New strategies for endovascular recanalization of acute ischemic stroke. 2013

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1. New Strategies for Endovascular Recanalization of Acute Ischemic Stroke José E. Cohen, MD a , Ronen R. Leker, MD b , Alejandro Rabinstein, MD c, * INTRODUCTION Early…
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  • 1. New Strategies for Endovascular Recanalization of Acute Ischemic Stroke José E. Cohen, MD a , Ronen R. Leker, MD b , Alejandro Rabinstein, MD c, * INTRODUCTION Early reperfusion is a strong predictor of good outcome in acute ischemic stroke (AIS).1,2 This finding was the basis for the evaluation of intravenous (IV) recombinant tissue plasminogen activator (tPA), the first effective therapy for AIS, and the rationale for a change in the approach to this disease. IV tPA represents a first step beyond the Disclosures: The authors did not receive funding in support of the preparation of this article, and have no conflicts of interest to disclose. a Department of Neurosurgery, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel; b Department of Neurology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel; c Department of Neurology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55905, USA * Corresponding author. E-mail address: KEYWORDS Acute ischemic stroke Revascularization Stent Thrombolysis Thrombectomy KEY POINTS Timely endovascular therapy can achieve reperfusion of brain tissue at risk of ischemic infarction (ischemic penumbra), thus providing the possibility of improving functional out- comes in patients with large intracranial artery occlusions and severe neurologic deficits. Acute endovascular therapy is safe when performed by experienced clinicians, and can be offered after failed intravenous thrombolysis as a rescue strategy or as primary therapy in patients with contraindications for intravenous thrombolysis. Mechanical thrombectomy devices have largely replaced intra-arterial thrombolysis as the preferred method of endovascular reperfusion therapy. Stent retrievers seem to be the most effective devices for acute interventional stroke ther- apy, based on early experience. Shortening the time to reperfusion and achieving complete or near-complete reperfusion are crucial to optimizing outcomes. More randomized trials are needed comparing intravenous thrombolysis versus primary endovascular thrombectomy and rescue thrombectomy versus placebo. Neurol Clin 31 (2013) 705–719 0733-8619/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
  • 2. classic nihilism after failed neuroprotection and neurorestoration attempts with thou- sands of costly compounds and studies.3 However, soon after the general recommendation of its use gained acceptance, it become evident that the one-size-fits-all concept of IV tPA cannot be applied for all acute strokes, because not all strokes are the same. Patients with mild strokes, such as some with small vessel occlusions, may not require IV tPA because they can do well without it. On the other extreme of the spectrum, major strokes that are usually caused by either middle-size or large-size vessel occlusion represent the Achilles heel of IV thrombolysis.4,5 The prognosis of patients with severe strokes (Na- tional Institutes of Health Stroke Score [NIHSS] !16) treated with IV tPA is poor. In landmark studies, one-third of these patients died, another one-third remained severely disabled (modified Rankin Scale [mRS] 4–5), and only one-fourth of patients were independent (mRS 0–2) at 3-month follow-up.3–5 In internal carotid artery (ICA) occlusions, IV tPA therapy only allows a recanalization rate of close to 10% and, in oc- clusions of the proximal (M1 portion) middle cerebral artery (MCA), the recanalization rate is less than 30%.1,2,6 Only one-third of patients with MCA occlusions who achieve recanalization after IV tPA have an excellent functional recovery (number needed to treat 10).4,5,7 In these cases, the large clot burden responsible for the occlusion is often not effectively lysed by IV tPA during the brief therapeutic window allowed by the tissue at risk. Limitations in achieving timely recanalization with IV tPA fueled the development of intra-arterial (IA) treatment strategies. These IA treatments for AIS are the focus of this article. IA THROMBOLYSIS: THERAPY, RATIONALE, AND RESULTS IA administration of thrombolytics improves the efficiency of drug delivery into the clot, thus increasing the chances for recanalization and decreasing the dose of drug needed to achieve this goal. IA thrombolysis has been empirically used for the last 3 decades in patients with large intracranial vessel occlusions. IA thrombolysis is per- formed by selective placement of a microcatheter proximal to the occlusion and direct infusion of a high dose of fibrinolytic agent, with the aim of disintegrating the clot and recanalizing the artery. The intervention is considered technically simple, although it is frequently time consuming. Reported recanalization rates are