Published online before print November 22, 2006, doi: 10.1161/01.STR.0000251720.25337.b0
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(Stroke. 2007;38:80.)
© 2007 American Heart Association, Inc.
Original Contributions |
Is Intra-Arterial Thrombolysis Safe After Full-Dose Intravenous Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke?
From the Departments of Neurology (H.M.S., K.C.A., N.R.G., A.M.K., R.M.S., J.C.G., E.A.N.) and Radiology (R.U.W., E.D.C.), University of Texas–Houston Medical School, Houston, Tex, and the Department of Neurology (M.S.C., III), Alabama Neurological Institute, Birmingham, Ala.
Correspondence to James C. Grotta, MD, Vascular Neurology Program, Department of Neurology, University of Texas Health Science Center–Houston, 6431 Fannin St, MSB 7.128, Houston, TX 77030. E-mail James.C.Grotta{at}uth.tmc.edu
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Abstract |
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Background and Purpose— The optimal approach for acute ischemic stroke patients who do not respond to intravenous recombinant tissue plasminogen activator (IV rt-PA) is uncertain. This study evaluated the safety and response to intra-arterial thrombolytics (IATs) in patients unresponsive to full-dose IV rt-PA.
Methods— A case series from a prospectively collected database on consecutive acute ischemic stroke patients treated with IATs after 0.9 mg/kg IV rt-PA during a 7-year interval was collected. Primary outcome measures included symptomatic intracranial hemorrhage and mortality. As indicators of response, secondary outcome measures were recanalization and discharge disposition.
Results— Sixty-nine patients (mean±SD age, 60±13 years; range, 26 to 85 years; 55% male) with a median pretreatment National Institutes of Health Stroke Scale score of 18 (range, 6 to 39) were included. IV rt-PA was started at 124±32 minutes (median, 120 minutes) and IAT, at 288±57 minutes (median, 285 minutes). IATs consisted of reteplase (n=56), alteplase (n=7), and urokinase (n=6), with an average total dosage of 2.8 U, 8.6 mg, and 700 000 U, respectively. Symptomatic intracranial hemorrhage occurred in 4 of 69 (5.8%) patients; 3 cases were fatal. Recanalization was achieved in 50 (72.5%) and a favorable outcome (home or inpatient rehabilitation) in 38 (55%).
Conclusions— IAT therapy after full-dose IV rt-PA in patients with persisting occlusion and/or lack of clinical improvement appears safe compared with IV rt-PA alone or low-dose IV rt-PA followed by IAT. A high rate of recanalization and favorable outcome can be achieved.
Key Words: acute stroke • endovascular treatment • intracranial hemorrhage • t-PA • thrombolysis
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Introduction |
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Intravenous recombinant tissue plasminogen activator (IV rt-PA) within 3 hours of stroke onset is the first and currently the only US Food and Drug Administration–approved therapy for acute ischemic stroke.1 However, up to 50% of patients have no reported benefit.1,2 Failure to recanalize the occluded artery is the cause of most poor clinical responses to IV rt-PA.3 In angiographic trials of IV rt-PA, the rate of recanalization of major arterial occlusions was low, with partial or complete recanalization in only 10% of occluded internal carotid arteries and in 25% of proximal middle cerebral arteries.4–6 Noninvasive monitoring by transcranial Doppler ultrasound (TCD) has revealed complete or partial recanalizations of 30% and 48%, respectively, and reocclusion in 34% of patients with any initial recanalization after IV rt-PA.7
Intra-arterial thrombolytics (IATs) have been reported to completely or partially recanalize occluded arteries in 50% to 85% of patients.2,8–11 However, the longer delay to initiation of therapy is an important limitation. The median time to start IATs in PROACT II was 5.3 hours, and only 3 patients had therapy started within 3 hours.8 Recanalization often occurred >7 hours after stroke onset. Such a long delay limits the effectiveness of IATs.10,11
With the combination of early treatment with IV and increased recanalization with IA routes, thrombolysis is reportedly feasible and safe, with better recanalization rates and potentially improved patient outcomes compared with either approach alone.12–17 In all of these studies, a low dose of IV rt-PA (0.6 mg/kg) was used.
