点击显示 收起
the Department of Neurology (R.G., N.A.V., A.H.T., M.D.H., K.U., L.R.W., T.G.J.), Stroke Institute, University of Pittsburgh Medical Center, Pennsylvania
Departments of Neurosurgery and Radiology (M.B.H.), University of Pittsburgh Medical Center, Pennsylvania
VA Health Systems Pittsburgh (T.G.J.), University Drive, Pittsburgh, Pa
Department of Neurosurgery (E.I.L.), University of Buffalo, State University of New York.
Abstract
Background and Purpose— Endovascular therapies using mechanical and pharmacological modalities for large vessel occlusions in acute stroke are rapidly evolving. Our aim was to determine whether one modality is associated with higher recanalization rates.
Methods— We retrospectively reviewed 168 consecutive patients treated with intra-arterial (IA) therapy for acute ischemic stroke between May 1999 and November 15, 2005. Demographic, clinical, radiographic, angiographic, and procedural notes were reviewed. Recanalization was defined as achieving thrombolysis in myocardial infarction 2 or 3 flow after intervention. A logistic regression model was constructed to determine independent predictors of successful recanalization.
Results— A total of 168 patients were reviewed with a mean age of 64±13 years and mean National Institutes of Health Stroke Scale score of 17±4. Recanalization was achieved in 106 (63%) patients. Independent predictors of recanalization include: the combination of IA thrombolytics and glycoprotein IIb/IIIa inhibitors (odds ratio [OR], 2.9 [95% CI, 1.04 to 6.7]; P<0.048), intracranial stent placement with angioplasty (OR, 4.8 [95% CI, 1.8 to 10.0]; P<0.001), or extracranial stent placement with angioplasty (OR, 4.2 [95% CI, 1.4 to 9.8]; P<0.014). Lesions at the terminus of the internal carotid artery were recalcitrant to revascularization (OR, 0.34 [95% CI, 0.16 to 0.73]; P value 0.006).
Conclusions— Intracranial or extracranial stenting or combination therapy with IA thrombolytics and glycoprotein IIb/IIIa inhibitors in the setting of multimodal therapy is associated with successful recanalization in patients treated with multimodal endovascular reperfusion therapy for acute ischemic stroke.
Key Words: stents stroke, acute thrombolysis
Introduction
Acute occlusion of a large intracranial or extracranial cerebral artery is the cause of ischemic stroke in roughly 70% of patients.1 Recanalization of these arteries in a timely manner has translated into improved clinical outcomes.2 There has been a rapid evolution in the development of techniques used to promote recanalization of arteries since the first description of the use of intra-arterial (IA) thrombolytics in a basilar artery occlusion.3 Since then, a randomized controlled study comparing IA prourokinase with no IA therapy showed safety and efficacy for IA therapy in middle cerebral artery (MCA) occlusion within 6 hours.4 There have been concerns with IA pharmacological thrombolysis because of the long duration required to recanalize the artery as well as the risks of intracerebral hemorrhage. Thus, mechanical methods such as microcatheter/microwire manipulations,5 snare devices,6 balloon angioplasty,7 and IA ultrasound8 have all been reported as alternative approaches to revascularization of an occluded cerebral artery. However, it is unclear as to which method is the most effective toward the aim of recanalization. The aim of this study was to retrospectively review our experience with acute stroke interventions to determine whether one technique was more effective in achieving complete or partial recanalization.
Methods
Case records of all patients admitted to the University of Pittsburgh Medical Center who received any form of IA therapy for acute ischemic stroke from May 1999 to November 15, 2005, were retrospectively reviewed after approval from our institutional review board. Patients were identified through a database maintained at our institution of all patients treated with endovascular therapies for acute ischemic stroke over this time period, and 168 consecutive patients were identified. Demographic information, National Institutes of Health Stroke Scale (NIHSS) and computed tomography (CT) scans were reviewed. Angiographic measures including pretreatment and post-treatment thrombolysis in myocardial infarction (TIMI) score graded as 0 for absent perfusion, grade 1 for minimal distal perfusion, grade 2 for partial perfusion, and grade 3 for complete perfusion were recorded.9 TIMI grades were assigned by 2 of the authors (R.G. and N.V.) who were blinded to the recanalization strategies used. Additionally, time from clinical stroke onset to angiography and recanalization were recorded. The location of the thrombus was defined as the proximal-most segment of occlusion. The lesion was defined as a focal clot if it was present in only 1 segment (ie, basilar artery, M1 MCA, M2 MCA, or internal carotid artery terminus) as determined through microcatheter injections distal to the clot.
