An investigational drug shows promise in a phase IIB study.

For more than a decade, intravenous tissue plasminogen activator (TPA) has been the only approved pharmacological treatment for acute ischemic stroke. Tenecteplase, an investigational drug, is a modified version of TPA with greater fibrin specificity and a longer half-life. Researchers conducted this randomized, phase IIB trial to compare standard TPA with two doses of tenecteplase (0.1 mg/kg or 0.25 mg/kg) for patients seen at one of three centers within 6 hours of stroke onset. Inclusion criteria were standard clinical criteria, a computed tomography (CT) perfusion deficit at least 20% greater than the infarct core, and CT angiography evidence of occlusion in the anterior, middle, or posterior cerebral arteries. The two primary endpoints were radiologic evidence of reperfusion at 24 hours and improvement on the NIH Stroke Scale (NIHSS) from before treatment to 24 hours after treatment. The two tenecteplase groups were pooled for analysis of the primary results.

Of 2768 patients screened, 75 met both clinical and CT criteria. The 75 participants were enrolled at a mean of 2.9 hours after stroke onset and had a mean NIHSS score of 14.4. Tenecteplase was significantly better than TPA with regard to radiologic reperfusion (79% vs. 55%) and with regard to clinical improvement (8-point vs. 3-point improvement on the NIHSS). At 3 months, 72% of the higher-dose tenecteplase patients had an excellent outcome, compared with 40% of the TPA group, a significant difference. The rates of hemorrhagic complications did not differ significantly between the TPA and tenecteplase groups.

Comment: This trial showed better short-term radiologic and clinical outcomes with tenecteplase than with TPA for acute ischemic stroke. The trial was not powered to assess 3-month outcomes, but the higher-dose tenecteplase patients had better 3-month outcomes than the TPA patients. A previous dose-ranging study of tenecteplase was inconclusive; the trial was terminated because of slow enrollment (Stroke 2010; 41:707).

This innovative study required additional radiologic criteria for thrombolysis treatment (CT perfusion and CT angiography), in addition to the standard clinical criteria. These criteria make pathophysiological sense, but they also restricted enrollment. A larger phase III study of tenecteplase should be considered, but the authors should also consider altering the enrollment criteria (e.g., by removing some of the exclusion criteria used in the current study) to make the treatment more broadly applicable to the acute ischemic stroke population. Until these further studies are complete, tenecteplase should not be used to treat ischemic stroke.

Source:Journal Watch Neurology