Curr Treat Options Cardio Med (2014) 16:318 DOI 10.1007/s11936-014-0318-1
Vascular Disease (R Schainfeld, Section Editor)
Interventional Management of Acute Ischemic Stroke: A Systematic Review J. Scott Pannell, MD David R. Santiago-Dieppa, MD Alexander A. Khalessi, MD, MS, FAHA* Address *Division of Neurosurgery, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103, USA Email: [email protected]
* Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Vascular Disease Keywords Acute ischemic stroke I Large-vessel occlusion Endovascular therapy I Retrievable stent
I
CT angiography
I
Intra-arterial stroke therapy
I
Opinion statement Historically, acute ischemic stroke (AIS) trials defined syndromes according to acute clinical presentation and post-ictus parenchymal imaging. With improvements in real-time arterial imaging, modern AIS treatment demands a structural approach based upon the level of cerebrovascular occlusion. The poor concordance of presenting National Institute of Health Stroke Scale (NIHSS) with vessel occlusion in recent trials bespeaks the need for an anatomic perspective. Specifically, patients with large-vessel occlusion (LVO) represent a distinct entity with a poorer prognosis than general AIS patients. Ongoing clinical trials and therapeutic strategies must recognize the varied natural history of AIS patients. Endovascular therapy offers promise in patients with the most severe strokes.
Introduction Acute ischemic stroke (AIS) is the fourth leading cause of death and disability in the United States [1]. Far from a single disease process, AIS is more accurately categorized as a heterogeneous group of disorders, with variable neurological outcomes depending upon a number of discerning factors. The presence of an intracranial large-vessel occlusion (LVO), the level of occlusion, presenting NIHSS, lateralization, collateral
circulation, etiology, core infarct size, and vessel recanalization rates are important factors that influence neurological outcomes and inform the role of endovascular neurosurgery in the treatment of AIS. The critical elements of successful treatment of ischemic stroke include patient selection, timely complete revascularization, and adequate medical care both before and after revascularization.
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Patient selection A critical step in the management of AIS is the identification of patients who will benefit from intra-arterial (IA) therapy. Patients presenting with AIS should be rapidly triaged and assessed by NIHSS to objectively quantify the severity of the stroke; they should undergo structural brain imaging to rule out intracranial hemorrhage (ICH) and to determine the extent of the ischemic territory, as well as advanced noninvasive vascular imaging by computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) to evaluate for LVO and collateral circulation. Important selection criteria for identifying patients who may benefit from endovascular therapy include 1) the presence of a confirmed LVO by noninvasive advanced vascular imaging, 2) absence of a significant completed infarct (defined as completed infarct greater than one-third of the distribution or a completed infarct matching the clinical deficit seen in the patient), 3) NIHSS greater than 8 or aphasia, and 4) the presence of collateral circulation [2•]. Confirming the presence of an LVO by vascular imaging is a pivotal step in the process of the treatment of AIS, as evidenced from a number of studies:
First, the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) study [3] and the FIRST study [4•] illustrate the dismal natural history of untreated LVO stroke. The PROACT II study evaluated patients with confirmed large-vessel occlusions and demonstrated a 75 % poor outcome (modified Rankin score 3–6) and 27 % mortality in patients who did not undergo endovascular revascularization. The prospective multicenter FIRST study enrolled LVO stroke patients presenting within eight hours of symptom onset with a NIHSS of at least 10. At 90 days, 80 % of patients had a poor outcome, 24 of 59 (40.7 %) died, and six (10 %) patients had an ICH. Second, IA treatment with thrombectomy devices is only useful with LVO target identification. In the Interventional Management of Stroke (IMS III) study, 20 % of patients randomized to intra-arterial thrombolysis (IAT) did not harbor an LVO or therapeutic target [5]. Third, revascularization of LVOs with IV rtPA alone is uncommon, ranging from 10 % in internal carotid occlusions to approximately 30 % in