IATs after full-dose (0.9 mg/kg) IV rt-PA are generally perceived as high risk, although it has never been tested.18,19 We report our safety, recanalization rates, and clinical outcome results of IATs for patients with persistent occlusion or poor clinical response after full-dose IV rt-PA.
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Subjects and Methods |
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Safety
Safety was determined by the incidence of life-threatening bleeding during the first 36 hours after treatment, defined as (1) symptomatic intracranial hemorrhage (ICH) or hemorrhagic transformation20,21 with clinical deterioration >2 points on the National Institutes of Health Stroke Scale (NIHSS) or (2) other severe systemic bleeding complications, such as groin hematoma, retroperitoneal hematoma, or gastrointestinal bleeding requiring transfusion of
3 U of blood.
Response
Response to treatment was determined by the final rate of recanalization according to the Thrombolysis in Cerebral Infarction (TICI) flow grading system.22 Favorable outcome was defined as discharge to home/rehabilitation versus discharge to nursing facility/death.
Patient Selection
From 1998 through 2005, eligible acute ischemic stroke patients presenting within 3 hours of symptom onset were treated with full-dose (0.9 mg/kg) IV rt-PA. Patients were intermittently monitored by TCD during IV rt-PA infusion. The following protocol for subsequent IATs was approved by the University of Texas Committee for the Protection of Human Subjects, and informed consent was obtained for IATs. If a patient had a severe disabling neurological deficit (no NIHSS cutoff was used), the neurointervention team was notified once the patient met any of the following criteria during IV rt-PA infusion: (1) no neurological improvement, determined as an unchanged NIHSS score from baseline, or worsening without hemorrhagic or advanced ischemic changes on a repeat CT scan or (2) no recanalization or early arterial reocclusion during the 1-hour rt-PA infusion, as detected by TCD monitoring obtained every 30 minutes.23–25 MRI findings were not obtained before IAT administration.
Thrombolytic Therapy
Patients meeting the inclusion criteria underwent immediate cerebral angiography via the femoral approach. When needed, patients underwent general anesthesia before their IAT was started. A diagnostic 6F guide catheter was advanced under fluoroscopic guidance into the symptomatic artery. If the suspected distribution of ischemia was in the carotid artery, then injection into the common carotid artery was performed to examine the carotid bifurcation. If a carotid occlusion was identified, with failure to opacify the carotid terminus, then the opposite carotid artery and/or vertebral artery was injected to identify collateral flow. If the suspected arterial distribution was vertebral basilar, then selective injection of 1 or both vertebral arteries was performed. A microcatheter and microguidewire were advanced through the guide catheter and navigated to the occluded vessel segment in proximity to the thrombus. The microcatheter tip was placed into the thrombus for thrombolytic administration. Because of its theoretical advantages, especially better clot penetration and longer half-life than rt-PA, reteplase was chosen, and a dose up to 6 U (based on previously published data2) was infused by slow hand push at an approximate rate of 1-U aliquots diluted in 3 mL over 5 to 10 minutes. In earlier cases before reteplase was readily available at our institution, urokinase (initially, until it was taken off the market) or alteplase was used and injected in a manner similar to that of reteplase at a rate of 50 000 to 100 000 U and 2 to 4 mg, respectively, given at 10-minute intervals. Control angiography was performed every 10 minutes to evaluate recanalization. Mechanical disruption of the clot with the microcatheter and/or microguidewire was also permitted. The patient’s neurological function was evaluated every 15 minutes during the procedure when permitted. Termination of the IAT treatment procedure occurred when (1) a TICI flow 2a was achieved, (2) thrombolytics had been administered until 6 hours from symptom onset (except for basilar artery occlusion, for which there was no time limit), (3) maximum dose limits were achieved (reteplase 6 U, urokinase 750 000 U, alteplase 24 mg), or (4) suspicion arose concerning extravasation of contrast material, suggesting vessel rupture. In addition to these criteria, the interventionist or vascular neurologist could use clinical judgment in determining when to stop IA therapy based on the perceived risks and benefits.