Pharmacological IA treatment modalities included: tissue plasminogen activator (t-PA; dose range 2 to 22 mg), urokinase (dose range 250 000 to 1 250 000 U), and intravenous eptifibatide, a glycoprotein IIb/IIIa (GP IIb/IIIa) receptor antagonist (bolus 180 μg/kg). Doses of t-PA were administered in 2-mg aliquots with 5-minute intervals between subsequent administrations through the microcatheter within the thrombus, whereas urokinase was infused in 25 000-U aliquots at 5-minute intervals between doses. Mechanical maneuvers included: snare or Merci retriever system (Concentric Medical, Inc.), angioplasty, or stent placement. Various coronary angioplasty balloons and stents were used and were undersized to 10% less than the estimated vessel diameter. Balloon-mounted and self-expanding stents were used depending on the location of the clot. All patients in whom a self-expanding stent was placed underwent angioplasty after stent placement except in one instance. Recanalization was defined as achievement of TIMI 2 or 3 grades. A separate analysis was performed on predictors of TIMI 3 grade.
Patients treated with intravenous t-PA before arrival underwent a CT angiogram to assess for large vessel occlusion. If this was demonstrated, without evidence of hemorrhage or extensive hypodensity on head CT, patients were referred to IA therapy. The general approach in treating patients was the use of IA thrombolytics if the patient arrived in <6 hours. If recanalization did not occur with the use of IA thrombolytics, then mechanical maneuvers were used with either balloon angioplasty or a Snare/Merci device. If these interventions failed, then a stent was placed across the lesion. For extracranial carotid occlusions, patients were treated directly with stenting and angioplasty. Eptifibatide was administered as an adjunct to thrombolytics if extensive clot burden was noted or if a stent was placed. Patients arriving beyond 6 hours were treated initially with mechanical maneuvers. If extensive clot burden was present, a snare or Merci device was used to reduce the clot burden before angioplasty or stenting. If the lesion was focal, then balloon angioplasty was attempted before stent placement.
After IA therapy, CT scans were assessed for hemorrhage by 2 of the authors (R.G. and N.V.) using previously published criteria.10 If a patient had a worsening of his/her NIHSS score by >4 points with a noted hemorrhage on head CT, this was recorded as a symptomatic hemorrhage. All other hemorrhages were defined as asymptomatic. Patients with a clinical improvement of >4 points on the NIHSS were also recorded after the procedure.
Statistics
Baseline characteristics for recanalization versus nonrecanalization were compared using Fisher exact test for categorical variables and Student t test for continuous variables. The same analysis was performed for patients with TIMI 3 flow versus non-TIMI 3 flow. A P value of <0.05 was considered significant. A logistic regression model was constructed analyzing variables with a P value <0.20 to assess for independent predictors of successful recanalization.
Results
A total of 168 patients were studied in this cohort with a mean age of 64±13 years and a mean NIHSS of 17±4. Recanalization was achieved in 106 patients (63%) and TIMI 3 flow in 47 patients (28%). A total of 60 (36%) patients had a noted intracranial hemorrhage after the procedure, with 24 (14%) of these being symptomatic hemorrhages. Thirty-five (21%) patients showed an improvement of >4 points on their NIHSS score at 24-hour follow-up. Table 1 outlines the demographics, location of clot, and types of therapy used. Patients treated with intracranial stenting and angioplasty had a 90% (18 of 20 patients) recanalization rate. There were 10 stents placed in the posterior circulation, 5 in the MCA, and 5 in the ICA terminus. Those treated with extracranial stenting and angioplasty had an 85% (23 of 27 patients) recanalization rate, whereas those treated with GP IIb/IIIa inhibitors and thrombolytics had an 81% (25 of 31 patients) recanalization rate. Table 2 summarizes the recanalization rates for patients treated with 1, 2, and 3 modalities. Of note, patients treated with 3 modalities were significantly more likely to achieve recanalization and TIMI 3 flow, without an increase in symptomatic or asymptomatic hemorrhages.