middle cerebral artery occlusions [6]. Recently published clinical trials, including the (IMS III) [5] and the IntraArterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS) Trial 3 [7], did not specifically identify LVO in AIS prior to randomization to IA therapy, but did yield useful data to inform IA therapy and predict outcomes. IMS III was a randomized open-label multicenter study that compared a combined intravenous (IV) and IA treatment approach to restoring blood flow to the brain with the current standard FDAapproved therapy of IV rtPA alone. Both approaches required treatment initiation within three hours of stroke onset. A total of 900 subjects with moderate to severe ischemic stroke were to be enrolled at multiple sites in the United States, Canada, Australia, and Europe. The study com-
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menced in August 2006 and was halted prematurely on April 9, 2012, after futility analyses. Importantly, the Data Safety and Monitoring Board emphasized that safety concerns between the two arms were not the basis for early termination of the study. After randomization, the endovascular and IV tPA cohorts experienced similar rates of functional independence (modified Rankin Score [mRS] of 0–2; 40.8 % vs. 38.7 %) and mortality (19.1 % vs. 21.6 %, P=0.52) at three-month follow-up. Subgroup analysis based upon NIHSS severity (NIHSS 8–19 compared with 920) suggested greater therapeutic benefit for endovascular therapy in the more severe stroke category, but did not achieve statistical significance. Rates of symptomatic ICH were comparable between groups (6.2 % vs. 5.9 %, P=0.83). Only 47 % of enrolled patients, however, had noninvasive vascular imaging at the time of enrollment. Nearly 20 % of patients assigned to the IA treatment arm had no LVO or had thrombus that was inaccessible by catheter therapies. Retrospectively, there was an observed benefit to IA therapy in patients with LVO documented on CT angiography. Specifically, when AIS patients with a documented LVO based upon preprocedural imaging are analyzed separately, three-month mRS was lower in patients who received IA therapies compared with IV rtPA alone (P=0.01). Although further trials are necessary to confirm these findings, the data from IMS III suggest a benefit to IA therapy in patients with confirmed LVO. In addition, the use of preprocedural CT angiography reduced time from groin puncture to start of thrombectomy by 10 minutes (PG.01). Transfer status or other unidentified confounders are unlikely to account for this observed benefit. Similarly, the SYNTHESIS trial did not assess for LVO and did not report the number of patients with LVO. Furthermore, the majority of SYNTHESIS patients had low NIHSS, indicative that many enrolled patients likely did not harbor LVOs and this patient cohort would not qualify for IA therapy on the basis of NIHSS by the current standards of care. Again, no safety concerns were discovered in the SYNTHESIS trial [7]. The absence of a significant infarct involving greater than one-third of the territory or a complete infarct matching the clinical deficit is also critically important. Multiple advancements in imaging have improved the process of evaluation for completed infarcts. Alberta Stroke Program Early CT Scores, CT perfusion, and MRI diffusion imaging are routinely used before interventions to identify and exclude patients with significant completed infarcts [8]. Larger infarcts involving greater than one-third of the territory are more likely to result in reperfusion hemorrhage and a poor outcome [9]. Patients with completed infarcts that match the deficit seen clinically are less likely to benefit from endovascular therapy, given the lack of clinical evidence of a penumbra. In a double-blinded study, Boxerman et al. reported equipoise between CT perfusion-based penumbra delineation and clinical penumbra as objectively determined by mismatch between infarct seen on CT and NIHSS [10]. Patients enrolled in the IMS III trial were excluded if non-contrast CT imaging demonstrated a large area of hypodensity consistent with a completed infarct. Patients with other early signs of infarction based on CT, however, were not excluded. In fact, approximately 43.1 % of endovascular therapy and 41 % of control patients included in IMS III had Alberta Stroke Program Early CT Scores of 7 or less, indicating that many of these patients likely had early completed infarcts at the time of intervention, which further dilutes the benefit of IA therapy.
