Stroke remains the third most common cause of death in industrialized nations, after myocardial infarction and cancer, and the single most common reason for permanent disability.1 In 1996, the Food and Drug Administration (FDA) approved intravenous (IV) thrombolysis with recombinant tissue-plasminogen activator (rt-PA, Alteplase) for the treatment of acute ischemic stroke within 3 hours of onset after reviewing the results of the National Institute of Neurological Disorders and Stroke (NINDS) and rt-PA Stroke Study Group trial.2 IV rt-PA thrombolysis was the first approved treatment for acute stroke that effectively treats the causative vascular occlusion. This strategy has the advantage of being relatively easy and rapid to initiate, and it does not require specialized equipment or technical expertise. Even though IV thrombolysis was initially a matter of relative controversy, it has now been endorsed as a Class IA level of evidence intervention by the major national guideline development organizations.3,4 A Cochrane Database Review including 18 trials (16 double-blind) with a total of 5727 patients who received thrombolytics (IV urokinase, streptokinase, rt-PA, or recombinant intra-arterial prourokinase) up to 6 hours after ischemic stroke showed a significant reduction in the proportion of patients who were dead or dependent (modified Rankin Scale (mRS) score 3-6) at follow-up at 3-6 months (odds ratio (OR) 0.84, 95% CI 0.75-0.95), despite a significant increase in the odds of death within the first 10 days
Acute Ischemic Stroke: An Evidence-based Approach, Edited by David M. Greer. Copyright © 2007 John Wiley & Sons, Inc.
(OR 1.81, 95% CI 1.46-2.24), most of which were related to symptomatic intracranial hemorrhage (OR 3.37, 95% CI 2.68-4.22).5 In addition, a pooled analysis of six major randomized placebo-controlled IV rt-PA stroke trials (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) I and II, European Cooperative Acute Stroke Study (ECASS) I and II, and NINDS I and II), including 2775 patients who were treated with IV rt-PA or placebo within 360 minutes of stroke onset, confirmed the benefit up to 3 hours and suggested a potential benefit beyond 3 hours for some patients. The pattern of a decreasing chance of a favorable 3-month outcome as the time interval from stroke onset to start of treatment increased was consistent with the findings of the original NINDS study.6
To extend the window of benefit for initiating IV rt-PA, it has been proposed that patient selection be based on mismatch between areas of abnormal perfusion-weighted imaging (PWI) compared with diffusion-weighted imaging (DWI) on magnetic resonance imaging (MRI). This idea that advanced neuroimaging and better-engineered thrombolytic agents may allow for an extension of the treatment window for thrombolysis and improved outcomes has been supported by the recent joint analysis of the phase II desmoteplase in acute stroke (DIAS) and desmoteplase in acute ischemic stroke (DEDAS) trials. This analysis included 94 patients with PWI/DWI mismatch on MRI who were treated with placebo (90 mg/kg) or 125 mg/kg of IV desmoteplase within 3-9 hours of stroke onset. Intention-to-treat analysis revealed reperfusion rates of 23.5%, 34.6%, and 62.1%, and good outcome rates of 22.9%, 37.9%, and 60%, respectively. The combined rate of intracerebral hemorrhage (ICH) in the desmoteplase group was only 1.7%.7
However, IV thrombolysis is not a panacea for acute stroke. The recanalization rates of IV rt-PA for proximal arterial occlusions range from only 10% for internal carotid artery (ICA) occlusions to 30% for proximal middle cerebral artery (MCA) occlusions.8 Analysis of the NINDS trial data shows a 12% absolute increase in good outcomes between the placebo and rt-PA groups at 3 months.9 In other words, eight stroke patients must be treated with rt-PA to achieve one additional good outcome. However, this analysis understates the impact of rt-PA on stroke patients because it fails to include the patients who partially improved.10 Indeed, an analysis based on the shift in mRS scores suggests a number needed to treat of only 3 for any improvement with IV rt-PA.11 Even when considering this argument, rates of improvement are far from ideal, and given the prevalence and impact of ischemic stroke, it is imperative to devise strategies that can be more effective. This is based on the implicit assumption that faster and more complete recanalization will translate into better long-term patient outcomes.
Local intra-arterial thrombolysis (IAT) has several theoretical advantages over IV thrombolysis. For instance, by using coaxial microcatheter techniques, the occluded intracranial vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombus. This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic infusion, and ideally it allows for more complete recanalization with lower total doses of thrombolytic. With the smaller dose, complications from systemic fibrinolytic effects, including ICH, can theoretically be reduced.
For these reasons, the treatment window for IAT can be extended beyond the typical IV window of 3 hours. Another major advantage is the combination of thrombolytic treatment with mechanical manipulation of the clot, which may improve recanalization rates.12 Indeed, mechanical thrombolysis with the use of little or no chemical thrombolysis has emerged as a key option for patients who either have a contraindication to chemical thrombolysis (e.g., recent surgery) or are late in their presentation.13,14 Furthermore, adjunctive endovascular treatment may be essential for the accomplishment of successful thrombolysis, for example, through stenting of a dissected vessel, or through angioplasty with or without stenting of a proximal occlusive lesion.15-17
The major disadvantages to endovascular strategies include the complexity of the procedure, the level of required technical expertise, delays in initiating endovascular treatment, and the additional risks and expense of an invasive procedure compared with IV rt-PA.
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