multicenter, prospective, single-group Thrombectomy REvascularization of large Vessel Occlusions in acute ischemic stroke (TREVO) trial of 60 patients with stroke at 7 European centers, treatment with the TREVO Retriever had a recanalization rate of 92% with a rate of independent functional outcome (mRS 02) of 55% at 90 days. This was followed by the open-label randomized TREVO 2 trial in which patients with angiographically confirmed large vessel occlusion were randomly assigned to TREVO versus Merci devices. The primary outcome was target vessel recanalization and was met by 86% 308
patients in the TREVO group and 60% in the Merci group. The primary safety end point, which was a composite of procedure-related adverse events, did not differ between groups.
Mechanical Thrombectomy Devices Compared With the Standard of Care With a Focus on Functional Outcome (Table 1) Broderick JP, Palesch YY, Demchuk AM, Interventional Management of Stroke (IMS) III Investigators, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903. Despite all the previously mentioned studies showing a benefit of pharmacologic and/or mechanical thrombectomy in recanalizing cerebral vessels and hinting at a clinical benefit, the only randomized clinical trial that was designed to show the clinical benefit of an endovascular approach and was positive remained the PROACT II trial. In 2013, 3 randomized clinical trials were published showing a lack of benefit with endovascular intervention. The first one was the IMS III. This trial compared the combined IV and IA administration of tPA with standard therapy (IV tPA only). The trial was similar to its 2 predecessors, IMS I and II, in terms of inclusion/exclusion criteria with patient enrollment based on clinical criteria (NIHSS ⱖ 10 with a time window of 3 hours from the onset of symptoms). The study allowed the use of the Merci device along with the 2 devices used in IMS II, the EKOS device and the standard microcatheter. The primary outcome was an mRS score of 0 to 2, indicating functional independence. The planned sample size was 900 patients. The trial was stopped early because of futility after 656 participants had undergone randomization with a similar good outcome rate of 41% in the endovascular group and 39% in the standard treatment group, a similar mortality rate (19% vs. 21%), and a similar symptomatic intracerebral hemorrhage rate (6.2% vs. 5.9%). The trial had several limitations. The endovascular devices used in the trial were first-generation devices, which were the only available technology at the time of trial initiation. Later, newer devices were allowed, but only a small proportion of patients were treated with these new devices. By the end of the trial, the Solitaire device was used in only 5 of 334 patients treated with stent retrievers, which was reflected in the low rate of near complete or complete recanalization. Initially, the trial allowed only two thirds of the standard IV tPA dose to be used in the endovascular arm. Later in the trial, the full dose was allowed. Patients without major arterial occlusion were enrolled in the trial because the selection was based on clinical criteria only (based on previous analysis showing more than 80% likelihood of large artery occlusion when NIHSS ⱖ 10). Later in the trial, computed tomographic angiography (CTA) was used to identify arterial occlusion. The rate of procedureor device-related complications was high at 16%. There was management variability in the treatment protocol of the endovascular arm of this trial. Air Medical Journal 34:6
Table 1. Comparison of Main Features of Recent Positive Endovascular Clinical Trials Trial Name MR CLEAN ESCAPE EXTEND-IA Years of 2010-2014 2013-2014 2010-2014 Recruitment Countries
Methods
REVASCAT 2012-2014
Netherlands
US, Ireland, South Korea, and UK
Australia, New Zealand
US, Canada, France, Austria, Germany, Denmark, Spain, Switzerland
Spain
6 hours
12 hours
6 hours
6 hours
8 hours
Allowed patients to receive IV tPA if presented within 4.5 hours
Allowed patients to receive IV tPA if presented within 4.5 hours
Enrolled only patients who had IV tPA
Enrolled only patients who had IV tPA
Rate of IV tPA use (endovascular vs. control)
87% vs. 91%
73% vs. 79%
100% in both
100% in both
Included patients who had IV tPA but did not recanalize after 30 minutes of infusion and patients who had contraindication for IV tPA 68% vs. 78%
Endovascular intervention
Retrievable stent 82% Other devices 2% Intra-arterial tPA (n ⫽ 1)
Retrievable stent 86%
Retrievable stent 100%
Retrievable stent 100%
Retrievable stent 100% Angioplasty (n ⫽ 1) Intra-arterial tPA (n ⫽ 1)
Primary outcome
mRS score at 3 months
mRS score at 3 months
Median reperfusion at 24 hours
mRS score at 3 months
mRS score at 3 months
mRS 0-2 at 3 months (endovascular vs. control)
33% vs. 19%
53% vs. 29%
71% vs. 40%a
60% vs. 35%
44% vs. 28%
Symptomatic intracranial hemorrhage (endovascular vs. IV tPA)
8% vs. 6%
4% vs. 3%
0 vs. 6%
0 vs. 3%
5% vs. 2%
Mortality at 3 months (endovascular vs. control)
9% vs. 8%
6% vs. 13% (statistically significant)
9% vs. 20%
12% vs. 26%
18% vs. 16%
Qualifying time window Other clinical criteria
Results
SWIFT PRIME 2012-2014
IV ⫽ intravenous; mRS ⫽ modified Rankin Scale; tPA ⫽ tissue plasminogen activator. aFunctional independent outcome.
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Kidwell CS, Jahan R, Gornbein J, MR RESCUE Investigators, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368:914-923.
Ciccone A, Valvassori L, Nichelatti M, SYNTHESIS Expansion Investigators, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368:904-913.
The Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial examined the use of perfusion imaging to identify potential candidates for endovascular thrombolysis. This was not the first study to evaluate radiologic parameters instead of time as a surrogate marker for brain tissue viability, but it was the first trial to use this technique to guide endovascular intervention. The biological reasoning for this approach is that within the ischemic area, there is a core of an irreversibly damaged infarction surrounded by a zone of salvageable tissue, the penumbra, and that the existence and the volume of the penumbra is dependent not only on the duration of ischemia but also on other factors that vary from one ischemic lesion to another such as collateral circulation, ischemic preconditioning, and tissue resilience. The MR RESCUE trial was a randomized, controlled, open-label (blinded outcome), multicenter trial that enrolled 118 subjects with ischemic stroke caused by large vessel, anterior circulation occlusion within 8 hours of symptom onset to undergo either mechanical embolectomy (Merci or Penumbra devices) or standard medical care. Patients who were treated with IV tPA without successful recanalization were eligible for endovascular therapy if vascular imaging after IV tPA treatment showed a persistent target occlusion. All patients underwent multimodal computed tomographic (CT) or magnetic resonance imaging (MRI), which was processed on a dedicated site computer that automatically identified the patient as favorable, unfavorable, or unknown penumbra and assigned patients to treatment accordingly (stratified randomization). The primary outcome was a functional state at 3 months as measured by the mRS. The trial recruited 127 patients between 2004 and 2011 and was published in 2013. There was no difference between the 2 treatment groups (endovascular vs standard care). The identification of “favorable” versus “nonfavorable” penumbra did not influence the outcome. The main critique of the MR RESCUE trial is that the technology clearly evolved over the 8-year span during which this trial was completed. For example, the neuroimaging methodology (arterial spin labeling), which has been shown to be a more accurate method to quantify perfusion, was not used. Real-time imaging analysis that was done before randomization was frequently inaccurate. The study software successfully processed only 58% of cases, and the final pattern assignment changed after core laboratory postprocessing in 8% of cases. Endovascular intervention did not use the more recent stent retriever devices and relied mainly on older devices. Another criticism is that the time to groin puncture was more than 6 hours after the onset of stroke symptoms, which is longer than other trials of endovascular interventions.