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Rapid and complete revascularization Regardless of the modality of revascularization, a key component to the treatment of AIS is the timely and complete revascularization of the involved territory, which is associated with better functional outcomes and lower mortality. In a meta-analysis of recanalization in 2,066 patients, Rha and Saver reported that, independent of the method of recanalization, good functional outcomes mRS 0–2 were more frequent in recanalized versus nonrecanalized patients ( odds ratio of 4.43) [11]. Recent crucial advancements in endovascular surgical technology have vastly improved both the degree of revascularization and mean time to onset of therapy [12]. The Solitaire FR with the Intention for Thrombectomy (SWIFT) study was a prospective multicenter trial comparing the efficacy and safety of the Solitaire FR with the Merci Retriever System device [13•]. The trial included 113 patients with ischemic stroke who were randomly assigned to undergo endovascular treatment with either the Solitaire FR or Merci device within eight hours of symptom onset. The trial was halted a year earlier than anticipated on the advice of the safety monitoring committee due to a significantly better clinical outcome in the Solitaire FR patient group. Successful recanalization was achieved in 83.3 % of patients with the Solitaire FR compared to 48.1 % with the Merci retriever, with good clinical outcome of 58.2 % versus 33.3 %, respectively. Overall, 40 % of patients had already been treated with IV rtPA but had failed to improve. sICH occurred in 2 % of the Solitaire FR group and 11 % of the Merci device group, with mortality rates of 17 % and 38 %, respectively. Similarly, the Thrombectomy REvascularisation of Large Vessel Occlusions in acute ischemic stroke (TREVO) 2 study compared Trevo retrievable stent with Merci device for thrombectomy in AIS patients with an LVO. A total of 178 patients were randomized (median NIHSS, 18) to one of the devices within eight hours of symptom onset. Successful recanalization was achieved in 89.7 % of patients in the Trevo group compared to 63.3 % in the Merci group, with good clinical outcome in 55 % and 40 %, respectively. sICH occurred in 6.8 % of the Trevo group and 8.9 % of the Merci group, with mortality rates of 33 % and 24 %, respectively [14]. The results of these trials support the existence of distinctive mechanisms of action among devices and that success and efficacy rates differ, therefore, based upon the thrombectomy approach applied, which must be taken into consideration in the design of future studies investigating the efficacy of mechanical thrombectomy. A case in point is the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) Trial 2, a multicenter randomized trial comparing standard medical care with embolectomy in patients presenting within eight hours with confirmed large-vessel anterior circulation stroke. The study found that embolectomy was not superior to standard medical therapy in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23) or non-penumbral pattern (mean score, 4.0 vs. 4.4, P=0.32) [15]. However, MR RESCUE included only first-generation endovascular thrombectomy technologies, resulting in only 16 of 64 patients (25 %) achieving a
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thrombolysis in cerebral infarction (TICI) reperfusion score of 2b or 3. Not only is this rate far below the new standards of revascularization established by the SWIFT and TREVO trials using modern thrombectomy technology, but it is also below the revascularization rate of the control group.
Standard medical therapy The role of medical therapy in the treatment of AIS is well-established and should be employed in all cases of AIS. The new 2013 American Heart Association Guidelines for the Early Management of Patients with Acute Ischemic Stroke provides complete current recommendations for standard medical therapy and is far beyond the scope of this article. Notably, key components of the guidelines include administration of intravenous (IV) rtPA (alteplase, Activase/Actilyse), blood pressure modulation, cardiac monitoring, respiratory support, normothermia, and normoglycemia. IV rtPA (alteplase, Activase/Actilyse) is the only treatment approved by the U.S. Food and Drug Administration (FDA) for AIS with class 1 evidence supporting its use, and represents the standard of care for stroke patients who are candidates. All eligible patients presenting within 4.5 hours of symptom onset and lacking contraindications should be treated with IV rtPA at a standard dose of 0.9 mg/kg. Importantly, the FDA indication for tissue plasminogen activator (tPA) extends only to three hours. Broadly applied level 1 evidence supports its use in the 4.5-hour time window [16, 17]. AIS patients who have elevated blood pressure should be closely monitored and the blood pressure carefully modulated based upon revascularization method and efficacy of revascularization attempts, if undertaken. In patients who are eligible for IV rtPA, the systolic blood pressure should be carefully lowered to below 185 mmHg and the diastolic blood pressure lowered to below 110 mmHg before fibrinolytic therapy is initiated. According to AHA guidelines, in patients with markedly elevated blood pressure who do not receive fibrinolysis, a reasonable goal is to lower blood pressure by 15 % during the first 24 hours after onset of stroke. The level of blood pressure that would mandate such treatment is not known, but consensus suggests that medications should be withheld unless the systolic blood pressure is greater than 220 mmHg or the diastolic blood pressure is greater than 120 mmHg. Similarly, although more nuanced, patients undergoing IA therapy without IV fibrinolysis should be allowed permissive hypertension until revisualization is achieved. If complete revascularization is realized, systolic blood pressure should be maintained below 130 mmHg. Patients with impaired consciousness or who have bulbar dysfunction causing compromise of the airway should be provided with ventilatory support. Supplemental oxygen should be administered to maintain oxygen saturation above 94 %. In hyperthermic patients with AIS, sources of hyperthermia (temperature 938 °C) should be identified and treated, and antipyretic medications should be administered to lower temperature. Hypoglycemia (blood glucose G60 mg/dL) or hyperglycemia in AIS patients should be treated, with the goal to achieve normoglycemia [17].
