Intraarterial Thrombolysis Trials in Acute Ischemic Stroke

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Stroke is a common cause of death and disability in industrialized nations. Technical advances and the increased availability of noninvasive brain imaging techniques have permitted precise and early diagnosis of acute cerebral ischemia. This has made emergent thrombolytic therapy for rapid restoration of cerebral perfusion increasingly possible. Herein, the authors present a review of the clinical trials investigating acute stroke treatment with intraarterial thrombolysis.

Section snippets

Computed Tomography (CT)

CT is readily available and permits rapid diagnosis of intracranial hemorrhage and alternative abnormalities in patients who are clinically suspected of having acute ischemic stroke (13). The European Cooperative Acute Stroke Study (ECASS) trials demonstrated a predictably higher rate of hemorrhagic conversion in patients treated with IV thrombolysis who had signs of acute ischemia on their baseline CT scans involving more than one-third of the MCA territory (8).

CT perfusion can help determine

THROMBOLYTIC AGENTS

Thrombolytic agents differ in stability, half-life, and fibrin selectivity. The best thrombolytic drug for use in acute stroke has yet to be determined. Most recent investigations have concentrated on recombinant prourokinase (r-proUK) and recombinant tissue-type plasminogen activator (rtPA). The thrombolytic effect of urokinase is augmented with heparin (18, 19).

IV THROMBOLYSIS TRIALS

The National Institute for Neurological Disorders and Stroke (NINDS) study used evidence of intracranial hemorrhage (ICH) as the only CT exclusion criteria (11). Patients who presented within 3 hours of ictus received IV administration of either 0.9 mg of tPA per kilogram of body weight (maximum, 90 mg) or placebo over 60 minutes. Compared with the placebo group, patients given tPA were 30% more likely to have minimal or no disability at 3 months. Although symptomatic ICH occurred within 36

IA THROMBOLYSIS TRIALS

Technical advances in the design of softer, more compliant microcatheters and steerable guide wires have made intracranial endovascular access increasingly feasible and safe. Small case series exploring the use of locally infused thrombolytics for acute stroke therapy have appeared in the literature since the late 1980s.

The theoretical advantages of IA thrombolysis include direct infusion of the medication into the occluding thrombus with higher local drug concentrations, lower systemic

PROACT I

The PROACT I study (38), which was conducted in 1994 to 1995, was the first randomized, double-blinded, multicenter trial in which the safety, recanalization frequency, and clinical efficacy of direct IA infusion of r-proUK was compared with that of placebo in patients with symptomatic MCA occlusion of less than 6 hours duration.

Clinical inclusion criteria required patients to have (a) new focal neurologic signs consistent with MCA territory occlusion within 6 hours of stroke onset, (b) a

PROACT II

The PROACT II study was a randomized, multicenter, open-label clinical trial with blinded follow-up involving 54 North American and Canadian centers (12). One-hundred eighty patients with acute ischemic stroke of less than 6 hours duration due to angiographically proved occlusion of the MCA were randomized to receive 9 mg IA r-proUK and low-dose heparin as used in PROACT I or lowdose heparin alone (control group). Infusion of saline as a placebo was not undertaken in this study due to ethical

COMBINED IV AND IA THROMBOLYSIS TRIALS

The time delay required for cerebral angiography and microcatheter positioning before the commencement of IA thrombolysis has been considered a disadvantage of this technique compared with IV thrombolysis. This has prompted investigators to combine the two therapies so that IV therapy can be initiated as soon as the decision to proceed with thrombolysis is made and adjunctive IA therapy can be instigated within the 6-hour time window.

In the Emergency Management of Stroke Bridging Trial (41), 35

VERTEBROBASILAR THROMBOLYSIS

Vertebrobasilar occlusion usually portends a grim prognosis, with overall mortality rates of 70%–80% (23). Despite a lack of large, randomized studies, a number of case series have been published since 1986 involving some 300 patients treated with local IA infusion of urokinase or tPA (22, 45, 46, 47, 48, 49).

Successful recanalization, either partial or complete, was achieved in approximately 70% of patients after a median infusion time of 120 minutes (22, 23), with survival rates of 55%–70%.

CURRENT STATUS OF IA STROKE THROMBOLYSIS

The results of clinical trials of thrombolysis for acute stroke have changed our algorithm for the management of acute ischemic stroke from systemic anticoagulation and/or aspirin alone to include the judicious use of more aggressive thrombolytic therapy.

IV thrombolysis appears to be better suited to recanalization of smaller distal emboli as opposed to large intracranial vessel occlusions that can be successfully lysed with local IA infusion (54). Rates of recanalization in the proximal MCA

CONCLUSION

Clinical trials have demonstrated a benefit of IA thrombolysis in selected patients with acute stroke in both the anterior and posterior cerebral circulations. The overall risk of symptomatic hemorrhagic transformation associated with thrombolytic therapy is not increased despite a higher frequency of early ICH and should not dissuade physicians from using such therapy in appropriate candidates. Education of the community and physicians along with further research about thrombolysis protocols

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    None of the authors have identified a potential conflict of interest.

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