Local Versus Systemic Thrombolysis for Acute Ischemic Stroke trial (SYNTHESIS) ran from 2004 to 2008 and assessed the feasibility, safety, and preliminary efficacy of IA thrombolysis compared with standard IV thrombolysis. The study randomized 54 patients who presented in the 3-hour time window to standard dose IV tPA or IA tPA (same dose as IV) that was allowed to be administered for up to 6 hours from symptom onset. Although there was a difference of about 40 minutes in delivering IA therapy compared with IV therapy, the functional outcome was better in the IA group without any differences in safety outcomes (mortality and symptomatic hemorrhage). The subsequent SYNTHESIS Expansion trial was similar in design to its predecessor with a few modifications. The time window was expanded from 3 to 4.5 hours after the onset of symptoms. The endovascular therapy included pharmacologic and/or mechanical options according to the interventionalist’s discretion. The primary end point was functional state at 3 months. The trial randomized 181 patients to the IV arm and 181 patients to the endovascular arm. There was no difference between the 2 study groups in terms of functional or safety outcomes. One criticism of this study was the significant difference between the time from symptom onset to IV tPA and the time from symptom onset to endovascular therapy—a whole hour (2.75 vs. 3.75 hours). Another important criticism is that endovascular therapy used latest generation stent retriever devices in only 23 patients.
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Berkhemer OA, Fransen PS, Beumer D, MR CLEAN Investigators, et al. A randomized trial of intraarterial treatment of acute ischemic stroke. N Engl J Med. 2015;372:11-20. The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) will be remembered as the first trial to show an unequivocal benefit of endovascular intervention for acute stroke. Five hundred patients were randomized to endovascular therapy plus standard care (which included IV tPA for appropriate patients) versus standard of care alone. Patients were eligible for the trial with an NIHSS score as low as 2 as long as they had a proximal arterial occlusion in the anterior cerebral circulation confirmed on imaging (mandatory CTA or magnetic resonance angiography before randomization), and IA treatment was available within 6 hours of the onset of symptoms. The primary end point was functional outcome at 90 days as measured by the mRS. There was an absolute difference of 13.5 percentage points in the rate of good outcome (mRS 0-2) in favor of the intervention (32.6% vs. 19.1%). The shift toward better outcomes in favor of the intervention was consistent for all categories of the mRS, except for death. Air Medical Journal 34:6
All clinical and imaging secondary outcomes favored the endovascular arm. There were no differences in mortality or hemorrhage rates between the 2 groups. It is important to recognize that 445 of 500 patients were treated with IV tPA, which indicates that the benefit of endovascular treatment was over and above the benefit from IV tPA. Eight-two percent of patients in the endovascular arm were treated with stent retrievers, whereas only 0.4% (1 patient) was treated with pharmacologic monotherapy. Finally, 13% of patients assigned to IA treatment also had a second revascularization procedure (cervical carotid artery stenting), which may have affected study results.
Goyal M, Demchuk AM, Menon BK, ESCAPE Trial Investigators, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019-1030. The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial was the second trial to report efficacy of endovascular treatment. This trial randomly assigned patients with acute stroke to receive standard care or standard care plus mechanical thrombectomy. There were important differences in study design between the ESCAPE and MR CLEAN trials. ESCAPE widened the treatment window from 6 hours to 12 hours but used more restrictive selection criteria, which included NIHSS ⬎ 5, with only internal carotid artery and MCA occlusion allowed and, more importantly, excluding patients with poor collateral flow and those with large infarction on noncontrast CT scans as assessed by the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). ASPECTS is a 10-point scoring system to quantify early ischemic changes in the MCA territory, with a score of 10 indicating normal and 1 point subtracted for each abnormal region such that a score of 0 indicates complete infarction of the whole MCA territory. ESCAPE excluded patients with ASPECTS score of 0 to 5. The primary outcome was the rate of functional independence at 3 months. After the results of the MR CLEAN trial were announced, an unplanned interim analysis was conducted, which showed efficacy of endovascular therapy with a higher rate of good outcome compared with the standard of care arm (53.0% vs. 29.3%, P ⬍ .001). Also, endovascular intervention was associated with reduced mortality (10% vs. 19%, P ⫽ .04), making it the first treatment in the history of acute stroke care to have a mortality benefit. Based on these results, ESCAPE was prematurely stopped after the enrollment of 316 patients out of 500 planned. There are important lessons to learn from the ESCAPE trial. First, we can expand the time window for the treatment of stroke if we focus on patients who are more likely to benefit from treatment. Despite enrolling patients for up to 12 hours after symptom onset, symptomatic intracerebral hemorrhage occurred in only 3.6% of patients receiving endovascular intervention (70% of whom had IV tPA before the intervention) and 2.7% of patients receiving only IV fibrinolysis. The second lesson is the clinical utility of multiphase CTA being November-December 2015
not only sensitive in detecting arterial occlusions but also less vulnerable to patient motion than CT perfusion, requiring no additional contrast and allowing for quick determination of collateral status. The third lesson is speed. The “time is brain” concept is well established in the field of stroke, but ESCAPE had a strong focus on speed of assessment and treatment. This was reflected on the trial aim, methods, and conduct. For example, ESCAPE discouraged MRI and encouraged multiphase CT imaging. Also, ESCAPE coined the concepts “first CT image to groin puncture” and “first CT image to reperfusion” and had specific target time windows of 60 and 90 minutes, respectively. The median time from study CT to first reperfusion was 84 minutes, and the median time from groin puncture to first reperfusion was 30 minutes. Finally, mechanical thrombectomy should use contemporary devices (retrievable stent used in 86% of patients).
