A new study suggests that the 0.25-mg/kg dose of the thrombolytic tenecteplase (TNK) is just as good at facilitating reperfusion of the blocked artery in patients with ischemic large-vessel stroke prior to planned thrombectomy as the higher 0.4-mg/kg dose.
Dr. Bruce Campbell
The EXTEND-IA TNK Part 2 trial was presented today at the American Stroke Association’s International Stroke Conference (ISC) 2020 in Los Angeles and was published online simultaneously (JAMA. 2020 Feb 20. doi: 10.1001/jama.2020.1511).
“We found the 0.4-mg/kg dose was no better than 0.25 mg/kg. There was absolutely no perceptible difference, so it appears that 0.25 mg/kg is enough,” lead investigator Bruce Campbell, MBBS, PhD, said in an interview.
“Our study was conducted in patients with large-vessel occlusions heading for thrombectomy, but I think the results can be extrapolated to patients with smaller occlusions too,” he added.
The study also showed that one-fifth of patients given tenecteplase experienced reperfusion before thrombectomy was performed. The percentage rose to one-third among patients from rural areas, whose longer times in transport led to an increase in the time between thrombolysis and thrombectomy.
“I think these data are as good as we’re going to get on the optimal dose of TNK. Our endpoint was reperfusion rates – a good, solid biological marker of benefit – but if a difference in clinical outcomes is wanted, that would take a trial of several thousand patients, which is never likely to be done,” said Dr. Campbell, who is from the Department of Neurology at the Royal Melbourne Hospital, Australia.
The researchers note that tenecteplase has a practical advantage over alteplase in that it is given as a bolus injection, whereas alteplase is given as bolus followed by a 1-hour infusion.
Results from the first EXTEND-IA TNK study suggested that tenecteplase 0.25 mg/kg produced higher reperfusion rates than alteplase (N Engl J Med. 2018;378:1573-82). However, the larger NOR-TEST study found no difference in efficacy or safety between a 0.4-mg/kg dose of tenecteplase and alteplase in patients with mild stroke (Lancet Neurol. 2017 Oct;16[10]:781-8).
TNK use in stroke varies around the world. The drug is not licensed for use in stroke anywhere, which Dr. Campbell attributes to a lack of incentive for the manufacturer, Genentech/Boehringer Ingelheim. That company also markets alteplase, the main thrombolytic used in stroke.
But many countries have now included TNK in their stroke guidelines, Dr. Campbell noted. “This has only recently occurred in the U.S., where it has a 2b recommendation, and the dose recommendations are somewhat confusing, advocating 0.25 mg/kg in large-vessel occlusions [as was used in the first EXTEND IA study] and 0.4 mg/kg in non–large vessel occlusions [from the NOR-TEST trial].
“This makes no biological sense whatsoever, recommending a higher dose for smaller occlusions, but that is just a literal translation of the design of the two major studies. I’m hoping our current results will help clarify the dosage issue and that might encourage more use of TNK altogether,” he commented.
For the current study, conducted in Australia and New Zealand, 300 patients who had experienced ischemic large-vessel stroke within 4.5 hours of symptom onset and who were scheduled for endovascular thrombectomy were randomly assigned to receive open-label thrombolysis with tenecteplase 0.4 mg/kg or 0.25 mg/kg.
The primary outcome, reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, occurred in 19.3% of both groups. There was also no difference in any of the functional-outcome secondary endpoints or all-cause mortality between the two doses.
“While we didn’t find any extra benefit of the 0.4-mg/kg dose over the 0.25-mg/kg dose, we also didn’t find any extra harm, and this gives us reassurance in the emergency situation if the weight of the patient is overestimated; then we have a window of safety,” Dr. Campbell commented. “While there was a nonsignificant numerical increase in intracranial hemorrhage in the 0.4-mg/kg group, the excess bleeds were caused by puncturing of the vessels during thrombectomy, so I don’t think we can blame the TNK dose for that.