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Conclusions Patients with AIS presenting with LVO are a distinctive subcategory of AIS patients for which the natural history is particularly unforgiving. Identification of LVO and exclusion of significant completed infarcts are critical steps in determining the efficacy of IA therapy. Stratification of stroke severity by NIHSS and comparison of infarcts seen on CT or MRI with NIHSS is also necessary to identify patients who may benefit from IA therapies. The IMS III and SYNTHESIS trials failed to provide an appropriate cohort of patients with confirmed LVO by preprocedural imaging to adequately study the efficacy of IA treatment. Appropriately identified AIS patients with confirmed LVO should undergo rapid and complete revascularization, and all eligible patients should receive IV rtPA. Patients with AIS who are ineligible for IV rtPA should undergo complete and rapid revascularization by IA therapy. All three major trials published within the past year – IMS III, SYNTHESIS, and MR RESCUE – failed in complete revascularization by current standards due to the employment of predominantly first-generation devices. MR RESCUE, in particular, was hindered by revascularization rates that failed to surpass even the control group. In IMS III, MR RESCUE, and SYNTHESIS, the safety of IA therapy was confirmed, and IA therapy was positioned in equipoise with IV therapy despite the lack of an appropriate cohort and the employment of obsolete technology. While current patient selection methods and IA therapy devices are vastly superior to those employed in the IMS III, MR RESCUE, and SYNTHESIS, the demonstration of safety and equipoise is critical, particularly when considering patients in whom IV therapy is contraindicated or ineffective. The patient population deemed eligible for treatment within the IMS III criteria represents only an approximate 1 % to 7 % of all patients with AIS. For patients presenting 1) outside the 4.5-hour window, 2) with “wake-up” stroke, and 3) with AIS and contraindications to IV rtPA, such as recent surgery, IA therapies are the only viable treatment [18–20]. In closing, we strongly support additional prospective investigations of IA therapy employing current revascularization technologies in the appropriate clinical setting. Moreover, regardless of the outcome of future trials, IA therapy is better considered as a complementary therapy to standard medical care for patients who are ineligible for or are unresponsive to IV rtPA than as a competing therapy. Real-time arterial imaging is a central component in the stratification of AIS patients based on natural history and risk-benefit profile of endovascular intervention.
Compliance with Ethics Guidelines Conflict of Interest Dr. J. Scott Pannell and Dr. David R. Santiago-Dieppa each declare no potential conflicts of interest relevant to this article.
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Dr. Alexander Khalessi is a consultant for Stryker and Covidien. Dr. Khalessi received payment for development of educational presentations including service on speakers’ bureaus from Covidien, Stryker, Penumbra, and Codman and research support from Penumbra. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance 1.
Kochanek KD, Xu JQ, Murphy SL, Miniño AM, Kung HC. Deaths: Final Data for 2009. Nat Vital Stat Rep. 2011;60(3). 2.• Khalessi AA, Fargen KM, Lavine S, Mocco J. Commentary: societal statement on recent acute stroke intervention trials: results and implications. Neurosurgery. 2013;73(2):E375–9. This publication represents the first complete consensus statement on catheter-based therapy for that was endorsed by the five major societies involved in catheterbased AIS treatment, including the Joint Cerebrovascular Section of the American Association of Neurological Surgeons (AANS), the Congress of Neurological Surgeons (CNS), the Society of Vascular and Interventional Neurology (SVIN), the Society of NeuroInterventional Surgery (SNIS), and the American Society of NeuroRadiology (ASNR). 3. 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(21):2003–11. 4.• Janardhan V, Gianatasio RM, Chen SH, et al. Abstract 194: preliminary results from the FIRST trial: a natural history of acute stroke from large vessel occlusion. Stroke. 2013;44:A194. This publication reinforced the distinctively poor natural history of AIS due to LVO. 5. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus tPA alone for stroke. N Engl J Med. 2013;368(10):893–903. 6. Wolpert SM, Bruckmann H, Greenlee R, Wechsler L, Pessin MS, del Zoppo GJ. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. The rt-PA Acute Stroke Study Group. AJNR Am J Neuroradiol. 1993;14(1):3–13. 7. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(10):904–13.
8.
