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Date: September 20th, 2022

Reference: Menon et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. The Lancet 2022

Guest Skeptic: Professor Daniel Fatovich is an emergency physician and clinical researcher based at Royal Perth Hospital, Western Australia. He is Head of the Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research; Professor of Emergency Medicine, University of Western Australia; and Director of Research for East Metropolitan Health Service.

Case: A 74-year-old man arrives from home by private vehicle complaining of right-sided weakness and dysarthria beginning two hours prior to arrival. Advance neuroimaging demonstrates no bleed and no large vessel occlusion. His NIHSS score is calculated to be 10 and he has no absolute contra-indications for systemic thrombolysis.

Background: A lot has happened since you were on the SGEM last time discussing stroke (SGEM#325). This includes the CADTH report on thrombolysis by Alteplase for acute ischemic stroke in less than 4.5 hours with a letter to the editor from some neurologists representing CSC expressing their serious concerns about the report.

Neurologist Dr. Ravi Garg was on an SGEM Xtra discussing his publication analysing the 1995 NINDS study. He showed the study had a high risk of selection bias. Dr. Garg concluded that the baseline imbalances observed in the NINDS study were more likely due to randomization errors than random chance. His advice was treatment decisions and guideline recommendations based on the original treatment effect reported in the NINDS tPA study should be done cautiously.

We also had stroke neurologist Dr. Jeff Saver on an SGEM Xtra discussing his SRMA using the fragility index. He holds a much different interpretation of the stroke literature than Dr. Garg. The conclusion to Dr. Saver’s publication was that intravenous alteplase given within three hours of symptom onset for acute ischemic stroke is one of the most robustly proven therapies in medicine.

Besides the disagreement about the strength of the evidence for tPA, there are challenges with administering this medication. It involves giving an infusion of 0.9mg/kg IV to a maximum dose of 90mg. The infusion starts with 10% of the total dose given as a bolus administered in one minute. The remaining amount is infused over 60 minutes.  Tenecteplase (TNK) is a genetically modified variant of alteplase with greater fibrin specificity (15-fold higher) and longer plasma half-life (22 min vs 3.5 min). Because of its ease of use as a single bolus and more favourable benefit-to-risk profile, it is preferred over alteplase as the fibrinolytic agent of choice for acute myocardial infarction.

Clinical Question: Is tenecteplase non-inferior to alteplase in treating acute ischemic stroke?

Reference: Menon et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. The Lancet 2022

  • Population: Adult patients aged 18 years and older with ischemic stroke who met eligibility criteria for alteplase (ischemic stroke causing disabling neurologic deficit, within 4.5 hours of onset). Patients eligible for endovascular thrombectomy in addition to intravenous thrombolysis were eligible for enrolment.
    • Exclusions: Standard contraindications to IV thrombolysis
  • Intervention: Tenecteplase (0.25 mg/kg) bolus
  • Comparison: Alteplase (0.09 mg/kg bolus + 60 min infusion total 0.9 mg/kg to maximum of 90mg)
  • Outcome:
    • Primary Outcome: Proportion mRS 0-1 at 90 days, up to 120 days
    • Secondary Outcomes: mRS 0-2 at 90-120 days; 90-120 day EQ-VAS & EQ-5D-5L, door to needle time, proportion given endovascular therapy, recanalization status at first angiographic acquisition, baseline CT to arterial puncture time, cognition assessment (online), hospital length of stay, discharge destination. SAFETY outcomes: sICH, oroligual angio-oedema, extracranial bleeding requiring blood transfusion, all < 24 hours of thrombolysis; 90-day all-cause mortality.
  • Type of Trial: Investigator-initiated, multicentre (22 stroke centres), parallel-group, open label, registry linked, RCT with blinded outcome assessment.

Authors’ Conclusions: “Intravenous tenecteplase (0.25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). No
  6. The patients in both groups were similar with respect to prognostic factors. No
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. No
  11. The treatment effect was large enough and precise enough to be clinically significant. No
  12. Financial conflicts of interest. Some authors report a relationship to the manufacturer.

Results: They recruited 1,577 patients into the trial. The median age was 74 years and 48% were female. The median baseline NIHSS score was 10.

Key Result: Tenecteplase was non-inferior to alteplase in stroke patients treated within 4.5 hours of symptom onset.

