Saurav Das, MD
@sauravmed
International Stroke Conference 2021
March 17–19, 2021
Session: Tenecteplase Is Ready for Clinical Practice (Debate) (183)
Whether tenecteplase (TNK) is ready for clinical practice is certainly one of the crucial questions faced by the stroke community today, especially in the changing landscape with emerging evidence for non-inferiority of direct thrombectomy compared to bridging recanalization treatment, the success of mobile stroke units (MSU), and our ability for pre-hospital treatment of patients within the golden hour of last known well. TNK is not a new drug. It is successfully used in treatment of myocardial infarction, and we have evidence from five randomized controlled trials (alluded to several times in the following debate) for non-inferiority compared to alteplase (tPA) in treatment of stroke. The nay-sayers do point to inherent issues with these trials and argue that we need more data. But the question is, how much longer is this wait going to be?
This debate was in 5 segments. In the first segment, Dr. Jeffrey Saver from the University of California, Los Angeles (UCLA) argued in favor of the motion. In the second segment, Dr. Patrick Lyden from Keck School of Medicine, University of South California, argued against the motion. In the third segment, both the speakers had an opportunity for rebuttal. In the fourth segment, Dr. Shelagh Coutts from the University of Calgary provided her balancing view. And in the final segment, Dr. Steven Warach from Dell School of Medicine, UT Austin, shared his practical experience with use of TNK for the past 15 months. The session was moderated by Dr. E. Clarke Haley Jr. from the University of Virginia, Charlottesville.
Segment 1: Gung ho! Here we go!
Dr. Saver made a very compelling pitch in favor of the motion. He outlined nine criteria to support adoption of a novel drug in regular clinical practice and discussed how TNK satisfies these. I have summarized these important points in Table 1 below. At the end of Dr. Saver’s pitch, 95% of the audience favored the motion.
Segment 2: Not so fast!
Dr. Patrick Lyden started by showing a picture of an Oxford Union debate where the same speaker is often assigned the role to persuade the audience from two opposite viewpoints, possibly hinting at his agreement with Dr. Saver despite his position in this debate. His primary critiques included the following: (a) the clinical trials Dr. Saver alluded to had an open label design; (b) in the rabbit experiments, the efficacy of TNK a lytic vs tPA was equivocal; (c) we do not know the correct dose of TNK for stroke treatment; and (d) most TNK trials primarily focused on reperfusion as the outcome and not on clinical outcomes. The Australian trial included 24-hour clinical improvement as a co-primary end point, but short-term outcomes will not be sufficient for FDA approval.
Segment 3: Rebuttals
Dr. Saver acknowledged that we do not yet have trial data for superiority of TNK over tPA; however, the motion is regarding non-inferiority. He said Dr. Lyden is bringing decade-old opinions to the debate. To Dr. Lyden’s argument that these trials were open label, Dr. Saver said they had a Prospective Randomized Open, Blinded Endpoint (PROBE) design in which the outcomes observer evaluating 90-day modified Rankin scale was blinded to eliminate potential bias. Dr. Lyden cited the example of the Australian TNK trial where, of 3000 patients screened for thrombolysis, only 75 were included in the final analysis. Many excluded patients due to reasons like internal carotid artery (ICA) or basilar artery occlusion, poor quality CT angiogram (CTA), mechanical thrombectomy, large core strokes, etc., would have been included for TNK- thrombolysis in real world practice.3 Therefore, Dr. Lyden argued, “The authors of this paper highlighted a need for phase III clinical trial data and did not claim what Dr. Saver alleges they had shown.” With this relatively strong rebuttal, Dr. Lyden succeeded to sway some of the audience in his favor. 75% favored the motion at this time.
Segment 4: The balancing view
Dr. Coutts reflected individually and noted observations salient to each of these 5 RCTs. The Australian TNK trial had small numbers, only 75 patients, 25 in each arm.2 The ATTEST trial, despite baseline poor prognostic characteristics in the TNK group, had a trend towards early neurological involvement and low sICH rate in this group. In this trial, tPA, and not TNK, was associated with increased prothrombin time, PAI-1 activity, reduction in fibrinogen and plasminogen over 24 hours, making the hemorrhage risk look higher.4 The NORTEST trial was different from the other trials due to the use of higher dose (0.4 mg/kg) TNK, but had predominance of milder strokes, transient ischemic attacks and 17% stroke mimics among the enrolled patients. Despite this, there was no difference in safety and efficacy of TNK compared to tPA.5 EXTEND IA-TNK provided some evidence for the “give and go” paradigm, which is one of the strongest arguments in favor of TNK given ease of bolus administration.6 EXTEND IA- II helps us in answering the dose question to some extent. TNK doses 0.25 mg/kg and 0.40 mg/kg were compared in patients with LVO strokes with no difference in efficacy and lower rates of sICH with 0.25 mg/kg dose.7 Dr. Coutts commented that Dr. Saver’s meta-analysis may, at best, be hypothesis-generating, but was not backed by desirable large numbers. She listed a number of ongoing RCTs which will add to the data, including the ATTEST 2, TASTE, TWIST, ACT, NORTEST2, TEMPO-2, and TIMELESS trials. She concluded that TNK is not ready for practice yet, we still need more data and, in her words, “we should stop giving opinions and turn into trial machines.”
Segment 5: Practical considerations
Dr. Warach has used TNK at his center in UT Austin since September 2019, and he started by outlining the practical advantages of TNK: (a) short preparation and administration time; (b) no requirement of second intravenous line or an infusion pump; (c) shorter time for interfacility transfer; and (d) lower cost per dose. Dr. Warach answered the common, frequently asked questions he has encountered regarding TNK use, which are summarized in Table 2.
In the last 15 months, they have treated 234 patients with TNK. The transition from tPA to TNK has enabled them to achieve faster thrombolysis and favorable outcome of independent ambulation at discharge. Unfavorable outcomes (composite of death, hospice, or symptomatic ICH) were also lower with TNK when compared to tPA (7% vs 11%) but did not meet their non-inferiority criteria. Pharmacy cost savings per one year were reduced by 400,000 USD.
At the end of this stimulating debate, I agree that we have quite a few ongoing TNK trials which will contribute new data, but I do not expect surprises. Additionally, the ease of drug administration, annual cost savings, and a solid roll-out plan available from a large implementing institution tip me in favor of the motion. I will advocate at my institution to make this switch from tPA to TNK. Will you?
References:
1. Burgos AM, Saver JL. Evidence that Tenecteplase Is Noninferior to Alteplase for Acute Ischemic Stroke: Meta-Analysis of 5 Randomized Trials. Stroke. 2019;50:2156-2162.
2. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019;50:e344-e418.
3. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366:1099-1107.
4. Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol. 2015;14:368-376.
5. Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017;16:781-788.
6. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018;378:1573-1582.
7. Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. JAMA. 2020;323:1257-1265.