Pexmana JH, Barber PA, Hill MD, Sevick RJ, Demchuk AM, Hudon ME, et al. Use of the Alberta Stroke Program Early CT Score (ASPECTS) for assessing CT scans in patients with acute stroke. AJNR Am J Neuroradiol. 2001;22:1534–42. 9. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017–25. 10. Boxerman JL, Jayaraman MV, Mehan WA, Rogg JM, Haas RA. Clinical stroke penumbra: use of National Institutes of Health Stroke Scale as a surrogate for CT perfusion in patient triage for intra-arterial middle cerebral artery stroke therapy. AJNR Am J Neuroradiol. 2012;33:1893–900. 11. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38(3):967–73. 12. Fargen KM, Meyers PM, Khatri P, Mocco J. Improvements in recanalization with modern stroke therapy: a review of prospective ischemic stroke trials during the last two decades. 2013;5(6):506–11. doi: 10.1136/neurintsurg-2012-010541 13.• Saver JL, Jahan R, Levy EI, 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(9849):1241–9. This was the first study to objectively demonstrate the superiority of retrievable stents over the Merci device in the treatment of AIS. 14. Nogueira RG, Lutsep HL, Gupta R, 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(9849):1231–40. 15. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914– 23.
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Ciccone A. 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(24):1581–7. Jauch EC, Saver JL, Adams Jr HP, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870–947. doi:10.1161/ STR.0b013e318284056a. Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for
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19.
20.
ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke. 2011;42(7):1952–5. Morgenstern LB, Staub L, Chan W, et al. Improving delivery of acute stroke therapy: the TLL Temple Foundation Stroke Project. Stroke. 2002;33(1):160– 6. de Los Ríos la Rosa F, Khoury J, Kissela BM, et al. Eligibility for intravenous recombinant tissuetype plasminogen activator within a population: the effect of the European Cooperative Acute Stroke Study (ECASS) III Trial. Stroke. 2012;43(6):1591–5.
Vascular Disease (R Schainfeld, Section Editor)
Interventional Management of Acute Ischemic Stroke: A Systematic Review J. Scott Pannell, MD David R. Santiago-Dieppa, MD Alexander A. Khalessi, MD, MS, FAHA* Address *Division of Neurosurgery, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103, USA Email: [email protected]
* Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Vascular Disease Keywords Acute ischemic stroke I Large-vessel occlusion Endovascular therapy I Retrievable stent
I
CT angiography
I
Intra-arterial stroke therapy
I
Opinion statement Historically, acute ischemic stroke (AIS) trials defined syndromes according to acute clinical presentation and post-ictus parenchymal imaging. With improvements in real-time arterial imaging, modern AIS treatment demands a structural approach based upon the level of cerebrovascular occlusion. The poor concordance of presenting National Institute of Health Stroke Scale (NIHSS) with vessel occlusion in recent trials bespeaks the need for an anatomic perspective. Specifically, patients with large-vessel occlusion (LVO) represent a distinct entity with a poorer prognosis than general AIS patients. Ongoing clinical trials and therapeutic strategies must recognize the varied natural history of AIS patients. Endovascular therapy offers promise in patients with the most severe strokes.
Introduction Acute ischemic stroke (AIS) is the fourth leading cause of death and disability in the United States [1]. Far from a single disease process, AIS is more accurately categorized as a heterogeneous group of disorders, with variable neurological outcomes depending upon a number of discerning factors. The presence of an intracranial large-vessel occlusion (LVO), the level of occlusion, presenting NIHSS, lateralization, collateral
circulation, etiology, core infarct size, and vessel recanalization rates are important factors that influence neurological outcomes and inform the role of endovascular neurosurgery in the treatment of AIS. The critical elements of successful treatment of ischemic stroke include patient selection, timely complete revascularization, and adequate medical care both before and after revascularization.