Table 3 summarizes the independent predictors of recanalization in the setting of multimodal therapy. Patients with lesions of the ICA terminus were recalcitrant to interventions, whereas those receiving combination pharmacological therapy with IA thrombolytics and GP IIb/IIIa inhibitors or extracranial or intracranial stenting and angioplasty were more likely to recanalize. Table 4 shows that focal clots and patients treated with extracranial or intracranial stenting and angioplasty were most likely to achieve TIMI 3 flow after the procedure.
The only predictor of achieving an improvement in NIHSS of >4 points at 24-hour follow-up was achieving TIMI 2 or 3 flow postprocedurally (odds ratio [OR], 5.7 [95% CI, 1.9 to 11.2]; P value <0.002), whereas older age was a negative predictor of clinical improvement (OR, 0.97 [95% CI, 0.95 to 0.99]; P<0.043).
Discussion
This study demonstrates that patients treated with combination pharmacological therapy with IA thrombolytics and GP IIb/IIIa receptor antagonist or mechanical interventions with stent placement had a higher likelihood of successful recanalization. The value of such an analysis helps to better understand which therapies are more effective in achieving recanalization. This, in turn, can lead to meaningful prospective clinical trials to determine the safety and efficacy of the therapy.
Since the publication of the Prolyse in Acute Cerebral Thromboembolism (PROACT) II study in 1999,4 there have been several reports of the use of various pharmacological and mechanical methods to achieve recanalization and, in turn, improved clinical outcomes. In the PROACT II study that considered M1 or M2 MCA occlusion patients treated with IA pro-urokinase, there was a 66% rate of a TIMI 2 or 3 grade versus 18% in the spontaneous recanalization group. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial considered a heterogeneous group of arteries, including ICA terminus lesions that were occluded, and revealed an overall rate of TIMI 2 or 3 flow in 48% of patients.11 Rates of recanalization likely vary according to location of clot, clot composition, etiology of the clot, and maneuvers used to recanalize the artery (ie, pharmacological agents and mechanical methods). It is thus difficult to compare the results of studies like PROACT II and MERCI to determine whether one treatment modality is more efficacious in revascularization of an occluded cerebral artery.
The use of multimodal therapy has been advocated as a method of achieving superior recanalization rates by tailoring the therapy to particular situations.12 Our study confirms this. Moreover, stent placement with angioplasty or the use of combination therapy with IA thrombolytics and GP IIb/IIIa antagonists are more likely to recanalize these vessels.
Thrombus composition consists of thrombin, platelets, and fibrin in varying proportions depending on the size and age of the clot. In the coronary literature, combination therapy with lower-dose thrombolytics and GP IIb/IIIa antagonists has been shown to improve rates of arterial patency when compared with full-dose thrombolytics alone.13 The same observations have preliminarily been noted in acute ischemic stroke in smaller cohorts of patients.14 It appears that the synergistic effects of thrombolytics combined with GP IIb/IIIa inhibitors observed in the coronary literature may apply to acute stroke therapy as well. Thrombolytics activate platelets because fibrinolysis occurs through the release of thrombin. As platelets are activated, the clot becomes resistant to lysis because of clot contraction from the release of plasminogen activator inhibitor 1.15 Combination therapy theoretically promotes penetration of thrombolytics into the thrombus because the platelets are inactivated by GP IIb/IIIa inhibitors.16 Other authors have observed that up to one third of patients develop acute reocclusion after thrombolysis, which leads to significant morbidity.17 This phenomenon may occur because of platelet accumulation on the exposed injured endothelium because the thrombus dissolves after thrombolysis. GP IIb/IIIa inhibitors can prevent reocclusion by inhibiting platelet accumulation and activation at the treated site. A third potential benefit from combination therapy is the prevention of downstream platelet microemboli that have been noted in rodent stroke models after thrombolysis.18 This may translate into better perfusion, as has been noted with significant resolution of ST segment elevation signifying microvascular reperfusion in the myocardium.19 Such observations in animal models and observational clinical studies along with evidence from coronary interventions help support the idea that combination therapy with thrombolytics and GP IIb/IIIa receptor antagonists may help in recanalization of cerebral vessels.