Campbell BC, Mitchell PJ, Kleinig TJ, EXTEND-IA Investigators, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372:1009-1018. The Extending the Time for Thrombolysis in Emergency Neurological Deficits—Intra-Arterial (EXTEND-IA) trial was designed to examine the impact of endovascular therapy with more advanced image selection to identify patients with the greatest chance of good outcome with intervention after stroke. This trial applied even more stringent radiologic selection criteria than the ESCAPE trial to identify patients who were likely to benefit in order to minimize the phenomenon of futile recanalization. The study used perfusion imaging and new imaging processing software and had contemporary definitions for salvageable penumbra. Randomly assigned patients with ischemic stroke received standard IV tPA and either endovascular thrombectomy with the Solitaire FR or IV tPA alone. Enrollment was limited to patients with occlusion of the internal carotid artery or the MCA and a core infarct of less than 70 mL as measured by CT perfusion. Conduct of trial was suspended after the MR CLEAN trial was reported with only 70 patients enrolled (35 in each group). Endovascular therapy reperfused 100% of identified ischemic territory versus 37% of ischemic territory reperfused in patients receiving IV fibrinolytic therapy. Endovascular therapy initiated at only 210 minutes after the onset of stroke led to functional independence in 71% versus 40% of patients receiving conventional therapy. The rate of symptomatic intracranial hemorrhage and death was comparable between these 2 groups. These results met the prespecified stopping rule, and the trial was ended early. EXTEND-IA is unique in that it showed for the first time in a phase III trial that CT perfusion imaging is an efficient and consistent means to identify patients with clinically significant salvageable ischemic brain. However, it is important to recognize that using the CT perfusion methodology described in EXTEND-IA excluded approximately 25% of clinically eligible patients with vessel occlusion, raising the question about treatment efficacy in that group. 311
Jovin TG, Chamorro A, Cobo E, REVASCAT Trial Investigators, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296-2306. Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT) was a Spanish trial, which randomized approximately 200 patients to IV tPA versus IV tPA plus thrombectomy with a Solitaire stent retriever system. The study selected patients who were treated with IV tPA in the 4.5-hour time window but did not recanalize or those who had a contraindication to IV tPA. Inclusion criteria included a baseline NIHSS of at least 6 points, visualization of an occlusion of the MCA with or without concomitant internal carotid artery occlusion, and ASPECTS of 7 or more if CT scan was used or 6 or more on diffusion weighted imaging if MRI was used. The results in this trial favored thrombectomy. The absolute between-group difference in the proportion of patients who were functionally independent (mRS 0-2) was 15.5%, favoring thrombectomy (43.7% vs. 28.2%; adjusted odds ratio ⫽ 2.1; 95% confidence interval, 1.1-4.0). A strength of this trial, as described by the authors, is the emphasis on consecutive patient enrollment. Previous trials may be criticized for a lack of consecutive patient enrollment leading to the possibility of “cherry picking.” A consistent retriever technology was used. A limitation of the trial acknowledged by the authors is inconsistent stroke imaging before intervention. This may have allowed the inclusion of patients with larger infarct sizes than other trials. Despite this, the study reports a remarkably low rate of symptomatic intracranial hemorrhage at 1.9% in both of the study groups. The rate of death was 18.4% in the thrombectomy group and 15.5% in the group receiving medical therapy alone. This death rate seems high relative to other recent trials and may reflect that many patients with hemorrhagic complications went on to die. Nonetheless, these data add to the evidence favoring endovascular intervention after stroke and extended the time window for treatment to 8 hours. REVASCAT is the only endovascular clinical trial out of the 5 recent trials that had a time window of 8 hours. Three of the other 4 studies had a time window of 6 hours.
Saver JL, Goyal M, Bonafe A, SWIFT PRIME Investigators, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285-2295. The Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) trial was funded by Covidien, the company that manufactures Solitaire stent retriever, and was designed and led by a steering committee that included academic investigators and representatives of the sponsor. This is another trial confirming the benefits of thrombectomy combined with IV tPA versus IV 312
tPA alone. Selection criteria included anterior intracranial circulation occlusion stroke treated with IV tPA within 4.5 hours in the absence of large ischemic core lesions and a time window for endovascular treatment of 6 hours from symptom onset. Similar to a number of previous trials, this trial was stopped early because of efficacy. Thrombectomy patients had good outcome (defined as mRS 0-2) in 60% of cases versus 35% of subjects receiving IV tPA alone. Ninety-day mortality was not significantly different (9% vs. 12%), and symptomatic intracranial hemorrhage was a remarkably low 0% in the group receiving thrombectomy versus 3% in patients receiving IV tPA. Even in the setting of optimal technology use, speed is still essential to achieve the best outcomes. Another benefit in this trial was the consistent use of a rapid image analysis system, which was operator independent. Thus, this potentially time-consuming step was streamlined. SWIFT PRIME only enrolled patients who were treated with IV tPA; therefore, the benefit of endovascular intervention reported is added to the benefit of IV tPA.
Powers WJ, Derdeyn CP, Biller J, et al. 2015 AHA/ASA focused update on the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. http://stroke.ahajournals.org/ search?fulltext⫽2013⫹guideline⫹for⫹early⫹ management⫹of⫹patients&submit⫽yes&x⫽0&y⫽0. Accessed September 29, 2015. A new guideline considering much of the evidence described previously has just recently been released by the American Heart Association/American Stroke Association. This guideline reflects the importance of acute stroke management as a public health problem and the rapid evolution of endovascular therapy. Selected highlights from the new guideline are listed below.
Highlights From Recommendations Regarding Endovascular Interventions • Patients eligible for IV tPA should receive IV tPA even if endovascular treatment is being considered. • If endovascular therapy is used, a stent retriever is recommended for patients in whom clinical condition qualifies. • As with IV tPA, reduced time from symptom onset to reperfusion with endovascular intervention is associated with improved outcomes. To ensure benefit, reperfusion should be achieved as early as possible (within 6 hours of the onset of stroke symptoms). • Endovascular therapy with stent retrievers may be considered in selected patients with acute stroke in whom treatment can be initiated (groin puncture) within 6 hours of symptoms and who have causative occlusion in more distal branches of the MCA, anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries. Air Medical Journal 34:6
• Use of salvage techniques including IA fibrinolysis may be reasonable to complement thrombectomy if completed within 6 hours of the onset of stroke symptoms.
