Tenecteplase vs Alteplase for Acute Ischemic Stroke
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Although thrombolytic treatment with alteplase, a recombinant tissue plasminogen activator, is the accepted therapy for ischemic stroke, alteplase has been proven to be far from ideal. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, has some pharmacokinetic advantages over alteplase. The authors of this study had previously found that patients who received tenecteplase at a dose of 0.1 mg/kg of body weight had superior results on imaging and greater early clinical improvement compared with patients who received alteplase at a dose of 0.9 mg/kg of body weight.
For this study [N Engl J Med. 2012;366(12):1099-1107], the authors conducted a phase 2B, randomized open-label blinded trial that compared the standard dose of alteplase (0.9 mg/kg) with 2 different doses of tenecteplase (0.1 mg/kg and 0.25 mg/kg). The trial was performed between 2008 and 2011 at 3 major stroke centers in Australia.
Patients were selected for the trial using computed tomographic perfusion and angiographic imaging. These methods were used to select patients who would be the most likely to benefit from early reperfusion (patients with large-vessel occlusion and a large perfusion lesion in the absence of a large infarct core). Eligible patients were those with first-ever hemispheric ischemic stroke who were ≥18 years of age, had a score >4 on the National Institutes of Health Stroke Scale (NIHSS), and a premorbid score of ≤2 on the modified Rankin scale. A total of 75 patients participated in the study. Each patient received treatment with intravenous tenecteplase or alteplase, administered within 6 hours after the onset of the stroke. Patients underwent magnetic resonance imaging at 24 hours and at 90 days for assessment of imaging outcomes.
There were 3 treatment groups of 25 patients each. The mean (±SD) NIHSS score for all patients in the trial was relatively high at 14.4 (±2.6). Most baseline clinical characteristics were well matched among the 3 groups, but the alteplase group included fewer persons who smoked (P=.01); this group also included fewer persons with diabetes (P=.01), which was reflected in a lower blood glucose level at baseline in the alteplase group (P=.05). Patients in the alteplase group received treatment at a mean of 2.7 hours, compared with 3.1 hours for those in the pooled tenecteplase groups. Only 3 patients received treatment after 4.5 hours.
There was a significant benefit associated with tenecteplase for both coprimary end points of the study, with greater reperfusion (P=.004) and greater clinical improvement (P<.001) at 24 hours in the pooled tenecteplase groups than in the alteplase group. The magnitude and significance of the reperfusion and early clinical improvement in the pooled tenecteplase groups did not change after correction for imbalances at baseline. Tenecteplase was also beneficial with respect to secondary outcomes. In the pooled tenecteplase groups, as compared with the alteplase group, infarct growth was reduced, and a higher proportion of patients had an excellent or good recovery (modified Rankin scale score of 0 to 2) at 90 days (72% vs 44%, P=.02).
Compared with alteplase, the 0.25-mg/kg dose of tenecteplase was associated with improvement on all imaging efficacy outcomes. In addition to an increased proportion of patients with early clinical improvement, the outcomes at 3 months were better in the higher-dose tenecteplase group; 72% of patients in this group had an excellent recovery (no clinically significant disability), compared with 40% of those in the alteplase group (P=.02). There were no more adverse outcomes with either dose of tenecteplase than with alteplase. There was an efficacy dose response between the 2 tenecteplase dose tiers, including higher reperfusion and recanalization rates at the higher dose, which translated into greater clinical improvement at 24 hours and an increase in the number of patients with excellent recovery at 90 days (P=.01).