Although IV rt-PA is an effective drug for the treatment of acute ischemic stroke, its impact on public health is limited because of the small number of patients eligible for treatment. In order to find more effective therapies and expand the pool of eligible patients, future research on IV thrombolysis for acute ischemic stroke is therefore warranted and has proceeded along the following main directions: (1) finding alternative, more effective, IV thrombolytics; (2) improving patient selection using advanced imaging to define a radiological surrogate for the core infarct and ischemic penumbra; (3) adjunct therapy with other antiplatelet or antithrombotic agents; (4) adjunct therapy with mechanical devices, such as ultrasound energy by transcranial Doppler ultrasound, or catheter-based clot retrieval; and (5) adjunct therapy with neuroprotective agents.
Desmoteplase, a recombinant plasminogen activator, derived from the Desmodus vampire bat salivary plasminogen activator, was evaluated in a phase III randomized placebo-controlled trial for ischemic stroke of 3-9 hours duration, with patient selection based on the presence of a radiological surrogate of the ischemic penumbra. Desmoteplase has theoretical advantages over recombinant human rt-PA: it is more fibrin-specific, has a longer half-life (allowing it to be given as a single bolus), and may exhibit less neurotoxicity than rt-PA.103 Phase II randomized trials showed better clinical outcomes with desmoteplase, and acceptable rates of sICH.104,105 The phase III trial failed, however, to show benefit over placebo (unpublished data).
The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic rt-PA (CLOTBUST) study was a phase II randomized trial which compared continuous transcranial Doppler ultrasound insonation, in subjects with ultrasound evidence of MCA occlusion being given IV rt-PA, to sham insona-tion.106 There was an increased rate of arterial recanalization with the continuous insonation (49% vs. 30%, p = 0.03) and no increased risk of sICH.
The effectiveness of catheter-based intra-arterial therapy to remove residual thrombus after IV rt-PA treatment is being tested in the Interventional Management of Stroke study (IMS-III). This study will randomize patients to 0.6 mg/kg IV rt-PA, followed by angiography with additional intra-arterial therapy as indicated, or IV full-dose rt-PA (0.9 mg/kg). A nonrandomized safety study suggested that intraarterial therapy, after 0.6 mg/kg IV rt-PA, could be accomplished with acceptable rates of sICH.107
Pharmacologic neuroprotection, which might be expected to prevent tissue necrosis or apoptosis until tissue reperfusion can be achieved with rt-PA, is a theoretically attractive adjunct to rt-PA treatment. Despite positive studies in animals,108 all evaluations of neuroprotective agents in humans have failed.109 Most recently, the promising initial results for intravenous NXY-059,110 a free-radical-trapping agent, were not replicated in a confirmatory phase III trial (unpublished data).
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