usually modest in very proximal occlusions (less than 30% in carotid T occlusions), but better in more distal occlusions, such as in M2 branches. Complications, including hemorrhagic complica- tions and distal emboli, are common. Prolyse in Acute Cerebral Thromboembolism (PROACT) II was the main randomized trial to examine the safety and efficacy of IA thrombolysis in patients with AIS caused by angiographically proven occlusion of M1 or M2 branches of the MCA.8 Outcomes in 121 patients treated with IA prourokinase plus heparin within 3 to 6 hours from stroke onset were compared with those in 59 patients treated with heparin alone. Patients in the two groups had similar risk factors and baseline criteria, and were randomized a mean of 4.7 hours from stroke onset in the treatment group and 5.1 hours in the control group. In the prourokinase plus heparin group, 40% of patients reached functional in- dependence at 90 days, compared with only 25% of patients treated with heparin alone (P 5 .04). Recanalization was achieved within 2 hours of treatment in 66% of patients treated with prourokinase plus heparin compared with 18% of controls (P .001). Com- plete recanalization, defined as Thrombolysis in Myocardial Infarction (TIMI) grade 3, was attained in 19% of treated patients and in only 4% of controls (P 5 .003). Symptom- atic intracranial hemorrhage (sICH) was seen in 10% of treated patients compared with Cohen et al706
  • 3. 2% of controls (P 5 .06), but the increase in sICH did not affect mortality rates, which were 25% and 27% respectively. Despite these promising results, treatment with prourokinase plus heparin was not approved by the US Food and Drug Administration (FDA), which demanded a confir- matory study that was never performed. Nevertheless, IA thrombolysis with uroki- nase or tPA has continued to be used frequently in centers across the world for emergency treatment of patients presenting within 6 hours of onset with AIS caused by occlusion of large proximal vessels, such as the distal ICA, proximal MCA, or basilar artery. PROACT II, a Japanese trial, and a meta-analysis have shown that IA fibrinolysis substantially increases recanalization rates and improves neurologic outcomes in pa- tients with major vessel occlusions.8–10 However, large thrombi are resistant to stan- dard microcatheter-delivered thrombolysis and prolonged delivery is usually required to open these occlusions; thus IA fibrinolysis often fails to improve outcomes even af- ter achieving recanalization.11–13 Several alternative strategies were not permitted and thus not evaluated in the context of PROACT II, including mechanical clot disruption with a microguidewire or repeatedly crossing the clot with the microcatheter with the goal of increasing clot sur- face exposure to the injected thrombolytic agent. Adjuvant clot angioplasty in refrac- tory cases was also not included in the PROACT II design. Outside of the large formal studies, these alternatives were sometimes used in practice to increase the chances of recanalization and they were precursors to the development of novel endovascular therapies, including IA ultrasound, mechanical embolectomy, and acute stenting. COMBINED IV-IA TPA AND IA ULTRASOUND The Interventional Management of Stroke (IMS) studies I (80 patients) and II (81 patients) examined the effects of initial lower dose of IV tPA (0.6 mg/kg) followed by IA tPA when recanalization was not achieved after the IV bolus.14 Some patients were also treated with IA ultrasound administered with the EKOS EkoSonic Endovascular System after evidence showed that ultrasound energy could hasten clot breakdown.15,16 Recanali- zation to TIMI 2 to 3 was achieved in 56% of patients in IMS-I, and 60% in IMS-II, with higher rates in patients who were also treated with the EKOS system. An mRS score of 0 to 2 was reached by 46% of IMS-II participants at 3 months after stroke. Mortality at 3 months was 16% in both IMS studies; sICH rates were 6.3% and 9.9%, respectively. The multicenter, randomized IMS-III trial was then designed to compare the standard IV tPA alone versus a combined IV/IA approach, with IV treatment initiated within 3 hours of AIS onset.17 The recently published results of this trial are presented later. The bridging concept tested in the IMS trials (ie, reduced-dose IV tPA followed if necessary by endovascular therapy) is no longer common in practice. Instead, most patients treated with combined therapy receive the full dose of IV tPA followed by endovascular intervention when this fails to achieve recanalization, a treatment para- digm known as rescue therapy. This practice has been supported by reports showing acceptable risks of sICH18,19 and fueled by the development of neurothrombectomy devices that often allow recanalization without requiring IA administration of an addi- tional thrombolytic dose. ENDOVASCULAR ANGIOPLASTY AND STENTING Balloon angioplasty, with or without stent placement, is another technique that can be used to recanalize acute arterial occlusions. This strategy, which is similar to the approach commonly taken in patients with acute myocardial infarction, was hampered Endovascular Recanalization in Acute Ischemic Stroke 707