We also found that the use of stenting and angioplasty was significantly more likely to achieve partial or complete recanalization in our cohort regardless of clot location (ie, intracranial or extracranial vessel). This result parallels the evolution of recanalization strategies in the coronary literature. The first Primary Angioplasty in Myocardial Infarction (PAMI) trial showed that patients undergoing balloon angioplasty for an acute myocardial infarction were more likely to have TIMI 3 flow compared with those receiving stents.20 It was felt that stent deployment may force embolization of particles distally, thereby reducing the rates of success. The addition of GP IIb/IIIa inhibitors to stenting showed a significant reduction in target vessel revascularization when compared with angioplasty and GP IIb/IIIa inhibitors.21 A more recent meta-analysis of 4 PAMI trials revealed a significantly higher incidence of TIMI 2 or 3 flow in the stent group compared with primary angioplasty.22 One of the major concerns in stenting of the intracranial circulation relates to the technical feasibility of navigating balloon-mounted coronary stents through the tortuous cerebral vasculature. Recent advances in stent technology including self-expanding stents designed for the intracranial circulation may help with navigation and delivery of these devices.23 Another concern is that of restenosis after stent placement. Currently, the restenosis rates after stenting of an intracranial occlusion are not known; however, in the setting of an acute occlusion that portends a high rate of devastating disability or mortality without rapid recanalization, this modality of treatment may be justified.
The last important finding of this study is that patients with focal clots were significantly more likely to achieve TIMI 3 flow. Patients with a high thrombus burden often require more aggressive treatments with pharmacological therapy and mechanical clot retriever devices to reduce the volume of clot. Additionally, extensive thrombus may be a marker of diminished cerebral blood flow to severely affected brain territory or a poor collateral supply. This may add to the difficulties in achieving successful recanalization in patients with extensive clot burden.
There are several limitations to this analysis. The first is the retrospective nature of this study. We do not feel that this hinders the main message of this study significantly because the treatment modalities used and angiographic data were all available for review. Second, the number of patients analyzed is consistent with other case series reported in the literature but does not have the power to detect differences among the various treatment groups studied. Nonetheless, a finding of significance in the stenting and angioplasty group and combination therapy with IA thrombolytics and GP IIb/IIIa inhibitors suggests that these therapies should be considered as a focus for prospective trials. Third, some may criticize our combining of the extracranial and intracranial occlusions into one series. The placement of a stent in the intracranial or extracranial circulation led to higher recanalization rates.
This study is not intended to show the safety and efficacy of one modality over another but simply to show that certain treatment modalities may be more effective in the opening of arteries. Because the retrospective nature of this study, we do not have long-term outcomes on this cohort and therefore cannot correlate recanalization rates to longer-term outcomes. This is best served in a controlled prospective series that can address safety and outcomes in a more meaningful manner.
In summary, the use of stenting and angioplasty or GP IIb/IIIa receptor antagonists in combination with IA thrombolytics is associated with a higher likelihood of achieving successful recanalization. ICA terminus lesions are still refractory to revascularization despite more aggressive treatment paradigms.
References
Fieschi C, Argentino C, Lenzi GL, Sacchetti ML, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci. 1989; 91: 311–321.
Brekenfeld C, Remonda L, Nedeltchev K, V Bredow F, Ozdoba C, Wiest R, Arnold M, Mattle HP, Schroth G. Endovascular neuroradiological treatment of acute ischemic stroke: techniques and results in 350 patients. Neurol Res. 2005; 27 (suppl 1): 29–35.
Zeumer H, Hacke W, Ringelstein EB. Local intraarterial thrombolysis in vertebrobasilar thromboembolic disease. AJNR Am J Neuroradiol. 1983; 4: 401–404.
Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. J Am Med Assoc. 1999; 282: 2003–2011.
Barnwell SL, Clark WM, Nguyen TT, O’Neill OR, Wynn ML, Coull BM. Safety and efficacy of delayed intraarterial urokinase therapy with mechanical clot disruption for thromboembolic stroke. AJNR Am J Neuroradiol. 1994; 15: 1817–1822.
Gobin YP, Starkman S, Duckwiler GR, Grobelny T, Kidwell CS, Jahan R, Pile-Spellman J, Segal A, Vinueal F, Saver JL. MERCI 1: a phase 1 study of mechanical embolus removal in cerebral ischemia. Stroke. 2004; 35: 2848–2854.
