Adjunctive Therapy

Fibrinolytic agents have prothrombotic properties as well. The plasmin generated by thrombolysis leads to the production of thrombin, which is a potent platelet activator and converts fibrinogen to fibrin. Indeed, studies have shown early reocclusion in as many as 17% of the patients treated with IAT 17 and 34% of the patients treated with IV rt-PA.63 Therefore, a strong rationale exists for the adjuvant use of antithrombotic agents.

Systemic anticoagulation with IV heparin during the periprocedural phase of IAT has several potential advantages, including augmentation of the thrombolytic effect,22 prevention of acute reocclusion, and reduction in the risk of catheter-related embolism. However, these benefits must be weighed against the potentially increased risk of ICH when heparin is combined with a thrombolytic agent.

Argatroban, lepirudin, and bivalirudin are all direct thrombin inhibitors. These agents should replace heparin in cases in which the diagnosis of heparin-induced thrombocytopenia (HIT) type II is confirmed or even suspected. HIT type II is an immune-mediated disorder characterized by the formation of antibodies against the heparin-platelet factor 4 complex, resulting in thrombocytopenia, platelet aggregation, and the potential for arterial and venous thrombosis. The possibility of HIT type II should be raised in patients who demonstrate a platelet count drop to less than 100,000, or by greater than 50% from baseline, in the setting of heparin therapy (usually 5-12 days after initial exposure). Unexplained thrombotic events should also evoke this diagnosis, even in the setting of a normal platelet count. Impaired renal function must be taken into account when selecting the appropriate agent; argatroban is the only direct thrombin inhibitor that is hepatically cleared.

The use of glycoprotein (GP) IIb/IIIa antagonists, such as Reopro (abciximab), Integrilin (eptifibatide), or Aggrastat (tirofiban) in ischemic stroke is still investiga-tional. No cases of major intracranial hemorrhage were seen in a pilot randomized, double-blind, placebo-controlled study in which 54 patients presenting within 24 hours after ischemic stroke onset were randomly allocated to receive escalating doses of abciximab.64 Conversely, the AbESTT-II trial, a phase III, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of abciximab in acute ischemic stroke treated within 6 hours after stroke onset or within 3 hours of awakening with stroke symptoms, was stopped early due to high rates of ICH. The NIH is currently sponsoring a phase II trial (ROSIE) looking at intravenous reteplase in combination with abciximab for the treatment of ischemic stroke within 3-24 hours from onset. Preliminary analysis of the first 21 patients enrolled has revealed no symptomatic ICH or major hemorrhage. The CLEAR trial is studying the combination of low-dose rt-PA and eptifibatide in patients with NIHSS scores greater than 5 who present within 3 hours from stroke onset.

The data for the use of GP IIb/IIIa inhibitors in conjunction with IAT are even more scant, and are limited to case reports. Intravenous abciximab has been successfully used as adjunctive therapy to IA rt-PA or UK in cases of acute stroke.65-67 Desh-mukh et al.67 reported on 21 patients with large vessel occlusion refractory to IAT with rt-PA who were treated with IV and/or IA abciximab, eptifibatide, or tirofiban. Twelve patients also received IV rt-PA and 18 patients underwent balloon angioplasty. Complete or partial recanalization was achieved in 17 of 21 patients. Three patients (14%) had asymptomatic ICH, but there were no cases of symptomatic ICH. Mangiafico et al.68 described 21 stroke patients treated with an intravenous bolus of tirofiban and heparin followed by IA urokinase. Nineteen of these patients also underwent balloon angioplasty. TIMI 2-3 flow was achieved in 17 of 21 patients. ICH occurred in 5 of 21 patients (3 symptomatic ICH and 2 SAH), and was fatal in 3 patients.68 Qureshi et al.69 described the use of IA reteplase and intravenous abciximab on 20 stroke patients. There was one symptomatic ICH. Partial or complete recanalization occurred in 13 of the 20 patients. Conversely, the use of abciximab was predictive of asymptomatic SAH (OR 19.2) in nine patients who received this drug as a study protocol violation in the Multi-MERCI part 1 trial.39

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