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Tenecteplase Knocking on the Door.

If there is one lesson from multiple stroke trials from the past 10 years, it is the value of rapid recanalization of blocked arteries and reperfusing the brain. Doing so in appropriately selected patients has led to one of the most powerful effects ever reported in medicine. The Lazarus effect, where mute and hemiplegic patients doomed for a life of chronic dependency recover their speech and can walk within hours after acute treatment, is regularly observed. Although reperfusion with endovascular treatment (EVT) is highly effective, it does not apply to all patients with stroke principally because they do not have large, accessible vessel occlusions. Others may reach endovascular-capable centers only after prolonged transport during which they can receive medical therapy with intravenous thrombolysis. Many pragmatic reasons exist to support the search for highly active and better thrombolytic drugs. Tenecteplase, a tissue-type plasminogen activator modified by 3 amino acids from alteplase, has the potential to deliver this kind of performance. It has greater fibrin specificity resulting in no evidence of systemic fibrinogen depletion, resistance to plasminogen activator inhibitor resulting in an initial serum halflife of 20 minutes, and a mean terminal half-life of 100 minutes, such that it can be conveniently given as a bolus dose on a weight-adjusted basis. At a dose of 0.5 mg/kg, it has been a standard of care for treating acute ST-segment–elevation myocardial infarction for many years, being given even in the prehospital arena. Evidence for its potential in ischemic stroke treatment is starting to accrue from several acute stroke pilot studies. Haley et al conducted 2 sequential pilot studies comparing tenecteplase to alteplase. The first, a dose-escalation safety study, stopped after too many patients at the 0.5 mg/kg dose experienced symptomatic intracranial hemorrhage. The second adaptive-design dose-finding study (0.1, 0.25, 0.4 mg/kg) was stopped early because of slow enrollment. Interestingly, the study considered the 0.4 mg/kg dose to be inefficacious. Parsons et al (n=75) demonstrated that among patients with a penumbral pattern on computer tomographic perfusion imaging, tenecteplase (0.1 or 0.25 mg/kg) resulted in greater reperfusion in both arms, compared with alteplase. The ATTEST study (Alteplase Versus Tenecteplase for Thrombolysis After Ischemic Stroke; n=104) used 0.25 mg/kg tenecteplase and demonstrated clear safety but no efficacy advantage over alteplase. TEMPO-1 (Tenecteplase for Minor Stroke With Proven Occlusion; n=50) similarly showed safety in a dose-escalation study in minor ischemic strokes. An individual patient data meta-analysis of these trials confirmed that there was no difference between any dose of tenecteplase and alteplase for either efficacy or safety end points, but higher doses tended to increase the hemorrhage rates. Finally, the NORTEST study (Norwegian Tenecteplase Stroke Trial; n=1100) also showed near identical efficacy and safety of tenecteplase at 0.4 mg/ kg compared with standard alteplase dose, but among milder strokes and without advanced imaging. In this context, EXTEND-IA TNK (Extending the Time for Thrombolysis in Emergency Neurological Deficits IntraArterial Using Intravenous Tenecteplase) combines the momentum of recent success with endovascular thrombectomy with the evolving literature examining tenecteplase treatment of ischemic stroke. The study enrolled 202 patients with stroke to be treated within 4.5 hours of symptom onset and having an internal carotid, middle cerebral, or basilar artery occlusion and evidence of a penumbral pattern on computed tomographic perfusion imaging. After ≈80 patients were enrolled, the computed tomographic perfusion requirement was removed. The primary outcome was first angiographic imaging showing reperfusion of 50% of the affected territory or absence of a target thrombus for EVT. Surprisingly, it was achieved in 22% of the tenecteplase 0.25 mg/kg patients compared with 10% of the alteplase patients, making EVT redundant in these patients. Clinical outcomes at 90 days were numerically better in the tenecteplase group. Is this the proof that tenecteplase is a better thrombolytic treatment than alteplase? The answer is not yet. First, the alteplase (control) group in this study contained more women, more atrial fibrillation, longer times from onset-to-thrombolysis, and greater use of general anesthesia, all of which may cumulatively change the prognosis. Second, such positive results were not present in previous comparative studies by other groups on a clinical level. And third, the question of the most effective tenecteplase dose remains: would 0.4 mg/kg not be better than 0.25 mg/kg, at least for large vessel occlusions? Or should the