Nakano S, Iseda T, Yoneyama T, Kawano H, Wakisaka S. Direct percutaneous transluminal angioplasty for acute middle cerebral artery trunk occlusion: an alternative option to intra-arterial thrombolysis. Stroke. 2002; 33: 2872–2876.
Mahon BR, Nesbit GM, Barnwell SL, Clark W, Marotta TR, Weill A, Teal PA, Qureshi AI. North American clinical experience with the EKOS MicroLysUS infusion catheter for the treatment of embolic stroke. AJNR Am J Neuroradiol. 2003; 24: 534–538.
Cheseboro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E. Thrombolysis in myocardial infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation. 1987; 1: 142–154.
Larrue V, von Kummer RR, Muller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke. 2001; 32: 438–441.
Smith WS, Sung G, Starkman S, Saver JL, Kidwell CS, Gobin YP, Lutsep HL, Nesbit GM, Grobelny T, Rymer MM, Silverman IE, Higashida RT, Budzik RF, Marks MP; MERCI Trial Investigators. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005; 36: 1432–1438.
Abou-Chebl A, Bajzer CT, Krieger DW, Furlan AJ, Yadav JS. Multimodal therapy for the treatment of severe ischemic stroke combining GP IIb/IIIa antagonists and angioplasty after failure of thromboysis. Stroke. 2005; 36: 2286–2288.
Antman EM, Guigliano RP, Gibson CM, McCabe CH, Coussement P, Kleiman NS, Vahanian A, Adgey AA, Menown I, Rupprecht HJ, Van der Wieken R, Ducas J, Scherer J, Anderson K, Van der Werf F, Braunwald E. Abciximab facilitates the rate and extent of thrombolysis. Results of the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. Circulation. 1999; 99: 2720–2732.
Straub S, Junghans U, Jovanovic V, Wittsack HJ, Seitz RJ, Siebler M. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke. 2004; 35: 705–709.
Booth NA, Robbie LA, Croll AM, Bennett B. Lysis of platelet-rich thrombi: the role of PAI-1. Ann N Y Acad Sci. 1992; 667: 70–80.
Coller BS. GP IIb/IIIa antagonists: pathophysiologic and therapeutic insights from studies of c7E3 Fab. Thromb Haemost. 1997; 78: 730–755.
Qureshi AI, Siddiqui AM, Kim SH, Hanel RA, Xavier AR, Kirmani JF, Suri MF, Boulos AS, Hopkins LN. Reocclusion of recanalized arteries during intra-arterial thrombolysis for acute ischemic stroke. AJNR Am J Neuroradiol. 2004; 25: 322–328.
Zhang L, Zhang ZG, Zhang R, Morris D, Lu M, Coller BS, Chopp M. Adjuvant treatment with a glycoprotein IIb/IIIa receptor inhibitor increases the therapeutic window for low-dose tissue plasminogen activator administration in a rat model of embolic stroke. Circulation. 2003; 107: 2837–2843.
De Lemos JA, Antman EM, Gibson CM, McCabe CH, Giugliano RP, Murphy SA, Coulter SA, Anderson K, Scherer J, Frey MJ, Van Der Wieken R, Van De Werf F, Braunwald E. Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial. Circulation. 2000; 101: 239–243.
Grines CL, Cox DA, Stone GW, Garcia E, Mattos LA, Giambartolomei A, Brodie BR, Madonna O, Eijgelshoven M, Lansky AJ, O’Neill WW, Morice MC. Coronary angioplasty with or without stent implantation for acute myocardial infarction. N Engl J Med. 1999; 341: 1949–1956.
Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, Guagliumi G, Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky AJ. Comparison of angioplasty with stenting, with our without abciximab in acute myocardial infarction. N Engl J Med. 2002; 346: 957–966.
Khan RM, Harjai KJ, Cox DA, Stone GW, Brodie BR, Boura J, Grines L, O’Neill W, Grines CL. Comparison of coronary stenting versus conventional balloon angioplasty on five-year mortality in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Am J Cardiol. 2005; 96: 901–906.
Henkes H, Miloslavski E, Lowens S, Reinartz J, Liebig T, Kuhne D. Treatment of intracranial atherosclerotic stenosis with balloon dilatation and self-expanding stent deployment (WingSpan). Neuroradiology. 2005; 47: 222–228.