318, Page 2 of 8
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Patient selection A critical step in the management of AIS is the identification of patients who will benefit from intra-arterial (IA) therapy. Patients presenting with AIS should be rapidly triaged and assessed by NIHSS to objectively quantify the severity of the stroke; they should undergo structural brain imaging to rule out intracranial hemorrhage (ICH) and to determine the extent of the ischemic territory, as well as advanced noninvasive vascular imaging by computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) to evaluate for LVO and collateral circulation. Important selection criteria for identifying patients who may benefit from endovascular therapy include 1) the presence of a confirmed LVO by noninvasive advanced vascular imaging, 2) absence of a significant completed infarct (defined as completed infarct greater than one-third of the distribution or a completed infarct matching the clinical deficit seen in the patient), 3) NIHSS greater than 8 or aphasia, and 4) the presence of collateral circulation [2•]. Confirming the presence of an LVO by vascular imaging is a pivotal step in the process of the treatment of AIS, as evidenced from a number of studies:
First, the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) study [3] and the FIRST study [4•] illustrate the dismal natural history of untreated LVO stroke. The PROACT II study evaluated patients with confirmed large-vessel occlusions and demonstrated a 75 % poor outcome (modified Rankin score 3–6) and 27 % mortality in patients who did not undergo endovascular revascularization. The prospective multicenter FIRST study enrolled LVO stroke patients presenting within eight hours of symptom onset with a NIHSS of at least 10. At 90 days, 80 % of patients had a poor outcome, 24 of 59 (40.7 %) died, and six (10 %) patients had an ICH. Second, IA treatment with thrombectomy devices is only useful with LVO target identification. In the Interventional Management of Stroke (IMS III) study, 20 % of patients randomized to intra-arterial thrombolysis (IAT) did not harbor an LVO or therapeutic target [5]. Third, revascularization of LVOs with IV rtPA alone is uncommon, ranging from 10 % in internal carotid occlusions to approximately 30 % in middle cerebral artery occlusions [6]. Recently published clinical trials, including the (IMS III) [5] and the IntraArterial Versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS) Trial 3 [7], did not specifically identify LVO in AIS prior to randomization to IA therapy, but did yield useful data to inform IA therapy and predict outcomes. IMS III was a randomized open-label multicenter study that compared a combined intravenous (IV) and IA treatment approach to restoring blood flow to the brain with the current standard FDAapproved therapy of IV rtPA alone. Both approaches required treatment initiation within three hours of stroke onset. A total of 900 subjects with moderate to severe ischemic stroke were to be enrolled at multiple sites in the United States, Canada, Australia, and Europe. The study com-
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menced in August 2006 and was halted prematurely on April 9, 2012, after futility analyses. Importantly, the Data Safety and Monitoring Board emphasized that safety concerns between the two arms were not the basis for early termination of the study. After randomization, the endovascular and IV tPA cohorts experienced similar rates of functional independence (modified Rankin Score [mRS] of 0–2; 40.8 % vs. 38.7 %) and mortality (19.1 % vs. 21.6 %, P=0.52) at three-month follow-up. Subgroup analysis based upon NIHSS severity (NIHSS 8–19 compared with 920) suggested greater therapeutic benefit for endovascular therapy in the more severe stroke category, but did not achieve statistical significance. Rates of symptomatic ICH were comparable between groups (6.2 % vs. 5.9 %, P=0.83). Only 47 % of enrolled patients, however, had noninvasive vascular imaging at the time of enrollment. Nearly 20 % of patients assigned to the IA treatment arm had no LVO or had thrombus that was inaccessible by catheter therapies. Retrospectively, there was an observed benefit to IA therapy in patients with LVO documented on CT angiography. Specifically, when AIS patients with a documented LVO based upon preprocedural imaging are analyzed separately, three-month mRS was lower in patients who received IA therapies compared with IV rtPA alone (P=0.01). Although further trials are necessary to confirm these findings, the data from IMS III suggest a benefit to IA therapy in patients with confirmed LVO. In addition, the use of preprocedural CT angiography reduced time from groin puncture to start of thrombectomy by 10 minutes (PG.01). Transfer status or other unidentified confounders are unlikely to account for this observed benefit. Similarly, the SYNTHESIS trial did not assess for LVO and did not report the number of patients with LVO. Furthermore, the majority of SYNTHESIS patients had low NIHSS, indicative that many enrolled patients likely did not harbor LVOs and this patient cohort would not qualify for IA therapy on the basis of NIHSS by the current standards of care. Again, no safety concerns were discovered in the SYNTHESIS trial [7]. The absence of a significant infarct involving greater than one-third of the territory or a complete infarct matching the clinical deficit is also critically important. Multiple advancements in imaging have improved the process of evaluation for completed infarcts. Alberta Stroke Program Early CT Scores, CT perfusion, and MRI diffusion imaging are routinely used before interventions to identify and exclude patients with significant completed infarcts [8]. Larger infarcts involving greater than one-third of the territory are more likely to result in reperfusion hemorrhage and a poor outcome [9]. Patients with completed infarcts that match the deficit seen clinically are less likely to benefit from endovascular therapy, given the lack of clinical evidence of a penumbra. In a double-blinded study, Boxerman et al. reported equipoise between CT perfusion-based penumbra delineation and clinical penumbra as objectively determined by mismatch between infarct seen on CT and NIHSS [10]. Patients enrolled in the IMS III trial were excluded if non-contrast CT imaging demonstrated a large area of hypodensity consistent with a completed infarct. Patients with other early signs of infarction based on CT, however, were not excluded. In fact, approximately 43.1 % of endovascular therapy and 41 % of control patients included in IMS III had Alberta Stroke Program Early CT Scores of 7 or less, indicating that many of these patients likely had early completed infarcts at the time of intervention, which further dilutes the benefit of IA therapy.