Highlights From Imaging Recommendations • Emergency imaging of the brain is recommended before any specific treatment for acute stroke (to avoid giving fibrinolytic therapy with hemorrhagic lesions). • Additional imaging beyond CT, CTA, MRI, and magnetic resonance angiography may be helpful but require additional study.
Highlights From Recommendations on Systems of Stroke Care • Patients require rapid transport to the closest available certified primary stroke center or comprehensive stroke center. Stroke centers are a regional resource capable of providing rapid imaging, IV tPA, and endovascular stroke treatment. • Endovascular therapy requires rapid patient access to cerebral angiography and qualified neurointerventionalists. Outcomes from patients and stroke systems should be tracked.
ischemic stroke. New treatment paradigms emphasize the importance of rapid treatment, which means that the role of emergency medical services and helicopter emergency medical services in acute stroke care is now more important than ever. Prehospital care should include successful identification of acute stroke and facilitation of transport to a stroke center equipped and ready to provide endovascular therapy. Acknowledgement The authors gratefully acknowledge the assistance of Ms. Sherry Willett in preparation of this series for Air Medical Journal. David J. Dries, MSE, MD, is the assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in St Paul, MN, and can be reached at [email protected]. Haitham M. Hussein, MD, MSc, is the medical director for Regions Hospital Comprehensive Stroke Center at HealthPartners Medical Group. 1067-991X/$36.00 Copyright 2015 by Air Medical Journal Associates http://dx.doi.org/10.1016/j.amj.2015.09.002
Summary The recently published data provide strong evidence of the clinical efficacy of endovascular intervention for acute
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David J. Dries, MSE, MD, and Haitham M. Hussein, MD, MSc
Stroke: Part 2 The game has changed! After decades of skepticism, lack of evidence, and negative trials, endovascular intervention has made it to the national guidelines for the treatment of acute stroke. Over the past several months, 5 clinical trials showed benefit of mechanical thrombectomy for the treatment of ischemic stroke secondary to anterior circulation occlusion. In this column, we review the history of endovascular therapy and the recent major studies with their impact on practice.
Intravenous Thrombolysis Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587. Hacke W, Kaste M, Bluhmki E, ECASS Investigators, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329. Schwamm LH, Ali SF, Reeves MJ, et al. Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With The Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;6:543-549. Marshall RS. Progress in intravenous thrombolytic therapy for acute stroke. JAMA Neurol. 2015;72:928-934. In the mid-1990s, the National Institute of Neurological Disorders and Stroke (NINDS) trial was the first to show efficacy of intravenous (IV) tissue plasminogen activator (tPA) for the treatment of acute stroke provided that it is administered within 3 hours of symptom onset. The Food and Drug Administration (FDA) subsequently approved the medication with the patient selection criteria of the NINDS trial. A little over a decade later, the time window was extended to 4.5 hours from symptom onset based on the European trial ECAS (European Cooperative Acute Stroke Study) III. Other IV thrombolytic agents such as streptokinase and urokinase were studied but did not yield clinical benefit. Unfortunately, the rate of utilization of IV tPA remains very low. In a recent analysis of national data, the utilization rate increased from 4% in 2003 to 7% in 2011 for acute stroke patients presenting in the 3-hour time window. Of course, a major limitation is the short time window. Attempts to extend the time window using imaging criteria have failed. Ongoing trials are currently evaluating a relatively recent thrombolytic agent called tenecteplase as well as the combination of more than 1 306
thrombolytic agent. The article by Marshall provides an elegant history of the evolution of IV thrombolytic therapy. Parallel to the IV thrombolysis paradigm, efforts were made to incorporate endovascular interventions in acute stroke care for patients with contraindications to IV therapy or who have large artery occlusions. Endovascular clinical trials went through 3 main phases: intra-arterial (IA) administration of thrombolytic agents, mechanical thrombectomy devices compared with the historic control or other devices with a focus on radiologic outcome, and mechanical thrombectomy devices compared with the standard of care with a focus on functional outcome.
Intra-Arterial Administration of Thrombolytic Agents del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: A phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29:4-11. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282:2003-2011. Reports of IA thrombolysis using streptokinase and urokinase for the treatment of acute stroke began to emerge in the early 1980s. It was not until the late 1990s that the first randomized trial, Prolyse in Acute Cerebral Thromboembolism (PROACT) II, showed a benefit with directed IA infusion of a thrombolytic agent in acute stroke. PROACT II used the thrombolytic agent prourokinase, which, to this day, is not approved by the FDA and not commercially available. This agent has a unique characteristic of an improved effect through coadministration of heparin. PROACT showed safety of arterial intervention and helped refine the treatment regimen because the heparin dose was reduced and the prourokinase dose was increased in the subsequent trial. PROACT II was a multicenter trial that enrolled patients with middle cerebral artery (MCA) occlusion and randomized them to IA infusion prourokinase ⫹ IV heparin versus IA infusion of saline ⫹ IV heparin. IA treatment had to be initiated within 6 hours from symptom onset. No mechanical thrombectomy was allowed. The primary outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 2 or less at 90 days. The mRS is a measure of disability and functional state. It ranges from 0 to 6 with a score of 0 being completely free of symptoms, a score of 5 indiAir Medical Journal 34:6
cating maximum disability, and a score of 6 indicating death. An mRS score of 0 to 2 is a common definition of a good outcome in stroke research. PROACT II showed higher rates of recanalization in the treatment group (66%) compared with the control group (18%) with an absolute benefit of 15% in the rate of good outcome at 3 months, which was statically significant. The rate of symptomatic hemorrhage was 10% in the prourokinase group and 2% in the control group (P ⬍ .001). It is important to recognize that the rate of good outcome and the overall benefit were higher in the prourokinase group despite the higher rate of symptomatic hemorrhage. There was no difference in mortality between the 2 groups. Despite the PROACT II results, the FDA did not approve prourokinase for the treatment of acute stroke (or any other indication). Given the different pharmacologic properties of the various thrombolytic agents, the results of PROACT II cannot be generalized; however, it remains a landmark study that proved the benefit of IA therapy for acute stoke.
with the standard microcatheter. The EKOS has a small-vessel ultrasound infusion system that uses low-energy ultrasound to alter the structure of the thrombus and facilitate access of the thrombolytic agent to potentially accelerate thrombolysis. The 3month mortality in IMS II subjects (n ⫽ 81) was 16%, which compared favorably with the mortality of placebo (24%) and tPA-treated subjects (21%) in the NINDS trial. The rate of symptomatic intracerebral hemorrhage in IMS II subjects (9.9%) was not significantly different than that for tPA-treated subjects in the NINDS trial (6.6%). IMS II subjects had significantly better outcomes at 3 months than NINDS placebo-treated subjects for all end points (odds ratio ⫽ 2.7) and better outcomes than NINDS tPA-treated subjects in some end points.
Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke. Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999;30:2598-2605.
Smith WS, Sung G, Starkman S, MERCI Trial Investigators, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005;36:1432-1438.
IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: The Interventional Management of Stroke Study. Stroke. 2004;35:904-911. IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II Study. Stroke. 2007;38:2127-2135. The Emergency Management of Stroke study was a doubleblind, randomized, placebo-controlled multicenter phase I study that tested the feasibility, efficacy, and safety of combined IV and local IA tPA versus IA placebo for stroke within 3 hours of onset of symptoms. The sample size was very small (17 subjects in the treatment group and 18 in the placebo group). There was no significant difference in the efficacy or safety outcomes at 7 to 10 days or at 3 months. In the Interventional Management of Stroke (IMS) trial, a cohort of 80 subjects with acute stroke and NIHSS ⱖ 10 presenting in the 3-hour time window after the onset of symptoms were treated with IV tPA but with a dose that was lower than the standard dose (0.6 not 0.9 mg/kg) followed by another small dose of tPA given through the IA route so that the combined IV and IA tPA dose was slightly less than the total standard IV tPA dose. The outcomes of the study subjects were compared with the outcome of the placebo and the treatment arms of the NINDS IV tPA trial. The results of the trial showed that this combined IV and IA approach yielded a similar clinical benefit and safety outcome when compared with the treatment arm of the NINDS trial. The IMS II trial had a similar study design but used a new microcatheter to administer IA tPA—the EKOS (EKOS Corporation, Bothell, WA, USA) microinfusion catheter along November-December 2015
Mechanical Thrombectomy Devices Compared With a Historic Control or Other Devices with a Focus on Radiologic Outcome
The MERCI Retriever (Stryker, Kalamazoo, MI) was the first device to be approved by the FDA for revascularization cerebral arteries (note that it was not approved for the treatment of stroke). It is a corkscrew-like device, which assumes its coiled shape once deployed, that can engage and extract a clot. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial was conducted in 2 parts. MERCI Part 1 was a safety trial that enrolled 30 patients with symptom onset more than 3 hours and less than 8 hours. Concomitant use of IA tPA was allowed. The primary outcome was arterial recanalization (not neurologic recovery), which was achieved in 43% of patients with mechanical thrombectomy alone and 64% of patients when additional IA tPA was given. At 30 days, 50% of the patients who achieved recanalization had a good functional outcome. There was only 1 technical complication and 12 incidents of asymptomatic intracerebral hemorrhage. MERCI Part 2 was also a single-arm study that enrolled 151 patients with the same inclusion/exclusion criteria as Part 1. The primary outcomes were recanalization and procedure complications (again, not the functional state). The intention-to-treat analysis showed a recanalization rate of 46%, a complication rate of 7%, and a symptomatic intracranial hemorrhage rate of 8%. The rate of good functional outcome was 28%, similar to the control arm of the PROACT II trial, whereas the mortality rate was 44%, which was higher than the treatment arm of PROACT II.
Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial. Safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40:2761-2768. The Penumbra System (Penumbra, Alameda, CA) was the second device used for direct mechanical IA intervention for 307
stroke. The system provides 2 revascularization options: aspiration and extraction. The supporting clinical trials followed the same steps as MERCI. A small trial (20 patients) showed the safety of the device in patients with acute stroke treated within 8 hours of symptom onset, and a larger trial (125 patients) showed noninferiority compared with the MERCI Retriever outcomes. In fact, the rate of recanalization (82%) was higher than MERCI (48%), whereas the rate of symptomatic hemorrhage was 11% and the rate of procedure-related complications was 13%. At 3 months, the rate of good functional outcome (mRS 2 or less) was 25% (27% in MERCI), and the mortality rate was 33% (44% in MERCI).
Saver JL, Jahan R, Levy EI, SWIFT Trialists, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet. 2012;380:1241-1249. The Solitaire Flow Restoration device (Covidien/ev3, Dublin, Ireland) is a self-expanding stent that is fully retrievable and can be reapplied. The device approval was based on the Solitaire With the Intention For Thrombectomy (SWIFT) trial, which was a multicenter, randomized, noninferiority, parallel-group trial. The study enrolled patients with stroke symptoms who did not have radiologic evidence of large volume completed infarction and who could be treated within 8 hours of symptom onset. The primary end point was partial or complete recanalization without symptomatic intracranial hemorrhage. The planned sample size was 200 subjects; however, the trial was stopped after randomizing 113 subjects because a preplanned interim analysis showed the superiority of the Solitaire device over the Merci device with the efficacy end point achieved in 61% and 24%, respectively. The Solitaire patients also had a higher rate of good functional outcome (mRS 0-2) and lower mortality rate at 90 days although the trial was not powered to examine clinical outcomes.
Nogueira RG, Lutsep HL, Gupta R, TREVO 2 Trialists, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet. 2012;380:1231-1240. TREVO (Stryker, Fremont, CA) is another stent retriever device that was evaluated in 2 trials. In the multicenter, prospective, single-group Thrombectomy REvascularization of large Vessel Occlusions in acute ischemic stroke (TREVO) trial of 60 patients with stroke at 7 European centers, treatment with the TREVO Retriever had a recanalization rate of 92% with a rate of independent functional outcome (mRS 02) of 55% at 90 days. This was followed by the open-label randomized TREVO 2 trial in which patients with angiographically confirmed large vessel occlusion were randomly assigned to TREVO versus Merci devices. The primary outcome was target vessel recanalization and was met by 86% 308
patients in the TREVO group and 60% in the Merci group. The primary safety end point, which was a composite of procedure-related adverse events, did not differ between groups.
