Thrombolysis of Acute Ischemic Stroke
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In 1996, the Food and Drug Administration (FDA) approved the use of intravenous recombinant tissue plasminogen activator (t-PA, alteplase) in patients who present within 3 hours from the onset of acute ischemic stroke. This approval was based on the positive results of the National Institute of Neurological Disorders and Stroke (NINDS) study.25 Currently, intravenous administration of t-PA within the 3-hour time window is the only FDA-approved treatment for acute ischemic stroke. However, two major clinical trials and one prospective observational registry have reported outcomes of death or more than 50% functional dependency at the 3-month follow-up evaluation (Table 1). Moreover, six randomized trials have failed to demonstrate a significant benefit for intravenous thrombolytic therapy initiated within 3 to 6 hours of stroke onset.Recently, multiple randomized trials have evaluated the safety and efficacy of IA thrombolysis administered 3 to 6 hours from symptom onset.33,34 In several case series, IA thrombolysis alone or in combination with mechanical thrombolysis has been reported as an alternative modality for treatment of acute ischemic stroke in a select group of patients.35-41 A randomized study may be necessary to determine whether thrombolysis with or without mechanical thrombolysis is superior to intravenous thrombolysis for acute ischemic stroke.
The IA approach to thrombolysis has theoretical advantages. First, angiographic evaluation helps to determine whether an occlusion exists and local IA therapy is necessary. Second, the IA approach allows delivery of the thrombolytic agent (i.e., t-PA or reteplase) to the site of occlusion without excessive systemic administration (a lesser amount of the drug can actually be used). Third, the endovascular surgeon can titrate the dose of the agent by angiographic visualization of the clot response to lysis. In situations where there is a poor response to chemical IA thrombolysis, angiographic evaluation will aid in the selection of methods of mechanical thrombolysis or other endovascular intervention. For example, an acute ischemic stroke from occlusion of the M1 segment of the MCA may occur in the setting of severe pre-existing atherosclerotic stenosis or embolic plaque. Combined use of chemical and mechanical forms of IA thrombolysis by use of either angioplasty, a stent, or a clot-retrieval device may be required for recanalization. Disadvantages of the IA approach include time and resources. With better patient education and earlier recognition of stroke symptoms, the time to treatment can be reduced. Currently, neither the chemical nor the mechanical method of IA thrombolysis for acute ischemic stroke has been approved by the FDA. Although chemical and mechanical forms of IA thrombolysis are promising novel therapies, patients with acute ischemic stroke still need to be transported expeditiously to an appropriate facility that can provide acute stroke therapy in a timely fashion. Time from onset to treatment is of paramount importance, regardless of the type of thrombolytic therapy used. Furthermore, advancements in imaging techniques, such as diffusion-weighted and perfusion-weighted MR imaging, Xenon-enhanced CT, and CT perfusion scanning, may allow improved patient selection for thrombolysis in the future.42-45 In this section, we will review the indications, techniques, and results of IA thrombolysis from major trials as well as from the authors’ experience.
A variety of drugs have been used for intravenous or IA thrombolysis for ischemic stroke in human clinical studies.46 A summary of thrombolytic agents is described in Table 2. All these agents act by converting plasminogen to plasmin. However, the first-generation thrombolytic agents such as urokinase (withdrawn from the market) and streptokinase are not fibrin-specific. Streptokinase is immunogenic and can cause drug resistance, fever, and allergic reactions. The second-generation thrombolytics include alteplase (t-PA) and pro-urokinase (r-pro UK), which are fibrin-selective; but high-doses of these drugs can lead to lower levels of fibrinogen and plasminogen. Third-generation thrombolytics include tenecteplase and reteplase, which are t-PA mutants. They have a longer half-life than alteplase and enhanced thrombolytic potency.47 Clinical trials are required to determine the appropriate dosing and candidates for these new, emerging thrombolytic agents.