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Rapid and complete revascularization Regardless of the modality of revascularization, a key component to the treatment of AIS is the timely and complete revascularization of the involved territory, which is associated with better functional outcomes and lower mortality. In a meta-analysis of recanalization in 2,066 patients, Rha and Saver reported that, independent of the method of recanalization, good functional outcomes mRS 0–2 were more frequent in recanalized versus nonrecanalized patients ( odds ratio of 4.43) [11]. Recent crucial advancements in endovascular surgical technology have vastly improved both the degree of revascularization and mean time to onset of therapy [12]. The Solitaire FR with the Intention for Thrombectomy (SWIFT) study was a prospective multicenter trial comparing the efficacy and safety of the Solitaire FR with the Merci Retriever System device [13•]. The trial included 113 patients with ischemic stroke who were randomly assigned to undergo endovascular treatment with either the Solitaire FR or Merci device within eight hours of symptom onset. The trial was halted a year earlier than anticipated on the advice of the safety monitoring committee due to a significantly better clinical outcome in the Solitaire FR patient group. Successful recanalization was achieved in 83.3 % of patients with the Solitaire FR compared to 48.1 % with the Merci retriever, with good clinical outcome of 58.2 % versus 33.3 %, respectively. Overall, 40 % of patients had already been treated with IV rtPA but had failed to improve. sICH occurred in 2 % of the Solitaire FR group and 11 % of the Merci device group, with mortality rates of 17 % and 38 %, respectively. Similarly, the Thrombectomy REvascularisation of Large Vessel Occlusions in acute ischemic stroke (TREVO) 2 study compared Trevo retrievable stent with Merci device for thrombectomy in AIS patients with an LVO. A total of 178 patients were randomized (median NIHSS, 18) to one of the devices within eight hours of symptom onset. Successful recanalization was achieved in 89.7 % of patients in the Trevo group compared to 63.3 % in the Merci group, with good clinical outcome in 55 % and 40 %, respectively. sICH occurred in 6.8 % of the Trevo group and 8.9 % of the Merci group, with mortality rates of 33 % and 24 %, respectively [14]. The results of these trials support the existence of distinctive mechanisms of action among devices and that success and efficacy rates differ, therefore, based upon the thrombectomy approach applied, which must be taken into consideration in the design of future studies investigating the efficacy of mechanical thrombectomy. A case in point is the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) Trial 2, a multicenter randomized trial comparing standard medical care with embolectomy in patients presenting within eight hours with confirmed large-vessel anterior circulation stroke. The study found that embolectomy was not superior to standard medical therapy in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23) or non-penumbral pattern (mean score, 4.0 vs. 4.4, P=0.32) [15]. However, MR RESCUE included only first-generation endovascular thrombectomy technologies, resulting in only 16 of 64 patients (25 %) achieving a
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thrombolysis in cerebral infarction (TICI) reperfusion score of 2b or 3. Not only is this rate far below the new standards of revascularization established by the SWIFT and TREVO trials using modern thrombectomy technology, but it is also below the revascularization rate of the control group.