Mechanical Thrombectomy Devices Compared With the Standard of Care With a Focus on Functional Outcome (Table 1) Broderick JP, Palesch YY, Demchuk AM, Interventional Management of Stroke (IMS) III Investigators, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903. Despite all the previously mentioned studies showing a benefit of pharmacologic and/or mechanical thrombectomy in recanalizing cerebral vessels and hinting at a clinical benefit, the only randomized clinical trial that was designed to show the clinical benefit of an endovascular approach and was positive remained the PROACT II trial. In 2013, 3 randomized clinical trials were published showing a lack of benefit with endovascular intervention. The first one was the IMS III. This trial compared the combined IV and IA administration of tPA with standard therapy (IV tPA only). The trial was similar to its 2 predecessors, IMS I and II, in terms of inclusion/exclusion criteria with patient enrollment based on clinical criteria (NIHSS ⱖ 10 with a time window of 3 hours from the onset of symptoms). The study allowed the use of the Merci device along with the 2 devices used in IMS II, the EKOS device and the standard microcatheter. The primary outcome was an mRS score of 0 to 2, indicating functional independence. The planned sample size was 900 patients. The trial was stopped early because of futility after 656 participants had undergone randomization with a similar good outcome rate of 41% in the endovascular group and 39% in the standard treatment group, a similar mortality rate (19% vs. 21%), and a similar symptomatic intracerebral hemorrhage rate (6.2% vs. 5.9%). The trial had several limitations. The endovascular devices used in the trial were first-generation devices, which were the only available technology at the time of trial initiation. Later, newer devices were allowed, but only a small proportion of patients were treated with these new devices. By the end of the trial, the Solitaire device was used in only 5 of 334 patients treated with stent retrievers, which was reflected in the low rate of near complete or complete recanalization. Initially, the trial allowed only two thirds of the standard IV tPA dose to be used in the endovascular arm. Later in the trial, the full dose was allowed. Patients without major arterial occlusion were enrolled in the trial because the selection was based on clinical criteria only (based on previous analysis showing more than 80% likelihood of large artery occlusion when NIHSS ⱖ 10). Later in the trial, computed tomographic angiography (CTA) was used to identify arterial occlusion. The rate of procedureor device-related complications was high at 16%. There was management variability in the treatment protocol of the endovascular arm of this trial. Air Medical Journal 34:6
Table 1. Comparison of Main Features of Recent Positive Endovascular Clinical Trials Trial Name MR CLEAN ESCAPE EXTEND-IA Years of 2010-2014 2013-2014 2010-2014 Recruitment Countries
Methods
REVASCAT 2012-2014
Netherlands
US, Ireland, South Korea, and UK
Australia, New Zealand
US, Canada, France, Austria, Germany, Denmark, Spain, Switzerland
Spain
6 hours
12 hours
6 hours
6 hours
8 hours
Allowed patients to receive IV tPA if presented within 4.5 hours
Allowed patients to receive IV tPA if presented within 4.5 hours
Enrolled only patients who had IV tPA
Enrolled only patients who had IV tPA
Rate of IV tPA use (endovascular vs. control)
87% vs. 91%
73% vs. 79%
100% in both
100% in both
Included patients who had IV tPA but did not recanalize after 30 minutes of infusion and patients who had contraindication for IV tPA 68% vs. 78%
Endovascular intervention
Retrievable stent 82% Other devices 2% Intra-arterial tPA (n ⫽ 1)
Retrievable stent 86%
Retrievable stent 100%
Retrievable stent 100%
Retrievable stent 100% Angioplasty (n ⫽ 1) Intra-arterial tPA (n ⫽ 1)
Primary outcome
mRS score at 3 months
mRS score at 3 months
Median reperfusion at 24 hours
mRS score at 3 months
mRS score at 3 months
mRS 0-2 at 3 months (endovascular vs. control)
33% vs. 19%
53% vs. 29%
71% vs. 40%a
60% vs. 35%
44% vs. 28%
Symptomatic intracranial hemorrhage (endovascular vs. IV tPA)
8% vs. 6%
4% vs. 3%
0 vs. 6%
0 vs. 3%
5% vs. 2%
Mortality at 3 months (endovascular vs. control)
9% vs. 8%
6% vs. 13% (statistically significant)
9% vs. 20%
12% vs. 26%
18% vs. 16%
Qualifying time window Other clinical criteria
Results
SWIFT PRIME 2012-2014
IV ⫽ intravenous; mRS ⫽ modified Rankin Scale; tPA ⫽ tissue plasminogen activator. aFunctional independent outcome.
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Kidwell CS, Jahan R, Gornbein J, MR RESCUE Investigators, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368:914-923.
Ciccone A, Valvassori L, Nichelatti M, SYNTHESIS Expansion Investigators, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368:904-913.
The Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial examined the use of perfusion imaging to identify potential candidates for endovascular thrombolysis. This was not the first study to evaluate radiologic parameters instead of time as a surrogate marker for brain tissue viability, but it was the first trial to use this technique to guide endovascular intervention. The biological reasoning for this approach is that within the ischemic area, there is a core of an irreversibly damaged infarction surrounded by a zone of salvageable tissue, the penumbra, and that the existence and the volume of the penumbra is dependent not only on the duration of ischemia but also on other factors that vary from one ischemic lesion to another such as collateral circulation, ischemic preconditioning, and tissue resilience. The MR RESCUE trial was a randomized, controlled, open-label (blinded outcome), multicenter trial that enrolled 118 subjects with ischemic stroke caused by large vessel, anterior circulation occlusion within 8 hours of symptom onset to undergo either mechanical embolectomy (Merci or Penumbra devices) or standard medical care. Patients who were treated with IV tPA without successful recanalization were eligible for endovascular therapy if vascular imaging after IV tPA treatment showed a persistent target occlusion. All patients underwent multimodal computed tomographic (CT) or magnetic resonance imaging (MRI), which was processed on a dedicated site computer that automatically identified the patient as favorable, unfavorable, or unknown penumbra and assigned patients to treatment accordingly (stratified randomization). The primary outcome was a functional state at 3 months as measured by the mRS. The trial recruited 127 patients between 2004 and 2011 and was published in 2013. There was no difference between the 2 treatment groups (endovascular vs standard care). The identification of “favorable” versus “nonfavorable” penumbra did not influence the outcome. The main critique of the MR RESCUE trial is that the technology clearly evolved over the 8-year span during which this trial was completed. For example, the neuroimaging methodology (arterial spin labeling), which has been shown to be a more accurate method to quantify perfusion, was not used. Real-time imaging analysis that was done before randomization was frequently inaccurate. The study software successfully processed only 58% of cases, and the final pattern assignment changed after core laboratory postprocessing in 8% of cases. Endovascular intervention did not use the more recent stent retriever devices and relied mainly on older devices. Another criticism is that the time to groin puncture was more than 6 hours after the onset of stroke symptoms, which is longer than other trials of endovascular interventions.