INTRAARTERIAL THROMBOLYSIS TRIALS
The recanalization efficacy and safety of IA thrombolysis using recombinant pro-urokinase has been evaluated in two randomized, multicenter, placebo-controlled trials.33,34 In the Prolyse in Acute Cerebral Thromboembolism (PROACT) I and II trials, patients with acute ischemic stroke resulting from MCA occlusion and onset of symptoms within 6 hours underwent IA thrombolysis with r-pro UK.33,34 The results of these trials are summarized in Table 3. Recanalization rates are based on the Thrombolysis in Myocardial Infarction (TIMI) grading system (Table 4).48 Recanalization rates (TIMI 2 or 3) were 58% in the r-pro UK group and 14% in the placebo group in the PROACT I trial. Because of the low number of patients in PROACT I, clinical efficacy of this treatment modality could not be established. However, because of the safety and recanalization rates observed in PROACT I, PROACT II was performed. This trial was designed to assess the efficacy of IA r-pro UK (9 mg given over 2 hours as opposed to 6 mg in PROACT I) as measured by the modified Rankin scale (mRS) score of 2 or less at 90 days. For the primary outcome measure of efficacy in PROACT II, 40% of patients receiving r-pro UK and 25% of those receiving placebo achieved an mRS score of 2 or better at 90 days (p=0.04). Recanalization rates (TIMI 2 or 3) were 66% in the r-pro UK group and 18% in the placebo group in this trial. A 15% absolute increase in favorable outcome was shown with r-pro UK. For every seven patients treated with r-pro UK, 1 would benefit. Despite an increased frequency of early symptomatic ICH, IA r-pro UK administered within 6 hours of symptom onset in stroke caused by MCA occlusion significantly improved clinical outcome.
PROACT II was a landmark trial in that for the first time in a randomized study, IA thrombolysis demonstrated clinical efficacy and extended the time window for therapy to 6 hours in a homogeneous group of patients with acute ischemic stroke.34 This trial was conducted in a standardized fashion in terms of the technique of IA thrombolysis, as well as the agent and the dose used. However, the FDA requested additional data to support the clinical efficacy and safety demonstrated in PROACT II before approving IA thrombolysis as a standard therapy for patients with acute ischemic stroke. The success of the PROACT II trial was not sufficient to gain FDA approval for pro-urokinase, the trial has paved the way for additional studies involving IA thrombolysis (with newer agents) in acute ischemic stroke.
Five studies have evaluated the feasibility, safety, and recanalization rate of a combination of intravenous and IA thrombolysis in patients with acute ischemic stroke.49-53 The results are summarized in Table 5. The rationale for the combination approach is based on the fact that clinically severe strokes resulting from occlusion of large intracranial vessels respond poorly to intravenous thrombolysis. By combining the two therapies, patients may receive intravenous therapy during the time required for initiation of IA thrombolysis, which may be more effective in opening large arteries. Direct comparison of these studies is difficult due to heterogeneity of the study population, dosage and type of thrombolytic agents used, and patient selection criteria. Symptomatic ICH rates within 7 days of treatment range from 6 to 12%. Mortality rates range from 15 to 45%. TIMI 3 recanalization rates range from 19 to 55%. In the Emergency Management of Stroke (EMS) Bridging Trial, the safety, feasibility and recanalization efficacy was assessed using the combination approach.52 However, because of the small sample size (35 patients), the clinical efficacy of this therapy could not be determined. Suarez et al. reported that 78% of patients treated by combination therapy had Barthel index scores >95 at 3 months.53 Ernst et al. reported mRS scores of 0 or 1 at or beyond 2 months follow-up for 44% of patients treated by combination therapy.49 On the basis of the results of these initial pilot studies, NINDS funded a phase II pilot study, the Interventional Management of Stroke (IMS) trial.54 This trial was an open-label Phase II study designed to provide preliminary results on the safety and efficacy of combination intravenous and IA t-PA therapies initiated within 3 hours of symptom onset in 80 ischemic stroke patients with an NIHSS score >10. Patients received 0.6 mg/kg of intravenously administered t-PA over 30 minutes (15% as a bolus) followed by intraarterially administered t-PA at a dose of up to 22 mg over 2 hours if thrombus is identified by a cerebral angiogram. A preliminary analysis of the study has shown a 16% rate of mortality at 3 months (compared to 24% in the NINDS placebo group) and a 6% rate of symptomatic ICH (compared to 1% in the NINDS placebo group). TIMI 2 and 3 recanalization rates of 40% and 10% were observed, respectively. Favorable outcome at 3 months, as defined by mRS of 0 or 1, was observed in 30% of patients. Further analysis of the study data is pending.