  • 4. for a long time by the absence of dedicated catheters for the cerebral vasculature. The cerebral blood vessels are suspended in cerebrospinal fluid, without the firm muscular support of the myocardium, thus they are more prone to dissections and tears. Further- more, the approach to intracranial arterial occlusions is often tortuous, making naviga- tion more difficult. However, various catheters and other devices designed specifically for the cerebral vasculature have been developed in recent years, removing some of the obstacles to endovascular angioplasty and stenting in patients after acute stroke. Levy and colleagues20 proposed that stent-assisted recanalization may improve recanalization rates in patients with acute stroke and persistent intracranial vessel oc- clusions after thrombolysis. In their retrospective analysis of 19 patients, stenting afforded successful recanalization in 79% of cases. Lesions at the ICA terminus, older age, and higher baseline NIHSS score were identified as negative outcome predictors. There were no cases of sICH in this small series. From their preliminary experience, the investigators concluded that stent-assisted recanalization for acute stroke resulting from intracranial thrombotic occlusion is associated with a high recanalization rate and low rate of intracranial hemorrhage (ICH). However, permanent stenting has the disadvantage of demanding the administra- tion of dual antiplatelet therapy, including a loading dose of clopidogrel, which can in- crease the risk of symptomatic ICH from reperfusion injury. At present, the advent of embolectomy techniques has restricted the use of permanent stents to the treatment of patients with symptomatic subocclusive atherosclerotic stenoses, acute occlusions occurring on atherosclerotic stenosis, and, less frequently, those with embolic occlu- sions that are refractory to thrombolysis or thrombectomy. THE NEUROTHROMBECTOMY ERA As it became increasingly clear that dissolving the clot with thrombolytic agents is not always possible, that dissolution may not be prompt enough to reduce the size of the infarction, and that thrombolysis carries a substantial risk of hemorrhage, new treat- ment approaches were sought. The advance of neuroendovascular techniques in par- allel with the development of new devices has enabled mechanical removal of the occlusive clot from large intracranial vessels. Thrombectomy techniques have several potential advantages compared with pharmacologic thrombolysis, including higher rates of recanalization, lower risk of ICH, and a longer treatment window.21–23 Several neurothrombectomy devices are now available, and they can be classified mechanis- tically into 4 groups (Table 1). The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) Retriever, the Pen- umbra System, and, more recently, the Solitaire FR Revascularization Device and TREVO Pro retriever have received 510(k) clearance from the FDA to treat patients with AIS. The other systems are approved for use in the European market. A summary of the main trials evaluating these devices is presented in Table 2. Clot Removal with MERCI or Aspiration with Penumbra Several devices have been designed to retrieve or aspirate the occluding clot from large intracranial arteries. The snare and basket MERCI devices (Concentric Medical, Mountain View, CA) are deployed into the clot and work as a corkscrewlike retrieval tool.26,27,33 The balloon of the guiding catheter is inflated proximally to the clot to achieve flow arrest and prevent distal embolization. The retrieval device is then pulled back into the catheter with the clot ensnared. Once the clot is removed, the procedure is completed by deflating the occluding proximal balloon and restoring circulation. This system received FDA approval in 2004. Cohen et al708
  • 5. Initial results published with the MERCI device explored its safety and efficacy in 151 patients with anterior or posterior circulation stroke secondary to large vessel oc- clusion who were treated within 8 hours of stroke onset.26 Primary outcomes were recanalization at the end of the procedure, defined as TIMI 2 to 3, and safety. Second- ary outcomes were mRS and NIHSS scores at 30 and 90 days, and death, myocardial infarction, or recurrent stroke within 30 days. A good neurologic outcome was defined as mRS less than or equal to 2 or NIHSS score improvement greater than or equal to 10 points. All patients included in the MERCI device study were ineligible for IV lysis. Mean age (Æ standard deviation) was 67 Æ 15.5 years and mean admission NIHSS score was 20.1 Æ 6.6. Strokes in the anterior circulation were seen in 90% of partici- pating patients; in 10%, strokes occurred in the posterior circulation. Mean onset time to treatment (OTT) was 4.3 Æ 1.7 hours, and mean procedure duration was 2.1 hours, yielding a