  • Primary Outcome: The primary outcome (90–120 day mRS score of 0–1)
    • 36.9% tenecteplase group vs 34.8% alteplase group
    • Unadjusted risk difference 2.1% (95% CI –2.6 to 6.9).
    • The lower bound 95% CI of the difference in primary outcome rate (-2.6%) was greater than -5%, thus meeting the prespecified non-inferiority threshold.
  • Secondary Outcomes: See Table 2

    • mRS 0-2 at 90-120 days: tenecteplase 56.4% vs 55.6% alteplase; sICH Tenecteplase 3.4% vs alteplase 3.2% (but only recorded to 24 hrs); death within 90 days: tenecteplase 15.3% vs alteplase 15.4%). NB mortality in NINDS was 21% placebo, alteplase 17%; ECASS III: 8.4% placebo, 7.7% alteplase). Extended Thrombolysis in Cerebral Infarction (eTICI) score ≥ 2b on initial angiography of EVT was 10.2% tenecteplase and 10.5% alteplase (n=502). Revised Arterial Occlusive Lesion Score (rAOL) score of ≥  2b on initial angiography of EVT was 19% tenecteplase and 16.3% alteplase (n = 499).

1) Open Label: Open label studies can advantage the new intervention. Blinding treatment allocation is a fundamental element of reducing bias in a clinical trial. The trial participants and clinicians were not blinded to the treatment allocation in AcT. Therefore, the trial was liable to ascertainment bias, sometimes referred to as detection bias. Ascertainment bias is the systematic distortion of the assessment of outcome measures by the investigators or trial participants because they are aware of treatment allocation. It results in an exaggerated difference between the treatments in outcome.

Knowledge of the treatment may influence the way in which staff and investigators manage patients during the study and influence the perspectives of patients. Previous studies have attempted to quantify this. Schulz et al (1995) report that ORs were exaggerated by 41% for inadequately concealed trials. [1] Nunan (2018) reports it can overestimate effect size by up to 30% – 40%. [2] Using blinded outcome assessments is an attempt to ameliorate this bias. However, the modified Rankin scale, despite its widespread use as an outcome instrument, shows a wide inter-rater variability that adds to the uncertainty.[3] Bias becomes a critical problem in any open label or poorly blinded trial of thrombolysis. [4]  Considering this bias might lead one to conclude that tenecteplase is not non-inferior to alteplase.

2) Comparison to Other Studies: In NINDS Part 2 (alteplase < 3 hours), a mRS 0-1 was reported as 26% placebo and 39% alteplase. Some argue the result reflected placebo doing badly rather than alteplase being good. In ECASS III (alteplase 3-4.5 hours), the original report for mRS 0-1 was 45.2% placebo and 52.4% alteplase. Subsequent re-analyses of these two foundational trials report different results: NINDS was due to a baseline imbalance in stroke severity favouring alteplase [5]. Saver et al [6] does not agree with the reanalysis by Hoffman and Schriger; in ECASS III the re-analysis concludes “Reanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3–4.5 hours after stroke onset. Clinicians, patients and policymakers should reconsider interpretations and decisions regarding management of acute ischaemic stroke that were based on ECASS III results.” [7]

In the AcT open label study, they report 36.9% tenecteplase vs 34.8% alteplase (for mRS 0-1) which is obviously for all patients within 4.5 hrs (kind of a combination of NINDS and ECASS III). Comparing results between studies is problematic due to unknown confounders. Also, NINDS was published in 1995 and ECASS III in 2008. Stroke care has evolved over time, and one would have thought that the AcT result would be much better than the ~35% result they got which was a long way short of placebo in ECASS III (45.2%).

3) Outcome Measure: The outcome in this study was the mRS score obtained by telephone interview. There are problems with the inter-rater reliability of the mRS. Scoring of mRS, even by a neurologist, is only moderately reliable at best when done face to face. Quinn (2009) reviewed 10 studies and report the overall reliability of the mRS was kappa 0.46 (moderate) and conclude: “There remains uncertainty regarding modified Rankin Scale reliability.”[3] In the AcT study mRS scores were obtained through standardised telephone interviews (masked to treatment allocation). It is likely that the kappa for a telephone assessment of mRS is even worse, which threatens the reliability and validity of the outcome measurement. It is noteworthy that studies with larger numbers of patients reported poorer reliability of the mRS.[3] In the SGEM Extra (Here Comes the NINDS Again) with the neurologist Dr. Ravi Garg, he outlined that the inter-rater reliability of the mRS was lowest at the junction of mRS 0-1 (good outcome) and mRS 2-6 (bad outcome) [3], leading to “endpoint wobble.”