Medical management followed the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial protocol. Antiplatelet therapy was started no earlier than 24 hours after the procedure, along with no evidence of ICH on the 24-hour CT scan. The standard guidelines of blood pressure management after IV rt-PA therapy were followed before and after the intervention. When successful recanalization was achieved (TICI 2a), a systolic blood pressure goal of <160 mm Hg was targeted. Standard orders included acetaminophen and a cooling blanket for temperature 100°F, as well as a regular insulin sliding scale with blood glucose every 4 to 6 hours. Repeat imaging was performed at 24 to 48 hours on all patients and immediately on any patient who experienced neurological deterioration (increase in the NIHSS of >2 points). All CT scans were analyzed for hemorrhagic transformation by a neuroradiologist blinded to treatment.
Statistical Analysis
Descriptive and frequency statistical analyses were performed and comparisons made with SPSS for Windows (version 11.5, SPSS Inc).
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Results |
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During the study period, 69 patients admitted with acute ischemic stroke met the inclusion/exclusion criteria and were treated with full-dose IV rt-PA, followed by IAT. Table 1 summarizes their baseline characteristics. Forty-eight of the 69 patients (69.5%) were monitored with TCD every 30 minutes from rt-PA bolus. The median time from symptom onset to starting IV rt-PA was 120 minutes (range, 59 to 180 minutes), and median time from symptom onset to starting IAT was 285 minutes (range, 150 to 450 minutes). Eighty-eight percent of IAT procedures were started within 6 hours from symptoms onset.
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The angiographic findings are summarized in Table 2. The majority (56%) of thrombi were classified as grade 4 (large thrombus present with greatest dimensions of 2 or more vessel diameters).2 More than two thirds of the patients had an initial grade 0 TICI perfusion (no perfusion beyond the occlusion). IAT was administered with reteplase (n=56), alteplase (n=7), and urokinase (n=6), with an average total dosage of 2.8 U (range, 0.35 to 8 U; 86% 
4), 8.6 mg (range, 4 to 18 mg), and 700 000 U (range, 75 000 to 1 500 000), respectively. Mechanical disruption of the clot was used in 52 (75%) with either the simple wire and/or angioplasty. The MERCI retriever device was not used. Carotid artery stents were placed in 3 patients. TICI flow 2a recanalization occurred in 50 patients (73%).
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Symptomatic ICH occurred in 4 patients (5.8%); all were parenchymal hematoma (PH)-2. All ICHs (n=24) that occurred were as follows: hemorrhagic infarction (HI-1) n=5, HI-2 n=6, PH-1 n=7, PH-2 n=5, and subarachnoid hemorrhage n=1, as shown in Table 3. One asymptomatic PH-2 was treated with fresh frozen plasma. Systemic bleeding complications included 3 patients with hematuria, 2 with groin hematoma, and 1 with gingival oozing, but none required transfusions. Angioedema occurred in 1 patient, requiring intubation. The mortality rate was 12 of 69 (17%). Of these patients, 3 had PH-2, 6 herniated attributable to cerebral edema (2 with successful recanalization and 4 without recanalization), and care was withdrawn in 3 patients. There was no significant difference in age (P=0.063), sex (P=0.651), or baseline NIHSS score (P=0.789) between the symptomatic ICH group and those not experiencing symptomatic ICH. As shown in Table 4, of the patients who experienced symptomatic ICH, 2 patients received urokinase (average dose, 287 500 U) and 2 received reteplase (average dose, 2.10 U). A favorable outcome was achieved in 38 of 69 patients (55%), with 17% discharged to home.
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Protocol violations included 1 patient who was treated despite an obvious hypodensity on the initial CT scan and 1 patient who was treated with abciximab after IAT therapy because of carotid reocclusion. Both ultimately experienced a PH-2, 1 asymptomatic and 1 fatal. In addition, 6 patients were treated with more than the maximum allowed dose of IAT, 1 of whom had an HI-1. Seven patients received IAT beyond the 6-hour time limit.