mean 5.5 hours from symptom onset to reperfusion. Recanalization to TIMI 2 to 3 was achieved in 46% of treated patients, a significant improvement compared with 18% recanalization rates for historical controls treated with heparin alone in the PROACT II study (P .0001). At 30 days after stroke, good outcomes were achieved by 22.6% of patients according to the mRS score and 34.1% as determined by improvement in the NIHSS score. At 90 days after stroke, these numbers improved to 27.7% and 32.4% respectively. Most importantly, the chance of attaining a good outcome was significantly greater in patients with vessel recanalization compared to those without. The chance for stroke, MI, or death at 30 days was 40%, and mortality was 43.5% at 90 days. Clinically significant procedural complications occurred in 10 of 141 patients (7.1%), and sICH was observed in 11 of 141 (7.8%). On multivariate analysis, recanalization was associated with good outcome, whereas increasing age and low admission NIHSS score were associated with higher mortality and poorer functional outcome. Table 1 Devices for thrombosis removal, aspiration, or fragmentation Device Supplier Mechanical Thrombectomy MERCI Retriever Concentric Medical Systems, Mountain View, CA Phenox Clot Retriever Phenox GmbH, Bochum, Germany Neuronet Device Guidant Corp./Boston Scientific, Indianapolis, IN Amplatz Goosneneck Microsnare Covidien/eV3, Plymouth, MN Alligator Retrieval Device Covidien/eV3, Plymouth, MN Solitaire FR Revascularization Device Covidien/eV3, Plymouth, MN TREVO Pro Retrieval System Stryker Corp, Kalamazoo, MI ReVive SE Neurovascular Thrombectomy Device Johnson Johnson/Codman Schurtleff, Raynham, MA Thromboaspiration Penumbra System Penumbra, Alameda, CA AngioJet Ultra Thrombectomy System MEDRAD, Warrendale, PA Laser Thrombolysis and Mechanical Clot Fragmentation Endovascular Photoacoustic Recanalization Laser EndoVasix, Belmont, CA Ultrasonification EKOS Echosonic Endovascular System EKOS Corp., Botell, WA Endovascular Recanalization in Acute Ischemic Stroke 709
  • 6. In the Multi-MERCI study, 160 patients were treated within 8 hours of stroke onset.27 In this study, prior treatment with IV tPA, mechanical clot disruption, IA tPA, and other adjunctive therapies was allowed. Some of the patients were treated with the newer generation L5 device. Mean age was 68.1 Æ 16.0 years and mean admission NIHSS score was 19 (range, 15–23). IV tPA had been administered to 29% of participants without recanalization before the procedure. The primary outcome measure was vessel recanalization; secondary outcomes were safety measures related to the de- vice and the procedure. Mean OTT was 4.3 hours, and mean onset to recanalization was 5.9 hours. Overall, vessel recanalization was achieved in 55% of patients with the retriever alone, and in up to 68% when adjunctive therapies were used. Recanalization rates were higher in posterior circulation and M2-MCA occlusions (88% and 80% respectively) than in ICA and M1-MCA occlusions (59% and 48% respectively). mRS less than or equal to 2 was achieved in 36% of participants and NIHSS scores improved by more than 10 points in 26%. sICH occurred in 16 patients (9.8%); 4 pa- tients (2.4%) had parenchymal hematoma type II. Clinically significant procedural complications occurred in 9 patients (5.5%). Treatment with IV tPA before MERCI de- vice deployment did not increase the chance of sICH. Overall mortality at 90 days was 34%, with significantly improved outcomes in patients achieving revascularization. Table 2 Leading studies of endovascular therapy for AIS Number, Active Arm NIHSS, Median Successful Recanalization, TIMI 2–3/TICI 2b-3 (%) Good Neurologic Outcome, mRS 0–2 90 d (%) Mortality, 90 d (%) sICH (%) IA Thrombolysis PROACT II8 121 17 66 40 25 10 Combined IV-IA Lysis IMS-I24 62 18 56 43 16 6 IMS-II14 55 19 60 46 16 10 IMS-III25 434 17 65–81a 41 19 6 Neurothrombectomy MERCI26 151 22 46 28 44 8 Multi-MERCI27 164 19 68 36 34 10 Penumbra28 125 18 82 25 33 11 SWIFT (Solitaire)29 58 17 83 37b 17 2 TREVO 2 (TREVO)30 88 19 85 40 33 7 MR-RESCUE31,c 34;30 17;19 67;77 21;17 18;20 9;0 Primary Modality SYNTHESIS32 181 13 NA 42 8 6 Abbreviations: NA, not available; NIHSS, National Institutes of Health Stroke Scale score; TICI, Thrombolysis in Cerebral Infarction; TIMI, Thrombolysis in Myocardial Infarction. a Depending on the vessel treated. b Fifty-eight percent when considering the definition of good functional outcome used in the trial: mRS 0 to 2, or mRS equal to the prestroke mRS if this was greater than 2, or NIHSS improve- ment greater than or equal to 10 points. c Data presented for embolectomy in patients with favorable penumbral pattern on magnetic resonance imaging (MRI); embolectomy in patients without favorable penumbral pattern on MRI. Cohen et al710
  • 7. Outcomes with the MERCI device now seem modest, but proximal intracranial vessel occlusion leading to stroke is associated with severe morbidity and mortality
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