Randomized Trial of Intraarterial Infusion of Urokinase Within 6 Hours of Middle Cerebral Artery Stroke

Abstract

Background and Purpose-The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan was organized to determine the safety and clinical efficacy of intraarterial infusion of urokinase (UK) in patients with stroke within 6 hours of onset. Methods-Patients with ischemic stroke presenting within 6 hours of onset and displaying occlusions of the M1 or M2 portion of the middle cerebral artery on carotid angiography were randomized to the UK or control groups. Clinical outcome was assessed by the modified Rankin Scale, National Institutes of Health Stroke Scale, and Barthel Index. Results-The Independent Monitoring Committee recommended stopping the trial after approval of intravenous infusion of recombinant tissue plasminogen activator in Japan. A total of 114 patients underwent randomization, 57 patients in each group. Background characteristics were comparable between the 2 groups. The primary end point of favorable outcome (modified Rankin Scale 0 to 2) at 90 days was somewhat more frequent in the UK group than in the control group (49.1% and 38.6%, OR: 1.54, 95% CI: 0.73 to 3.23) but did not reach a significant level (Pϭ0.345). However, excellent functional outcome (modified Rankin Scale 0 to 1) at 90 days, a preplanned secondary end point, was more frequent in the UK group than in the control group (42.1% and 22.8%, Pϭ0.045, OR: 2.46, 95% CI: 1.09 to 5.54). There were significantly more patients with National Institutes of Health Stroke Scale 0 or 1 at 90 days in the UK group than the control group (Pϭ0.017). The 90-day cumulative mortality was 5.3% in the UK group and 3.5% in the control group (Pϭ1.000), and intracerebral hemorrhage within 24 hours of treatment occurred in 9% and 2%, respectively (Pϭ0.206). Conclusions-The trial was aborted prematurely and the primary end point did not reach statistical significance.Nevertheless, the secondary analyses suggested that intraarterial fibrinolysis has the potential to increase the likelihood of excellent functional outcome.

Guidelines for acute ischemic stroke treatment: part II: stroke treatment

“…Prourokinase is not FDA-approved and is not available as reperfusion therapy. Further small randomized clinical trials of prourokinase (PROACT I) 29 and urokinase (MELT) 30 and a meta-analysis of the PROACT I, PROACT II, and MELT trials suggest that intra-arterial thrombolysis can be beneficial in patients with proximal MCA occlusion. Although intra-arterial thrombolysis with rt-PA is not supported by randomized clinical trials, data from observational and nonrandomized comparative studies suggest it can be beneficial 31,32 .…”

Intra-arterial Therapy for Acute Ischemic Stroke

“…The second major randomized trial was the Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) [41]. As with the PROACT II trial, the MELT trial evaluated the safety and efficacy of intra-arterial urokinase in patients with M1 or M2 segments of the MCA occlusions of <6-h duration.…”

Statement of ESMINT and ESNR regarding recent trials evaluating the endovascular treatment at the acute stage of ischemic stroke

“…In total, 68/118 patients (57.6 %) were found to have a favorable penumbral pattern following pretreatment imaging. The 118 patients were classified into four groups: embolectomy/penumbral (34 patients); standard care/ penumbral (34); embolectomy/non-penumbral (30); and standard care/non-penumbral (20). Statistical analysis testing to determine whether there was an interaction between treatment assignment and penumbral pattern determined no significance.…”

“…IA chemical thrombolysis was evaluated in several randomized trials showing its efficacy and safety (versus placebo and not versus IV recombinant tissue plasminogen activator (IV rtPA) as it was not authorized at the time of these trials) [16][17][18][19][20]. The rationale for IA chemical thrombolysis was to infuse the thrombolytic drug as close as possible to the clot (proximal, inside, or distal to the clot), in order to increase the local concentration of the drug, while simultaneously limiting its systemic concentration.…”