Qureshi et al. evaluated the safety and efficacy of reteplase (the only second-generation thrombolytic agent available in addition to alteplase for the IA treatment of acute ischemic stroke) in 16 patients who were poor candidates for intravenous alteplase therapy because of the 3 hours or longer interval from symptom onset to presentation or severe neurological deficit on presentation (NIHSS scores ranged from 10 to 26).41 The authors used a modified TIMI grading system (Table 6) and reported TIMI 3 or 4 (equivalent to the original TIMI grade 3) recanalization rates in 88% of patients. Such a high rate of recanalization was achieved despite 8 of 16 patients presenting with occlusion of either the cervical (n=4) or intracranial (n=4) internal carotid artery (ICA). Early neurological improvement (defined as a decrease of 4 or more points in the NIHSS score at 24 hours) was observed in 44% of patients. Recently, Qureshi developed a new grading scheme to account for more precise location of occlusion in the cerebral vasculature and existence of collateral circulation, which are not described in the original and modified TIMI grading schemes.55 Further studies will be needed to evaluate the durability of IA thrombolysis using reteplase in acute ischemic stroke.
INDICATIONS FOR INTRAARTERIAL THROMBOLYSIS
On the basis of these major trials and case series, the authors recommend the following indications and contraindications for IA thrombolysis in acute ischemic stroke (summarized in Table 7). Patients who present between 3 and 6 hours from the onset of anterior circulation stroke may be considered for IA thrombolysis. Through combined efforts of the stroke team, expeditious evaluation, laboratory tests, and imaging studies such as CT or MR imaging and cerebral angiography need to be completed within 6 hours so that IA thrombolysis can be initiated. Speed is even more crucial with IA treatment than with intravenous thrombolysis because of the time necessary for preparation before endovascular intervention. In patients who present with posterior circulation stroke, because of the lack of evidence from randomized clinical trials regarding the efficacy of IA vertebrobasilar artery thrombolysis, the authors recommend reserving IA thrombolysis for those in whom treatment can be initiated within 6 hours. Although there have been anecdotal reports of clinical improvement and successful recanalization of basilar artery (BA) occlusion with IA thrombolysis as long as 24 hours after the onset of stroke symptoms,2 unless diffusion-weighted MR imaging can be performed to exclude early ischemic changes, the authors do not recommend IA thrombolysis more than 6 hours from symptom onset. As we develop reliable means of selecting potential candidates on the basis of physiological rather than chronological criteria by using advanced imaging systems, we may be able to determine which patients presenting beyond the 3- or 6-hour time window may benefit from thrombolysis.
Patients who present with severe neurological deficits (NIHSS ≥10) may be considered for IA thrombolysis. In the Standard Treatment with Alteplase to Reverse Stroke (STARS) study, 389 patients who presented within 3 hours of symptom onset underwent intravenous thrombolysis with alteplase.26 The study revealed a 22% decrease in the odds of recovery for every 5-point increase in baseline NIHSS score. Patients in whom the baseline NIHSS score was higher than 10 had a 75% decrease in the odds of recovery. In addition, Tomsick et al. reported poor outcomes associated with intravenous thrombolysis administered within 90 minutes of symptoms in patients with NIHSS ≥10.15 We do not mean to imply that an NIHSS score ≥10 is a contraindication for intravenous thrombolysis. In fact, in the NINDS study, intravenous thrombolysis resulted in better outcomes than placebo, regardless of the patient’s baseline NIHSS score.25 However, at institutions capable of providing IA therapy in a timely fashion, this select group of patients may be considered for IA thrombolysis as an alternative treatment in view of the poor outcomes observed with intravenous thrombolysis.
Another select group of patients who may be considered for IA thrombolysis include those who have undergone major surgery within 2 weeks from the onset of stroke symptoms.56-58 The NINDS trial excluded these patients from intravenous thrombolysis.25 For these patients, an IA approach may allow the administration of lower doses of thrombolytic agents needed to achieve recanalization, with or without adjunctive mechanical thrombolysis, than in the case of intravenous thrombolysis. This method may minimize hemorrhagic complications.