Local Versus Systemic Thrombolysis for Acute Ischemic Stroke trial (SYNTHESIS) ran from 2004 to 2008 and assessed the feasibility, safety, and preliminary efficacy of IA thrombolysis compared with standard IV thrombolysis. The study randomized 54 patients who presented in the 3-hour time window to standard dose IV tPA or IA tPA (same dose as IV) that was allowed to be administered for up to 6 hours from symptom onset. Although there was a difference of about 40 minutes in delivering IA therapy compared with IV therapy, the functional outcome was better in the IA group without any differences in safety outcomes (mortality and symptomatic hemorrhage). The subsequent SYNTHESIS Expansion trial was similar in design to its predecessor with a few modifications. The time window was expanded from 3 to 4.5 hours after the onset of symptoms. The endovascular therapy included pharmacologic and/or mechanical options according to the interventionalist’s discretion. The primary end point was functional state at 3 months. The trial randomized 181 patients to the IV arm and 181 patients to the endovascular arm. There was no difference between the 2 study groups in terms of functional or safety outcomes. One criticism of this study was the significant difference between the time from symptom onset to IV tPA and the time from symptom onset to endovascular therapy—a whole hour (2.75 vs. 3.75 hours). Another important criticism is that endovascular therapy used latest generation stent retriever devices in only 23 patients.
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Berkhemer OA, Fransen PS, Beumer D, MR CLEAN Investigators, et al. A randomized trial of intraarterial treatment of acute ischemic stroke. N Engl J Med. 2015;372:11-20. The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) will be remembered as the first trial to show an unequivocal benefit of endovascular intervention for acute stroke. Five hundred patients were randomized to endovascular therapy plus standard care (which included IV tPA for appropriate patients) versus standard of care alone. Patients were eligible for the trial with an NIHSS score as low as 2 as long as they had a proximal arterial occlusion in the anterior cerebral circulation confirmed on imaging (mandatory CTA or magnetic resonance angiography before randomization), and IA treatment was available within 6 hours of the onset of symptoms. The primary end point was functional outcome at 90 days as measured by the mRS. There was an absolute difference of 13.5 percentage points in the rate of good outcome (mRS 0-2) in favor of the intervention (32.6% vs. 19.1%). The shift toward better outcomes in favor of the intervention was consistent for all categories of the mRS, except for death. Air Medical Journal 34:6
All clinical and imaging secondary outcomes favored the endovascular arm. There were no differences in mortality or hemorrhage rates between the 2 groups. It is important to recognize that 445 of 500 patients were treated with IV tPA, which indicates that the benefit of endovascular treatment was over and above the benefit from IV tPA. Eight-two percent of patients in the endovascular arm were treated with stent retrievers, whereas only 0.4% (1 patient) was treated with pharmacologic monotherapy. Finally, 13% of patients assigned to IA treatment also had a second revascularization procedure (cervical carotid artery stenting), which may have affected study results.
Goyal M, Demchuk AM, Menon BK, ESCAPE Trial Investigators, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019-1030. The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial was the second trial to report efficacy of endovascular treatment. This trial randomly assigned patients with acute stroke to receive standard care or standard care plus mechanical thrombectomy. There were important differences in study design between the ESCAPE and MR CLEAN trials. ESCAPE widened the treatment window from 6 hours to 12 hours but used more restrictive selection criteria, which included NIHSS ⬎ 5, with only internal carotid artery and MCA occlusion allowed and, more importantly, excluding patients with poor collateral flow and those with large infarction on noncontrast CT scans as assessed by the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). ASPECTS is a 10-point scoring system to quantify early ischemic changes in the MCA territory, with a score of 10 indicating normal and 1 point subtracted for each abnormal region such that a score of 0 indicates complete infarction of the whole MCA territory. ESCAPE excluded patients with ASPECTS score of 0 to 5. The primary outcome was the rate of functional independence at 3 months. After the results of the MR CLEAN trial were announced, an unplanned interim analysis was conducted, which showed efficacy of endovascular therapy with a higher rate of good outcome compared with the standard of care arm (53.0% vs. 29.3%, P ⬍ .001). Also, endovascular intervention was associated with reduced mortality (10% vs. 19%, P ⫽ .04), making it the first treatment in the history of acute stroke care to have a mortality benefit. Based on these results, ESCAPE was prematurely stopped after the enrollment of 316 patients out of 500 planned. There are important lessons to learn from the ESCAPE trial. First, we can expand the time window for the treatment of stroke if we focus on patients who are more likely to benefit from treatment. Despite enrolling patients for up to 12 hours after symptom onset, symptomatic intracerebral hemorrhage occurred in only 3.6% of patients receiving endovascular intervention (70% of whom had IV tPA before the intervention) and 2.7% of patients receiving only IV fibrinolysis. The second lesson is the clinical utility of multiphase CTA being November-December 2015
not only sensitive in detecting arterial occlusions but also less vulnerable to patient motion than CT perfusion, requiring no additional contrast and allowing for quick determination of collateral status. The third lesson is speed. The “time is brain” concept is well established in the field of stroke, but ESCAPE had a strong focus on speed of assessment and treatment. This was reflected on the trial aim, methods, and conduct. For example, ESCAPE discouraged MRI and encouraged multiphase CT imaging. Also, ESCAPE coined the concepts “first CT image to groin puncture” and “first CT image to reperfusion” and had specific target time windows of 60 and 90 minutes, respectively. The median time from study CT to first reperfusion was 84 minutes, and the median time from groin puncture to first reperfusion was 30 minutes. Finally, mechanical thrombectomy should use contemporary devices (retrievable stent used in 86% of patients).
