Genetically modified thrombolytic boosts reperfusion after stroke
Alteplase is sometimes administered to dissolve clots before endovascular thrombectomy in patients with ischemic stroke. But a new study in the New England Journal of Medicine demonstrates tenecteplase, a genetically modified form of alteplase, is associated with better blood flow restoration and improved functional outcomes.
Researchers randomized 202 patients to receive one of the two thrombolytics. All patients were eligible to undergo thrombectomy and treated within 4.5 hours of symptom onset.
A total of 22 percent of patients treated with tenecteplase and 10 percent of those treated with alteplase met the primary outcome—greater than 50 percent reperfusion of the ischemic territory or the absence of a retrievable clot upon angiography. In addition, the median modified Rankin scale score at 90 days was two in the tenecteplase group and three in the alteplase group. The modified Rankin scale measures neurological deficit on a scale of 0 to 6, with lower scores representing better functional outcomes.
“We expected the effect on the clinical outcome of endovascular thrombectomy to obscure any potential difference between tenecteplase and alteplase and therefore chose the technical efficacy of substantial reperfusion for the primary outcome,” wrote lead author Bruce C.V. Campbell, PhD, and colleagues.
“The trial was powered for noninferiority, not for superiority, and the significance of superiority for the primary outcome of reperfusion was therefore less robust. Patients in the tenecteplase group had significantly better functional outcomes than those in the alteplase group in an ordinal analysis of the modified Rankin scale scores but not according to the proportion of patients who were left with minimal or no deficit or to the proportion of patients with early clinical improvement of their stroke deficit.”
The alteplase patients received 0.9 milligrams per kilometer of body weight or a maximum of 90 mg, administered intravenously for approximately one hour. Tenecteplase is more fibrin-specific and has a longer half-life, allowing for one-time administration at 0.25 mg/kg or a maximum dose of 25 mg.
“The ability to administer tenecteplase in a single bolus, as compared with the one-hour infusion of alteplase, may be of practical benefit in patients with stroke with large-vessel occlusion who are transported between, as well as within, hospitals to access endovascular thrombectomy, but this was not formally assessed in this trial,” the researchers noted. “In some systems, transport cannot occur until the infusion of alteplase is complete.”
Campbell et al. said the earlier reperfusion by the faster-acting tenecteplase may have contributed to the improved outcomes in that group. Importantly, there were no significant differences between the groups at baseline, and each arm had similar rates of cerebral hemorrhage (1 percent).
“The additional thrombectomy procedures that were averted with tenecteplase in the present trial highlight the benefit and convenience of this therapy as compared with alteplase,” Alison E. Baird, MB, PhD, MPH, wrote in a related editorial. “However, to put this in perspective, in absolute terms, less than 25 percent of the tenecteplase-treated patients had substantial recanalization, whereas recanalization rates with stent-retriever thrombectomy are 80 percent or higher.”
Baird noted another study is underway investigating whether higher doses of tenecteplase—0.4 mg/kg or a maximum of 40 mg—can lead to higher rates of reperfusion without increasing the risk of intracerebral hemorrhage. For now, she said the trial by Campbell et al. indicates tenecteplase may contribute to better clinical outcomes than alteplase, but more stringent studies are necessary to prove its superiority.
“Noninferiority or superiority needs to be shown in a phase 3 trial with clinically relevant primary-outcome measures, not just with higher rates of recanalization. Ideally, such a trial would involve patients who are eligible for thrombectomy and are undergoing bridging therapy,” she wrote. “Changes to practice would require not only further demonstration that tenecteplase is noninferior or superior in clinical efficacy to alteplase but also evidence of convenience, accessibility, affordability, and practicality.”
Daniel joined TriMed’s Chicago editorial team in 2017 as a Cardiovascular Business writer. He previously worked as a writer for daily newspapers in North Dakota and Indiana.