The authors suggest that the exclusion criteria used in the NINDS study be followed (Table 8). In the European Cooperative Acute Stroke Study (ECASS) I, safety and efficacy of thrombolysis with 1.1 mg/kg of intravenous alteplase were evaluated in patients treated within 6 hours of ischemic stroke.32 However, the enrollment of 17% of the patients (n=109) was a violation of the study criteria. The most frequent protocol violation was the inclusion of patients with early signs of infarction within more than one-third of the MCA territory on CT imaging. The incidence of ICH was significantly more frequent in the alteplase-treatment group. The authors recommend strict adherence to this imaging criterion for now until more clearly defined MR imaging or other imaging-based selection criteria become available.
TECHNIQUES OF CHEMICAL THROMBOLYSIS
Before IA thrombolysis is initiated, heparin is administered because of the risk of thromboembolic complications associated with prolonged microcatheterization of intracranial vessels.59 In the PROACT I trial, heparin was intravenously infused before selective microcatheterization of the occluded vessel.33 However, during the study, the dose of intravenous heparin was decreased from a 100-unit/kg bolus, followed by 1000 units administered hourly for 4 hours, to a 2000-unit/kg bolus, followed by 500 units administered hourly for 4 hours, because of an increased incidence of ICH. With the initial heparin regimen, the frequency of hemorrhagic transformation within 24 hours was 72.7% in the r-pro UK group and 20% in the placebo group. After the reduction in the heparin dose, the frequency of ICH at 24 hours decreased to 20% in the r-pro UK group and 0% in the placebo group. However, the recanalization rate also decreased from 81.8% in the high-dose heparin group to 40% in the low-dose heparin group. The PROACT II trial34 adopted the low-dose heparin regimen used in PROACT I. The use of other antithrombotic or antiplatelet drugs (such as abciximab or reteplase) during the first 24 hours was prohibited by the protocols of these trials. The authors believe that close attention to the activated coagulation time before the initiation of IA thrombolysis is paramount, as high-dose heparin therapy may augment hemorrhagic complications.
In both PROACT trials, an infusion microcatheter (<3.0 French) was advanced into the proximal one-third of the MCA thrombus over a microwire.33,34 If the microcatheter could not be placed in the proximal portion of the thrombus, the catheter was placed just proximal to the thrombus. A superselective angiogram was performed through the microcatheter to document the placement of the microcatheter. Mechanical disruption of the clot was not permitted in these trials. Recombinant r-pro UK (4.5 mg) or saline placebo was infused at a rate of 30 ml/hr. After 1 hour of r-pro UK infusion, another angiogram was performed through the microcatheter. If any of the proximal thrombus had dissolved, the endovascular surgeon advanced the microcatheter tip into the proximal portion of any remaining clot in the MCA. Even if complete lysis occurred in the first hour, another 4.5 mg of r-pro UK was infused into the proximal MCA over the subsequent hour. The final angiogram was performed at 2 hours through the diagnostic catheter in the cervical ICA in both the r-pro UK and control groups to assess recanalization rates.
The authors have reported their preliminary experience with IA reteplase (Retavase, Centocor, Inc., Malvern, PA).41 The patients were intubated and placed on a ventilator before cerebral angiography was performed. Propofol was intravenously administered for sedation. Prior to selective microcatherization of the occluded vessel, heparin (50 units/kg body weight) was administered intravenously to achieve an activated coagulation time of more than 250 seconds. A 6-French guide catheter was placed in the ICA or vertebral artery (VA) proximal to the occlusion site. A 2.3-French microcatheter was advanced to the occluded vessel in the proximity of the thrombus through the guide catheter over a microguidewire. A superselective angiogram was performed via the microcatheter in the occluded vessel to document the placement of the microcatheter (Fig. 1a). Reteplase was prepared in a 100-ml solution at a concentration of 1 unit of reteplase per 10 ml of sterile normal saline and then infused via the microcatheter at a rate of approximately 1 unit (10 ml) over the course of 10 minutes. Angiograms were performed via the guide catheter after each unit of reteplase was delivered to evaluate the status of recanalization (Fig. 1b). If the technique resulted in recanalization of a large artery occlusion (e.g., BA or cervical ICA) but the thrombus had moved distally to occlude the middle cerebral or posterior cerebral artery, the technique was repeated in the affected distal vessel until recanalization was achieved or the maximum dose of 8 units of reteplase was used (Fig. 1c). Unlike in the PROACT trials, we terminated infusion of reteplase before administering the maximum dose if recanalization was observed. Mechanical thrombolysis was performed at the discretion of the endovascular surgeon. Heparin was discontinued at the end of the procedure.
