Tenecteplase vs. Alteplase for Ischemic Stroke

Published - Written by Lisa Rosenbaum

Though, for clinicians, ordering a drug these days is as simple as a click of a button, for the drug, getting to within reach of our fingertips is no easy feat. Most drugs fail in early phases of testing, and those that eventually reach our clinical armamentarium have spent years getting there. Rarely do we pause to consider the animal models, the testing in healthy volunteers, the measured dose escalations, and the hundreds of millions of dollars required to establish the safety and efficacy of a new drug, or an old one for a new purpose. In this week’s NEJM, however, we have the opportunity to see how a drug, in this case tenecteplase for acute ischemic stroke, fares in one of the earlier phases of this long journey.

Currently, intravenous alteplase, a recombinant tissue plasminogen activator, is the only drug approved for treatment of acute ischemic stroke. However, alteplase is not without significant drawbacks, both in terms of its imperfect ability to achieve reperfusion, as well as its tendency to cause intracranial hemorrhage. Tenecteplase, a genetically engineered tissue plasminogen activator, may be a superior alternative, as it has a longer half–life, and greater fibrin specificity. In pilot testing, tenecteplase seemed to offer therapeutic benefit among stroke patients at doses that were lower than those used for acute coronary syndromes. However, no randomized testing of tenecteplase versus alteplase has occurred. Thus, “A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke,” is a Phase IIB trial that randomized 75 patients to either standard dose alteplase, or tenecteplase at two different doses.

Inclusion criteria were quite rigorous: of the 2768 patients assessed within six hours after symptom onset, only 75 were ultimately enrolled. Most were excluded based upon the usual contraindications to thrombolytic therapy. However, eligibility was further limited based upon CT perfusion and angiographic imaging parameters, so that only patients whose degree of angiographic obstruction outweighed the degree of true infarct were enrolled.  The greater the area of true infarct, the less likely patients are to clinically improve following reperfusion. Thus, these strict radiographic criteria were likely used because, theoretically, patients with more significant “perfusion/diffusion” mismatch have the best chance of benefitting from lytic therapy.

The results are promising for tenecteplase’s future. The coprimary outcomes were the degree of clinical improvement at 24 hours, as well as the amount of reperfusion achieved at 24 hours as assessed by MRI. The two tenecteplase groups were combined and compared to the alteplase group. For both clinical and radiographic parameters, tenecteplase proved superior to alteplase. Of course, bleeding is always a major concern in these trials, so it is also notable that there were no significant differences in intracranial hemorrhage or other adverse events between the two groups. Secondary endpoints included clinical improvement at 90 days, and for this outcome tenecteplase was also superior. Dose-tiered analysis was also performed. Patients who received the higher dose of tenecteplase had superior clinical outcomes, with 72% achieving excellent clinical recovery as opposed to 42% in the alteplase group.

What does this all mean? For now, this means a big step forward for tenecteplase on its road to becoming a new option for the treatment of acute ischemic stroke. But as striking as the effects seen in this trial may be, tenecteplase’s future remains a big “what if.” Phase 3 testing is required not only to assess this drug among a larger group of patients, but also to enroll patients based on typical eligibility criteria for thrombolytic therapy, rather than the more stringent radiographic criteria used here. But even if tenecteplase never reaches your fingertips, trials like these remind me that when I get impatient clicking through a slew of computer prompts to make a drug materialize, I ought to take a deep breath and consider how long it took for that drug to reach my screen.