Published online before print December 11, 2003, doi: 10.1161/01.STR.0000110121.57772.18
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(Stroke. 2004;35:114.)
© 2004 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Degree of Arterial Recanalization: An End Point For Efficacy in Future Intravenous Thrombolytic Trials
Neurovascular Unit, Vall d’Hebron Hospital, Barcelona, Spain
From a pathophysiologic viewpoint, acute stroke is, in most cases, the consequence of an arterial occlusion, and the primary mechanism of action of thrombolysis is clot lysis, resulting in recanalization and reestablishment of cerebral blood flow. The National Institutes of Neurological Disorders and Stroke (NINDS) trial1 clearly demonstrated a beneficial effect of intravenous recombinant tissue plasminogen activator (rtPA) when given <3 hours after symptom onset. However, the NINDS trial, like other clinical trials of intravenous thrombolysis, did not monitor presence and location of arterial occlusion and recanalization at different times after stroke. Criticism of the widespread use of tPA was based on the lack of vascular imaging in the standard emergent evaluation of acute stroke for a rational selection of patients who will obtain more benefit from thrombolysis. In the last few years, however, a tremendous progress and widespread implementation of noninvasive neurovascular techniques including transcranial Doppler (TCD), computed tomography angiography (CTA), and magnetic resonance angiography (MRA) have been achieved. These imaging modalities are being increasingly performed in the acute stroke setting without substantial delay in a large number of centers worldwide. Previous TCD and MRI studies have shown that early recanalization strongly associated with early neurological improvement, reduced infarct size, and favorable prognosis.2–4 However, the term recanalization involves various grades of success with differential effects on ischemic tissue evolution, clinical course, and outcome.
In the accompanying article, Neumann-Haefelin and colleagues5 studied 82 highly selected and homogeneous stroke patients with middle cerebral artery (MCA) main stem occlusions. All patients underwent a multiparametric MRI protocol including diffusion- and perfusion-weighted imaging (DWI, PWI) and MRA within 6 hours of stroke onset. The same protocol was repeated at 24 hours and 1 week. The authors applied the Thrombolysis In Myocardial Infarction (TIMI) score to assess the degree of arterial recanalization on 24-hour MRA. Using this angiographic grading system, patients were grouped into those with persistent occlusion (TIMI 0), minimal (TIMI 1), partial (TIMI 2), or complete (TIMI 3) recanalization. Patients who achieved TIMI 1 and 2 were pooled and regarded as incomplete recanalization. After adjustment for baseline stroke severity, initial DWI lesion, and PWI/DWI mismatch volume, the authors found that both incomplete and complete recanalization associated with a reduced DWI lesion growth compared with persisted occlusion. Moreover, a graded response in long-term outcome was seen in relation to the completeness of recanalization. These findings are in consonance with previous TCD and MRI studies,2–4,6 indicating that the amount of early recanalization represents one of the major determinants of stroke outcome. The present study highlights that even minimal recanalization may contribute to rescue penumbra tissue from infarction. Moreover, the authors confirm previous observations indicating that persistent MCA occlusion during the first 24 hours of onset represents one of the worst possible scenarios in terms of tissue damage enlargement and outcome. A previous MRI study7 showed a significant increase in DWI lesion at day 5 in patients without recanalization at 48 hours, which indicates further infarct dynamics and progressive infarct growth even after several days in patients with persistent occlusion. Nevertheless, the observations of Neumann-Haefelin et al also reveal a crude reality, that minimal recanalization, although better than persistent occlusion, leads to an unacceptably high rate (55%) of poor outcome and dependency at 3 months compared with partial and complete recanalization. Therefore, in the context of patients with proximal MCA occlusion, minimal recanalization is simply "better than nothing."
The mechanism of neurological improvement and reduced lesion growth in some patients with proximal MCA occlusion who achieve minimal recanalization is related to an increased perfusion as a result of distal displacement of the offending clot into the MCA main stem. Minimal clot migration or partial clot dissolution may restore collateral flow, when the most proximal aspect of the M1 MCA thrombus was partially obstructing collateral channels through the cortex, particularly via the anterior cerebral artery (ACA). The release of collaterals may lead to reperfusion of the ACA/MCA border-zone and cortical periphery of the ischemic penumbra.4 On the other hand, the proximal MCA thrombus may involve the lenticulostriate arteries supplying the ganglia basal and internal capsule. Minimal recanalization with distal clot migration may be enough to restore flow and function to the posterior limb of the internal capsule, where the motor fibers are represented, leading to an improvement of motor function. This may explain the beneficial effect of minimal recanalization on long-term outcome, since recovery of motor function may play an important role in the degree of independence for daily living activities in stroke survivors.
