Presenter: Dr. Rhiannan Pinnell (FRCPC-EM R1)

Host: Dr. Paul Atkinson

Article:

Research Question/PICO

• Research Question
  • “The aim of the Alteplase compared to Tenecteplase (AcT) trial was to determine whether intravenous tenecteplase, at a dose of 0·25 mg/kg, is non-inferior to alteplase in all patients presenting early after acute ischaemic stroke who meet standard of care criteria for intravenous thrombolysis.”
• Population:
  • Patients >18year presenting to stroke center within 4.5h of symptom onset with disabling acute ischemic stroke
• Intervention
  • TNK at a dose of 0.25mg/kg
• Comparison
  • Standard dose alteplase
• Outcome:
  • “Excellent neurological outcome” as measured by the proportion of patients with a mRS of 0-1 at 90-120 days

Background

• There are 2 mainstays of treatment for ischemic stroke – thrombolysis and endovascular therapy (EVT).
  • Thrombolytics are “clot buster” medications, whereas EVT is an interventional radiology procedure which physically removes the clot
• The major thrombolytic used since the 90s has been alteplase or tPa.
• Current guidelines indicate that within 6 hrs since onset of disabling stroke, consider thrombolysis (disabling) and/or EVT. Strongly recommended for <4.5h as long as there are no standard lytic contraindications.
  • Per Canadian stroke best practices, median door to needle time <30 min, 90% should be less than 60 min.
• There are 2 issues with tPA
  • First, there is a fair bit of debate surrounding both the quality of evidence and the efficacy of this treatment. Throughout the numerous trials, some have been neutral and others have been stopped early due to increased harm/bleeding compared to placebo. The current practice is based mostly on ECASS-3 (2008) and NINDS 2 (1995) and there are some concerns around the fragility indices and baseline imbalance in stroke severity.
  • Also, tPA must be given as an infusion as the half life is only 5-10 mins.
• What is new?
  • Tenecteplase has a higher fibrin specificity and longer half life so it can be given as a single dose.
  • Currently preferred for MI, given as 5 tier weight-based system which works out to around 0.5-0.55mg/kg.
• Prior phase 2 studies of TNK for ischemic stroke have found that 0.25mg/kg probably best dose. Phase 3 studies have found that TNK at 0.4mg/kg is not superior to standard alteplase.
• To date, there have been no phase 3 comparisons between 0.25 and standard alteplase.

Methods

• Design:
  • Prospective multicentre RCT at 22 Canadian stroke centers (both regional and EVT capable).
  • Open label for treatment, outcome mRS was taken over the phone by a blinded evaluator.
  • Non-inferiority, with subsequent superiority calculations.
  • Used “minimal sufficient balance” algorithm to balance allocation by site.
• Funding: Funded by Canadian Institutes of Health Research & Alberta Strategy for Patient Oriented Research Support Unit.
• Population:
  • Inclusion
    • 18+ w/ ischemic stroke, presenting within 4.5h. Could be eligible for EVT but did not have to be.
  • Exclusion
    • Standard contraindications for IV thrombolysis (ICH, etc.)
  • Intervention/procedures:
    • Alteplase – 0.9mg/kg IV to max of 90, w 10% bolus in 1 min, rest over 1 hr
    • TNK – bolus of 0.25mg/kg
  • Outcomes
    • Primary
      • mRS 0-1 at 90-120 days
      • 
    • Secondary
      • mRS 0-2 at 90-120
      • EQ-VAS and EQ-5D-5L 90-120
      • Door to needle
      • Proportion given EVT
      • Recanalization at angiogram
      • Baseline CT to arterial puncture time
      • Cognition assessment
      • Length of stay in hospital
      • Discharge destination
      • Safety: sICH, orolingual angio-edema, extracranial bleeding requiring transfusion (within 24h of thrombolysis). 90 day all cause mortalit
  •  Statistics
    • Non-inferiority was established if the lower 95% CI of in TNK group was more than -5%
    • Sample size 1600 for 90% power assuming 35% in tPA and 38% in TNK group have mRS 0-1
    • Intention to treat analysis

Results

• Sample
  • Size: 1577. 0.6% lost to follow up.
  • Baseline characteristics (No statistical calculations reported for baseline differences)
    • Median age 74y, 48% female.
    • Baseline NIHSS 10 in alteplase group, 9 in TNK group
    • 93-94% at comprehensive stroke centre
    • 32% got EVT
    • Times (min in TNK vs alteplase group)
      • Symptom onset to hospital arrival: 82 vs 83
      • Symptom onset to randomization:121 vs 123
      • Door to CT 15 vs 16
      • Symptom onset to needle 128 vs131
      • Door to needle 36 vs 37
      • CT to arterial puncture 60 vs 58,
      • Puncture to reperfusion 31 vs 27
    • Median follow up at 97 days
  • Results
    • Primary:
      • 90-120 day mRS 0-1 36.9% of patients who received TNK, 34.8% of those who received alteplase.
      • Unadjusted risk difference ****** Lower bound 95% CI of difference of rate of primary outcomes (-2.6-6.9) >-5%, so non-inferior.
      • No difference based on subgroup – e.g. age, sex, NIHSS, large vessel occlusion (defined as internal carotid artery, M1 segment middle cerebral artery (MCA) occlusion, or functional M1 MCA, occlusion (ie, all ipsilateral M2-MCA segments)), etc.
    • Secondary:
      • No significant difference in any secondary outcomes or in safety outcomes in either intention to treat or per protocol analysis.

Authors conclusions

• “The AcT trial provides robust empirical evidence that tenecteplase is comparable to alteplase in patients presenting with acute ischaemic stroke, with similar function, quality of life, and safety outcomes. Given the ease of administration of tenecteplase compared with alteplase, these results provide a compelling rationale to support switching the standard-of-care intravenous thrombolytic agent for acute ischaemic stroke from alteplase to tenecteplase at a dose of 0·25 mg/kg.”

Discussion at Journal Club

Strengths

• ED focus
• Large size, multi center. Involved a range of types of hospitals, from community to academic.
• RCT with what appears to be good randomization (although no statistics were reported regarding the success of randomization).
• Excellent per protocol analysis (800/806, 762/771) and very low loss to follow up.

Weakness

• Conception: Is there an issue surrounding the fundamental comparison to alteplase, since this is so debated? We had some debates about this, and whether there should have been a control group who did not receive a lytic, but concluded that this would probably have been impossible from an ethics board perspective.
• Baseline values: Numerically slightly more patients with baseline NIHSS <8 (40.5%) in TNK group vs alteplase (38.4%)
• Methods:
  • This was an open label study. Although the authors did blind the outcome assessors, they did not blind the patients. This still has a risk of exaggerating results, as the Rankin scale has inter-rater variability.
  • There are many secondary outcomes used, which is sometimes seen as scavenging for statistical significance. In this non-inferiority trial, however, it may be a benefit as they are looking for any possible dangers.
  • There may be some issues with using the Rankin score as dichotomous – e.g. there a large difference between “requires some assistance” and “bedridden”
  • There was no subgroup analysis looking at the impact of EVT.

Bottom line

• This is a well performed study and has good internal validity. It opens up another alternative for stroke treatment – but, based on a non-inferiority trial, TNK wouldn’t be considered a mandatory alternative yet. What it does provide is the opportunity to conduct future studies that could show it to be superior.
• TNK might also improve treatment timelines (e.g. giving a dose right before going to EVT), as well as permit patients to be lysed and immediately transported with EMS (as currently there are barriers surrounding running the infusion during transport).