With advancements in the technology of new catheters, wires, drugs, and devices for IA thrombolysis, speedy and improved recanalization is expected in the future. However, the clinical acumen and experience of those who use these tools are very important. Endovascular surgeons need to know not only the potential candidates for IA thrombolysis, but also when to stop the procedure and avoid catastrophic consequences. Finally, in the PROACT II trial, there was an average 3-hour delay between patient arrival at a hospital and initiation of IA thrombolysis.33 More efficient methods of triage, evaluation, and preparation are needed.
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.
- Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 2000;283:1145-1150.
- Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245-1251.
- Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Lancet. 1995;346:1509-1514.
- Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial--Europe Study Group. N Engl J Med. 1996;335:145-150.
- Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282:2019-2026.
- Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, Rosen D, Stewart-Wynne EG, Tuck RR. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. 1996;276:961-966.
- Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017-1025.
- del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. 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, 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. JAMA. 1999;282:2003-2011.
- Eckert B, Koch C, Thomalla G, Roether J, Zeumer H. Acute basilar artery occlusion treated with combined intravenous Abciximab and intra-arterial tissue plasminogen activator: report of 3 cases. Stroke. 2002;33:1424-1427.
- Endo S, Kuwayama N, Hirashima Y, Akai T, Nishijima M, Takaku A. Results of urgent thrombolysis in patients with major stroke and atherothrombotic occlusion of the cervical internal carotid artery. AJNR Am J Neuroradiol. 1998;19:1169-1175.
- Jahan R, Duckwiler GR, Kidwell CS, Sayre JW, Gobin YP, Villablanca JP, Saver J, Starkman S, Martin N, Vinuela F. Intraarterial thrombolysis for treatment of acute stroke: experience in 26 patients with long-term follow-up. AJNR Am J Neuroradiol. 1999;20:1291-1299.
- Kim SH, Qureshi AI, Suri MFK, Ali Z, Yahia AM, Saad M, Boulos AS, Guterman LR, Hopkins LN. Mechanical thrombolysis using balloon angioplasty and snare with low-dose intraarterial reteplase (third-generation thrombolytic) for ischemic stroke. A prospective study (paper 13). J Neurosurg. 2002;96:168A.
- Nesbit GM, Clark WM, O'Neill OR, Barnwell SL. Intracranial intraarterial thrombolysis facilitated by microcatheter navigation through an occluded cervical internal carotid artery. J Neurosurg. 1996;84:387-392.
- Qureshi AI, Suri MF, Shatla AA, Ringer AJ, Fessler RD, Ali Z, Guterman LR, Hopkins LN. Intraarterial recombinant tissue plasminogen activator for ischemic stroke: an accelerating dosing regimen. Neurosurgery. 2000;47:473-479.
- Qureshi AI, Ali Z, Suri MF, Kim SH, Shatla AA, Ringer AJ, Lopes DK, Guterman LR, Hopkins LN. Intra-arterial third-generation recombinant tissue plasminogen activator (reteplase) for acute ischemic stroke. Neurosurgery. 2001;49:41-50
Reprinted with permission from Mohr JP, Choi DW, Grotta JC, Weir B, Wolf PA (eds): STROKE: PATHOPHYSIOLOGY, DIAGNOSIS, AND MANAGEMENT (4th edition), pp. 1475-1520 (chapter 78), Copyright Elsevier 2004. Permission has been granted to reproduce this material in online electronic format for non-exclusive world English rights.