Although several case series have consistently demonstrated that early recanalization represents one of the powerful predictors of good long outcome after thrombolysis,2–4 some stroke patients experience little or no improvement and remain disabled despite tPA-induced recanalization. Other factors in addition to recanalization—including stroke severity, older age, systolic hypertension, location of arterial occlusion, collateral blood supply, and time from stroke onset to treatment—may play an important role in determining clinical outcome in patients treated with tPA. The beneficial effect of early restoration of cerebral blood flow on stroke outcome may be hampered in part by factors such as extent of irreversible brain injury before recanalization, excessive glucose burden at the time of reperfusion, and blood pressure changes during thrombolysis.
The TIMI score is an angiography-based grading system, which was originally developed and used to describe flow in the coronary arteries.8 Its clinical use has been extended to cerebral circulation. However, the TIMI grading system had certain limitations when applied to assess recanalization of intracranial arteries. The TIMI system evaluates local recanalization and, therefore, it does not accurately reflect the dynamic nature of the recanalization process during stroke thrombolysis. For instance, the phenomenon of proximal clot fragmentation followed by downstream embolization occluding smaller arteries cannot be adequately represented by the TIMI system. Moreover, TIMI flow grades obtained with time-of-flight MRA may be underestimated in comparison to angiography, making it sometimes difficult to differentiate between TIMI 1 and 2. This limitation has been solved, at least in part, by Neumann-Haefelin et al evaluating the extent of residual PWI lesion to better discriminate between TIMI 1 and TIMI 2.
Selection of a study end point for phase I and II trials depends mainly on the expected mechanism and effect of the given drug.9 The study of Neumann-Haefelin et al adds to the cumulative evidence suggesting that the noninvasive assessment of the degree of arterial recanalization, as an indicator of biologic activity of a thrombolytic drug, should be used as an end point for efficacy in future intravenous thrombolytic trials. New thrombolytic agents or approaches to enhance the efficacy of tPA such as combination with glycoprotein IIb-IIIa inhibitors or ultrasounds need to be properly tested, establishing their ability to achieve early recanalization. CLOTBUST is a multicenter randomized phase II trial that uses recanalization on TCD at 120 minutes of tPA bolus as primary efficacy end point. The feasibility to assess arterial occlusion and recanalization in stroke thrombolysis is supported by the increasing distribution and around-the-clock availability of noninvasive neurovascular techniques. Further studies are required to identify the time point of recanalization that better reflect the maximum thrombolytic effect (60 minutes, 120 minutes, or 24 hours) and to evaluate whether the combination of imaging protocols (ie, TCD monitoring plus MRI) adds to the knowledge of the effects of the speed and degree of clot dissolution after thrombolysis on ischemic tissue evolution and outcome.
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References |
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- The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.
[Abstract/Free Full Text] - Molina CA, Montaner J, Abilleira S, Arenillas JF, Ribo M, Huertas R, Romero F, Alvarez-Sabin J. Time course of tissue plasminogen activator-induced recanalization in acute cardioembolic stroke: a case-control study. Stroke. 2001; 32: 2821–2827.
[Abstract/Free Full Text] - Alexandrov AV, Burgin SW, Demchuk AM, El-Mitwalli A, Grotta JC. Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-term improvement. Circulation. 2001; 103: 2897–2902.
[Abstract/Free Full Text] - Felberg RA, Okon NJ, El-Mitwalli A, Burgin WS, Grotta JC, Alexandrov AV. Early dramatic recovery during intravenous tissue plasminogen activator infusion: clinical pattern and outcome in acute middle cerebral artery stroke. Stroke. 2002; 33: 1301–1307.
[Abstract/Free Full Text] - Neumann-Haefelin T, du Mesnil de Rochemont R, Fiebach JB, Gass A, Nolte C, Kucinski T, Rother J, Siebler M, Singer OC, Szabo K, et al. Effect of incomplete (spontaneous and postthrombolytic) recanalization after middle cerebral artery occlusion: a magnetic resonance imaging study. Stroke. 2004; 35: 109–115.
[Abstract/Free Full Text] - Parsons MW, Barber PA, Chalk J, Darby DG, Rose S, Desmond PM, Gerraty RP, Tress BM, Wright PM, Donnan GA, Davis SM. Diffusion- and perfusion-weighted MRI response to thrombolysis in stroke. Ann Neurol. 2002; 51: 28–37.[CrossRef][Medline] [Order article via Infotrieve]
- Schellinger PD, Jansen O, Fiebach JB, Heiland S, Steiner T, Schwab S, Pohlers O, Ryssel H, Sartor K, Hacke W. Monitoring intravenous recombinant tissue plasminogen activator thrombolysis for acute ischemic stroke with diffusion and perfusion MRI. Stroke. 2000; 31: 1318–1328.
[Abstract/Free Full Text] - TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial: phase I findings: N Engl J Med. 1985; 312: 932–936.[Medline] [Order article via Infotrieve]
- Higashida RT, Furlan AJ. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003; 34: e109–e137.[Medline] [Order article via Infotrieve]
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