A conversation with Dr. Bruce Campbell, MBBS (Hons), BMedSc, PhD, FRACP, co-principal investigator of the EXTEND-IA TNK trial and Head of Stroke at Royal Melbourne Hospital, University of Melbourne, about EXTEND-IA TNK and its implications for stroke care.
Interviewed by Kaustubh Limaye, MD, an Assistant Professor in the Division of Cerebrovascular Diseases at the University of Iowa (@kaustubhslimaye).
They will be discussing the article “Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke,” published in The New England Journal of Medicine.
EXTEND-IA TNK randomized 202 ischemic patients with large vessel occlusion 1:1 between 0.25mg/kg tenecteplase and 0.9mg/kg alteplase prior to endovascular thrombectomy. The proportion of patients who had substantial (>50%) reperfusion or no retrievable thrombus on the initial angiographic assessment was approximately doubled in the tenecteplase group (22% vs. 10%), which met the non-inferiority threshold (p=0.002) and was indeed superior (p=0.03) to alteplase. Functional outcomes at day 90 were also significantly improved in the tenecteplase group in ordinal (shift) analysis of the modified Rankin Scale. Symptomatic intracerebral hemorrhage occurred in 1/101 patients in each group.
Dr. Limaye: First, accept my heartiest congratulations for the completion and success of the EXTEND-IA TNK trial. I think the results will benefit acute stroke patients with large vessel occlusion and open up more avenues in streamlining care of such patients. Would you like to share with our readers the timeline of this trial – from conceptualization to execution?
Dr. Campbell: Thank you! We started designing EXTEND-IA TNK in the period between EXTEND-IA stopping and being presented/published at the 2015 International Stroke Conference. We felt that there was an opportunity to further enhance outcomes with improved intravenous thrombolysis given common delays in transferring patients for thrombectomy. Recruitment got underway in March 2015 and completed in October 2017.
Dr. Limaye: What are the main differences in this trial and the NOR-TEST trial?
Dr. Campbell: NOR-TEST used a higher dose (0.40mg/kg versus 0.25mg/kg in EXTEND-IA TNK), but the main difference is the patient population, which was very mild in NOR-TEST (median NIHSS 4 versus 17 in EXTEND-IA TNK) and only 3.7% of NOR-TEST patients underwent thrombectomy.
Dr. Limaye: Like the initial cardiac studies with TNK, do you think there is a need for dose escalation safety studies in ischemic stroke patients?
Dr. Campbell: There were TNK dose escalation stroke studies performed by Haley et al, and the higher doses (0.4 and 0.5mg/kg) seemed to be associated with increased bleeding. However, numbers were small (e.g., 3/19 symptomatic hemorrhages with 0.4mg/kg), and NOR-TEST suggests that the risk at 0.4mg/kg is probably not higher than alteplase, so we are now testing 0.4mg/kg versus 0.25mg/kg in thrombectomy candidates.
Dr. Limaye: Did you find a difference in outcomes for patients who were enrolled using the CT perfusion profile and those who did not have a baseline CT perfusion profile?
Dr. Campbell: Everyone had CT perfusion performed, and, despite removing core restrictions relatively early in the study, only 5.4% had a core >70mL. As expected, outcomes were numerically worse in these patients, but there were no safety concerns.
Dr. Limaye: What are the advantages of tenecteplase over alteplase as compared to cost, availability and reimbursement for use in ischemic stroke in Australia?
Dr. Campbell: Tenecteplase is slightly cheaper per vial. Most patients (>55kg) require 2 vials of alteplase but only 1 vial of tenecteplase, so the saving is approximately AU$2000 per patient. There’s no specific reimbursement for either drug in Australia, so it comes out of the hospital budget. Tenecteplase is usually stocked for use in myocardial infarction, so is readily available.
Dr. Limaye: What changes in acute stroke protocol are expected in Australia after the publication of EXTEND-IA TNK?
Dr. Campbell: Our national guidelines committee will consider the data in coming months. Some states are adding tenecteplase to formulary for stroke, but there are crucial ongoing trials in the non-thrombectomy population (TASTE, ATTEST-2) that we need to complete.
Dr. Limaye: What are the important differences between EXTEND-IA TNK and the proposed part 2 of the trial?
Dr. Campbell: Part 2 is testing the “NOR-TEST dose” of 0.40mg/kg versus 0.25mg/kg using the same outcomes (substantial reperfusion at the initial angiographic assessment, day 90 functional outcomes and early neurological improvement) but testing for superiority. The rationale is that large vessel occlusion patients with high clot burden would be the most likely group to benefit from a higher dose. We are expanding the site network, particularly to add rural sites with long inter-hospital transfers to thrombectomy centers and mobile stroke units.
Dr. Limaye: Do you foresee TNK replacing alteplase or being used in late window trial arm with endovascular therapy? What other future studies are needed with TNK in acute ischemic stroke?
Dr. Campbell: We chose a non-inferiority design for EXTEND-IA TNK because we felt that TNK would replace alteplase if it were “at least as good” as alteplase, given the convenience advantages. I think EXTEND-IA TNK achieved that goal for large vessel occlusion patients, but we still need to complete the 0-4.5hr studies in non-thrombectomy patients. The idea of adding TNK to thrombectomy beyond 4.5hr in imaging-selected patients is definitely an interesting concept.
Dr. Limaye: Can you share with us changes made in stroke triage at Royal Melbourne Hospital and Australia in general after the late window trials like DAWN and DEFUSE 3 were published?
Dr. Campbell: We have just revised the Australian Stroke Guidelines and have a strong recommendation for thrombectomy in patients with ICA/M1 occlusion 6-24hr after last known well with CT perfusion or MR imaging evidence of salvageable brain. At RMH we’ve generally adopted DEFUSE 3 criteria given that substantially more patients are included versus DAWN and the treatment benefit seemed similar between the DAWN-eligible and ineligible patients within DEFUSE 3. We are expanding the use of CT perfusion to make it standard at all of our regional referring centers to avoid transferring patients with no chance of having favorable imaging on arrival at the comprehensive center.
Dr. Limaye: In Australia, what pre-hospital scales are commonly used? How does EMS triage patients to a Primary stroke center (PSC) or decide to bypass PSC for a comprehensive stroke center (CSC) in Australia?
Dr. Campbell: My Western Australian colleagues have recently started using RACE to bypass suspected LVO within metropolitan Perth. We’ve just published the ACT-FAST algorithm (Zhao et al. Stroke. 2018), and field validation is ongoing to assess the potential benefit of bypass, but, so far, the Australian system (except Perth) remains ambulance delivery to the nearest thrombolysis-capable center.
Dr. Limaye: I thank you for taking time out of your busy schedule to talk to us regarding the EXTEND-IA TNK trial. We look forward to talking to you in the future about the EXTEND-IA TNK 2.
Dr. Campbell: My pleasure.