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Discussion |
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Our study demonstrates that combined full-dose 0.9 mg/kg IV rt-PA followed by IAT is feasible and may have safety comparable with both IV rt-PA alone and combined low-dose IV rt-PA/IAT (Table 5).1,17,26 The severity of the initial neurological deficit was comparable in all studies. There was a shorter time to starting IV treatment, but the IAT time was delayed by a median of >40 minutes. We set no arbitrary minimum time cutoff for starting IAT after IV rt-PA, nor did we purposefully delay onset of IAT to observe the patient’s clinical course for recovery. The median interval between the IV rt-PA bolus and onset of IAT treatment was 165 minutes (see Table 1). Delays could be explained in part by the availability of only a single angiographic suite dedicated for these studies and the preference of our interventionist for most patients to be anesthetized for the procedure;
54% of cases were performed by 1 interventionist (E.D.C). Nevertheless, we believe that our data reflect the real-world problems of initiating IAT, even in a comprehensive stroke center.
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When comparing our 18- to 85-year-old middle cerebral artery occlusion subgroup with that in the PROACT II trial, we noted several differences.27 First, although the median NIHSS score on admission was the same for both studies (NIHSS score of 17), our symptomatic ICH rate was 6% compared with 10.2% in PROACT II (P=0.551). Our low symptomatic ICH rate may reflect the younger age of our patients (mean of 61 versus 64 years), the restricted use of heparin, and the use of mechanical clot disruption in more than three fourths of our cases, allowing for relatively lower doses of the IA lytic drug. Furthermore, our rate of successful recanalization was 76%, compared with 66% found in PROACT II, although the latter trial did not allow mechanical clot disruption and used a slower rate of IA lytic delivery. However, overall, our results suggest that IV rt-PA influenced recanalization without increasing symptomatic ICH.
The motivation for this study was to find a "salvage" treatment that could be offered to patients presenting within 3 hours of symptom onset and who are treated with IV rt-PA but whose vessels still do not recanalize. We thought it important not to omit IV rt-PA, because 20% of patients scheduled for IAT after IV rt-PA never receive the IA regimen, either because of technical problems or because the clot has already lysed by the time IAT begins.8,9,11,18 We elected to use full-dose IV rt-PA because as many as 80% of patients with NIHSS scores 10 have residual occlusion of a major intracranial artery after low-dose treatment and because eligible patients should not be deprived of the only approved treatment available.12,13,17
There are other non-IAT strategies to improve the results obtained with IV rt-PA. Continuous 2-MHz TCD produces sustained complete middle cerebral artery recanalization at 2 hours in 38% compared with 13% of controls.28 Other ongoing studies are combining IV rt-PA with heparin, GP2b3a antagonists, or direct thrombin inhibitors.29
There are several limitations to this study, including (1) small number of patients, (2) lack of a control group, (3) heterogeneous sizes and sites of occluded arteries, (4) lack of long-term outcome data, (5) the need for anesthesia to allow safe navigation of the branch artery, and (6) use of multiple IATs. Finally, IAT was performed by a veteran stroke team, and thus, our findings may not be generalizable to other settings.
In conclusion, combined full-dose IV rt-PA within 3 hours of symptom onset followed by IAT to treat acute ischemic stroke patients is sufficiently safe to warrant further evaluation. Such an approach would be particularly useful in supporting the "drip and ship" approach, whereby patients are given full-dose IV rt-PA at a primary stroke center and then transferred to a comprehensive stroke center for IAT.
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Acknowledgments |
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Sources of Funding
K.C.A. is supported by NIH training grant ST32NS007412-08 to the University of Texas Health Science Center–Houston Vascular Neurology program. N.R.G. is supported by NIH training grant T32NS04712 to the University of Texas Health Science Center–Houston Vascular Neurology program.
Disclosures
None.
Received May 27, 2006; revision received August 7, 2006; accepted August 22, 2006.
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