The investigators used the Rankin Focused Assessment (RFA) instrument (he RFA consists of a 4-page form accompanied by a 5-page instruction sheet) via blinded trained research coordinators. The supportive citation on the RFA concludes it “yields high inter-rater reliability” but this was based upon a study of only 50 patients, of whom seven  had died by day 90. There were several limitations to this small study, including that all assessors were from a single trial group, and the study did not compare in the same patients mRS scores obtained with the RFA and scores obtained with any of the current common methods of scoring. In this RFA study, assessments were done in person and not by telephone.

4) Baseline Imbalance: A strong predictor of how someone will do after a stroke is how bad their symptoms were at presentation. There was a baseline imbalance in stroke severity in NINDS and ECASS III, that favoured the alteplase group and could explain the entire result. This baseline imbalance in stroke severity is a recurring problem in stroke clinical trials, and also occurred in the studies of Factor VII for ICH. In AcT, NIHSS < 8 was 40.5% tenecteplase and 38.4% alteplase. This difference was 2.1% = the unadjusted difference in the primary outcome. These small differences might be enough to influence the final result. It’s also worth highlighting that AcT did not seem to have tracked rates of stroke mimics.

5) Human Behaviour and History Repeating: Giving a stat dose of tenecteplase is much simpler and hence more appealing than setting up an alteplase infusion. Human behaviour is such that we gravitate towards what’s simpler and easier. I remember when tenecteplase became approved for acute myocardial infarction thrombolysis. Everyone virtually rejoiced because it was so much easier. People will use the AcT result to promote easier thrombolysis, despite our skepticism. The paper also says that some national guideline committees have endorsed tenecteplase for patients with intracranial large vessel occlusions eligible for thrombectomy.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We are skeptical of the authors’ conclusion.

SGEM Bottom Line: We remain skeptical about thrombolysis for acute ischemic stroke whether it is done with alteplase or tenecteplase.

Case Resolution: The stroke team arrives, confirms the NIHSS score and lack of any contraindications to thrombolysis. They proceed to have discuss the potential benefits and potential harms of thrombolysis while you return to managing the rest of the busy emergency department.

Clinical Application: The Achilles heel of this trial is the a priori assumption that alteplase is an effective treatment for acute ischemic stroke. If you accept the claim, then you can conclude it is reasonable to use tenecteplase. If you do not accept the claim, then tenecteplase  has not been demonstrated to be superior to placebo and would not necessarily be reasonable.

Dr. Daniel Fatovich

What Do I Tell the Patient? Your symptoms are caused by a stroke, which is typically caused by a blockage in a brain artery. You’re going to meet the stroke team who will offer you a treatment to break up the clot (you may have heard of it). They will tell you why you should have it. They believe it is good therapy and tend to be very enthusiastic as they believe it increases the chance of a better outcome.

It’s important to know not everyone agrees; it’s controversial; many specialists say it’s not useful.  There is no evidence that it saves lives, but does increases the chance of dying. So, you need to decide what to do.

Keener Kontest: There was no winner last week. The correct answer was  Robert Barany first described the nystagmus seen in posterior canal BPPV in 1921. Peter made a YouTube video all about it with a special guest, Dr. Glaucomflecken.

Listen to the podcast this week to hear the keener contest question. If you are the first person to email the correct answer to TheSGEM@gmail.com with “keener” in the subject line you will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Jama 1995;273(5):408-12. [published Online First: 1995/02/01]
  2. Nunan D, Heneghan C, Spencer EA. Catalogue of bias: allocation bias. BMJ Evid Based Med2018;23(1):20-21. doi: 10.1136/ebmed-2017-110882 [published Online First: 2018/01/26]
  3. Quinn TJ, Dawson J, Walters MR, et al. Reliability of the modified Rankin Scale: a systematic review. Stroke2009;40(10):3393-5. doi: 10.1161/strokeaha.109.557256 [published Online First: 2009/08/15]
  4. Radecki RP, Chathampally YG, Press GM. rt-PA and Stroke: Does IST-3 Make It All Clear or Muddy the Waters?Answers to the November 2012 Journal Club Questions. Ann Emerg Med 2013;61(4):489-98. doi: 10.1016/j.annemergmed.2012.12.008 [published Online First: 2013/03/26]
  5. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med 2009;54(3):329-36, 36 e1-35. doi: S0196-0644(09)00281-9 [pii]
  6. Saver JL, Gornbein J, Starkman S. Graphic reanalysis of the two NINDS-tPA trials confirms substantial treatment benefit. Stroke. 2010 Oct;41(10):2381-90. doi: 10.1161/STROKEAHA.110.583807. Epub 2010 Sep 9. PMID: 20829518; PMCID: PMC2949055.
  7. Alper BS, Foster G, Thabane L, et al. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evid Based Med 2020 doi: 10.1136/bmjebm-2020-111386