Standard medical therapy The role of medical therapy in the treatment of AIS is well-established and should be employed in all cases of AIS. The new 2013 American Heart Association Guidelines for the Early Management of Patients with Acute Ischemic Stroke provides complete current recommendations for standard medical therapy and is far beyond the scope of this article. Notably, key components of the guidelines include administration of intravenous (IV) rtPA (alteplase, Activase/Actilyse), blood pressure modulation, cardiac monitoring, respiratory support, normothermia, and normoglycemia. IV rtPA (alteplase, Activase/Actilyse) is the only treatment approved by the U.S. Food and Drug Administration (FDA) for AIS with class 1 evidence supporting its use, and represents the standard of care for stroke patients who are candidates. All eligible patients presenting within 4.5 hours of symptom onset and lacking contraindications should be treated with IV rtPA at a standard dose of 0.9 mg/kg. Importantly, the FDA indication for tissue plasminogen activator (tPA) extends only to three hours. Broadly applied level 1 evidence supports its use in the 4.5-hour time window [16, 17]. AIS patients who have elevated blood pressure should be closely monitored and the blood pressure carefully modulated based upon revascularization method and efficacy of revascularization attempts, if undertaken. In patients who are eligible for IV rtPA, the systolic blood pressure should be carefully lowered to below 185 mmHg and the diastolic blood pressure lowered to below 110 mmHg before fibrinolytic therapy is initiated. According to AHA guidelines, in patients with markedly elevated blood pressure who do not receive fibrinolysis, a reasonable goal is to lower blood pressure by 15 % during the first 24 hours after onset of stroke. The level of blood pressure that would mandate such treatment is not known, but consensus suggests that medications should be withheld unless the systolic blood pressure is greater than 220 mmHg or the diastolic blood pressure is greater than 120 mmHg. Similarly, although more nuanced, patients undergoing IA therapy without IV fibrinolysis should be allowed permissive hypertension until revisualization is achieved. If complete revascularization is realized, systolic blood pressure should be maintained below 130 mmHg. Patients with impaired consciousness or who have bulbar dysfunction causing compromise of the airway should be provided with ventilatory support. Supplemental oxygen should be administered to maintain oxygen saturation above 94 %. In hyperthermic patients with AIS, sources of hyperthermia (temperature 938 °C) should be identified and treated, and antipyretic medications should be administered to lower temperature. Hypoglycemia (blood glucose G60 mg/dL) or hyperglycemia in AIS patients should be treated, with the goal to achieve normoglycemia [17].
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Conclusions Patients with AIS presenting with LVO are a distinctive subcategory of AIS patients for which the natural history is particularly unforgiving. Identification of LVO and exclusion of significant completed infarcts are critical steps in determining the efficacy of IA therapy. Stratification of stroke severity by NIHSS and comparison of infarcts seen on CT or MRI with NIHSS is also necessary to identify patients who may benefit from IA therapies. The IMS III and SYNTHESIS trials failed to provide an appropriate cohort of patients with confirmed LVO by preprocedural imaging to adequately study the efficacy of IA treatment. Appropriately identified AIS patients with confirmed LVO should undergo rapid and complete revascularization, and all eligible patients should receive IV rtPA. Patients with AIS who are ineligible for IV rtPA should undergo complete and rapid revascularization by IA therapy. All three major trials published within the past year – IMS III, SYNTHESIS, and MR RESCUE – failed in complete revascularization by current standards due to the employment of predominantly first-generation devices. MR RESCUE, in particular, was hindered by revascularization rates that failed to surpass even the control group. In IMS III, MR RESCUE, and SYNTHESIS, the safety of IA therapy was confirmed, and IA therapy was positioned in equipoise with IV therapy despite the lack of an appropriate cohort and the employment of obsolete technology. While current patient selection methods and IA therapy devices are vastly superior to those employed in the IMS III, MR RESCUE, and SYNTHESIS, the demonstration of safety and equipoise is critical, particularly when considering patients in whom IV therapy is contraindicated or ineffective. The patient population deemed eligible for treatment within the IMS III criteria represents only an approximate 1 % to 7 % of all patients with AIS. For patients presenting 1) outside the 4.5-hour window, 2) with “wake-up” stroke, and 3) with AIS and contraindications to IV rtPA, such as recent surgery, IA therapies are the only viable treatment [18–20]. In closing, we strongly support additional prospective investigations of IA therapy employing current revascularization technologies in the appropriate clinical setting. Moreover, regardless of the outcome of future trials, IA therapy is better considered as a complementary therapy to standard medical care for patients who are ineligible for or are unresponsive to IV rtPA than as a competing therapy. Real-time arterial imaging is a central component in the stratification of AIS patients based on natural history and risk-benefit profile of endovascular intervention.
Compliance with Ethics Guidelines Conflict of Interest Dr. J. Scott Pannell and Dr. David R. Santiago-Dieppa each declare no potential conflicts of interest relevant to this article.
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Dr. Alexander Khalessi is a consultant for Stryker and Covidien. Dr. Khalessi received payment for development of educational presentations including service on speakers’ bureaus from Covidien, Stryker, Penumbra, and Codman and research support from Penumbra. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance 1.
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