Campbell BC, Mitchell PJ, Kleinig TJ, EXTEND-IA Investigators, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372:1009-1018. The Extending the Time for Thrombolysis in Emergency Neurological Deficits—Intra-Arterial (EXTEND-IA) trial was designed to examine the impact of endovascular therapy with more advanced image selection to identify patients with the greatest chance of good outcome with intervention after stroke. This trial applied even more stringent radiologic selection criteria than the ESCAPE trial to identify patients who were likely to benefit in order to minimize the phenomenon of futile recanalization. The study used perfusion imaging and new imaging processing software and had contemporary definitions for salvageable penumbra. Randomly assigned patients with ischemic stroke received standard IV tPA and either endovascular thrombectomy with the Solitaire FR or IV tPA alone. Enrollment was limited to patients with occlusion of the internal carotid artery or the MCA and a core infarct of less than 70 mL as measured by CT perfusion. Conduct of trial was suspended after the MR CLEAN trial was reported with only 70 patients enrolled (35 in each group). Endovascular therapy reperfused 100% of identified ischemic territory versus 37% of ischemic territory reperfused in patients receiving IV fibrinolytic therapy. Endovascular therapy initiated at only 210 minutes after the onset of stroke led to functional independence in 71% versus 40% of patients receiving conventional therapy. The rate of symptomatic intracranial hemorrhage and death was comparable between these 2 groups. These results met the prespecified stopping rule, and the trial was ended early. EXTEND-IA is unique in that it showed for the first time in a phase III trial that CT perfusion imaging is an efficient and consistent means to identify patients with clinically significant salvageable ischemic brain. However, it is important to recognize that using the CT perfusion methodology described in EXTEND-IA excluded approximately 25% of clinically eligible patients with vessel occlusion, raising the question about treatment efficacy in that group. 311
Jovin TG, Chamorro A, Cobo E, REVASCAT Trial Investigators, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296-2306. Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset (REVASCAT) was a Spanish trial, which randomized approximately 200 patients to IV tPA versus IV tPA plus thrombectomy with a Solitaire stent retriever system. The study selected patients who were treated with IV tPA in the 4.5-hour time window but did not recanalize or those who had a contraindication to IV tPA. Inclusion criteria included a baseline NIHSS of at least 6 points, visualization of an occlusion of the MCA with or without concomitant internal carotid artery occlusion, and ASPECTS of 7 or more if CT scan was used or 6 or more on diffusion weighted imaging if MRI was used. The results in this trial favored thrombectomy. The absolute between-group difference in the proportion of patients who were functionally independent (mRS 0-2) was 15.5%, favoring thrombectomy (43.7% vs. 28.2%; adjusted odds ratio ⫽ 2.1; 95% confidence interval, 1.1-4.0). A strength of this trial, as described by the authors, is the emphasis on consecutive patient enrollment. Previous trials may be criticized for a lack of consecutive patient enrollment leading to the possibility of “cherry picking.” A consistent retriever technology was used. A limitation of the trial acknowledged by the authors is inconsistent stroke imaging before intervention. This may have allowed the inclusion of patients with larger infarct sizes than other trials. Despite this, the study reports a remarkably low rate of symptomatic intracranial hemorrhage at 1.9% in both of the study groups. The rate of death was 18.4% in the thrombectomy group and 15.5% in the group receiving medical therapy alone. This death rate seems high relative to other recent trials and may reflect that many patients with hemorrhagic complications went on to die. Nonetheless, these data add to the evidence favoring endovascular intervention after stroke and extended the time window for treatment to 8 hours. REVASCAT is the only endovascular clinical trial out of the 5 recent trials that had a time window of 8 hours. Three of the other 4 studies had a time window of 6 hours.
Saver JL, Goyal M, Bonafe A, SWIFT PRIME Investigators, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285-2295. The Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) trial was funded by Covidien, the company that manufactures Solitaire stent retriever, and was designed and led by a steering committee that included academic investigators and representatives of the sponsor. This is another trial confirming the benefits of thrombectomy combined with IV tPA versus IV 312
tPA alone. Selection criteria included anterior intracranial circulation occlusion stroke treated with IV tPA within 4.5 hours in the absence of large ischemic core lesions and a time window for endovascular treatment of 6 hours from symptom onset. Similar to a number of previous trials, this trial was stopped early because of efficacy. Thrombectomy patients had good outcome (defined as mRS 0-2) in 60% of cases versus 35% of subjects receiving IV tPA alone. Ninety-day mortality was not significantly different (9% vs. 12%), and symptomatic intracranial hemorrhage was a remarkably low 0% in the group receiving thrombectomy versus 3% in patients receiving IV tPA. Even in the setting of optimal technology use, speed is still essential to achieve the best outcomes. Another benefit in this trial was the consistent use of a rapid image analysis system, which was operator independent. Thus, this potentially time-consuming step was streamlined. SWIFT PRIME only enrolled patients who were treated with IV tPA; therefore, the benefit of endovascular intervention reported is added to the benefit of IV tPA.
Powers WJ, Derdeyn CP, Biller J, et al. 2015 AHA/ASA focused update on the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. http://stroke.ahajournals.org/ search?fulltext⫽2013⫹guideline⫹for⫹early⫹ management⫹of⫹patients&submit⫽yes&x⫽0&y⫽0. Accessed September 29, 2015. A new guideline considering much of the evidence described previously has just recently been released by the American Heart Association/American Stroke Association. This guideline reflects the importance of acute stroke management as a public health problem and the rapid evolution of endovascular therapy. Selected highlights from the new guideline are listed below.
Highlights From Recommendations Regarding Endovascular Interventions • Patients eligible for IV tPA should receive IV tPA even if endovascular treatment is being considered. • If endovascular therapy is used, a stent retriever is recommended for patients in whom clinical condition qualifies. • As with IV tPA, reduced time from symptom onset to reperfusion with endovascular intervention is associated with improved outcomes. To ensure benefit, reperfusion should be achieved as early as possible (within 6 hours of the onset of stroke symptoms). • Endovascular therapy with stent retrievers may be considered in selected patients with acute stroke in whom treatment can be initiated (groin puncture) within 6 hours of symptoms and who have causative occlusion in more distal branches of the MCA, anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries. Air Medical Journal 34:6
• Use of salvage techniques including IA fibrinolysis may be reasonable to complement thrombectomy if completed within 6 hours of the onset of stroke symptoms.
Highlights From Imaging Recommendations • Emergency imaging of the brain is recommended before any specific treatment for acute stroke (to avoid giving fibrinolytic therapy with hemorrhagic lesions). • Additional imaging beyond CT, CTA, MRI, and magnetic resonance angiography may be helpful but require additional study.
Highlights From Recommendations on Systems of Stroke Care • Patients require rapid transport to the closest available certified primary stroke center or comprehensive stroke center. Stroke centers are a regional resource capable of providing rapid imaging, IV tPA, and endovascular stroke treatment. • Endovascular therapy requires rapid patient access to cerebral angiography and qualified neurointerventionalists. Outcomes from patients and stroke systems should be tracked.
ischemic stroke. New treatment paradigms emphasize the importance of rapid treatment, which means that the role of emergency medical services and helicopter emergency medical services in acute stroke care is now more important than ever. Prehospital care should include successful identification of acute stroke and facilitation of transport to a stroke center equipped and ready to provide endovascular therapy. Acknowledgement The authors gratefully acknowledge the assistance of Ms. Sherry Willett in preparation of this series for Air Medical Journal. David J. Dries, MSE, MD, is the assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in St Paul, MN, and can be reached at [email protected]. Haitham M. Hussein, MD, MSc, is the medical director for Regions Hospital Comprehensive Stroke Center at HealthPartners Medical Group. 1067-991X/$36.00 Copyright 2015 by Air Medical Journal Associates http://dx.doi.org/10.1016/j.amj.2015.09.002
Summary The recently published data provide strong evidence of the clinical efficacy of endovascular intervention for acute
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