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Reference: Albers GW et al. TIMELESS Investigators. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection. NEJM Feb 2024

Date: April 12, 2024

Guest Skeptic: Dr. Vasisht Srinivasan is an Emergency Medicine physician and neurointensivist at the University of Washington and Harborview Medical Center in Seattle, WA. He is an assistant professor in Emergency Medicine, Neurology, and Neurosurgery at the School of Medicine at the University of Washington.

Case: A 70-year-old woman was brought into the emergency department by EMS after her family reported she was having trouble talking.  They noticed this earlier in the day and let her rest, but when she had trouble moving her right arm, they called 911.  Initial evaluation by medics revealed right hemiplegia, a right facial droop, left gaze deviation, and aphasia.  When she arrives in your ED, her family tells you she was last seen normal about 12 hours ago.  A code stroke is activated, and the initial CT head shows no signs of hemorrhage or early ischemic changes.  A CT angiogram shows a proximal middle cerebral artery occlusion.  CT perfusion showed a 10 mL core and 189 mL penumbra.  As you speak to your stroke team, the question of thrombolysis comes up, as her core is quite small, and the stroke may still be very early in its time course.

Background: The question of thrombolysis for acute ischemic stroke dates back nearly 30 years to the initial NINDS trial published in 1995 [1].  Since that time, numerous studies and analyses have been undertaken to categorize the potential benefits and potential harms associated with thrombolysis in stroke [2-8]. We have discussed this issue multiple times on the SGEM including:

With the pentad of thrombectomy trials published in 2015 [9-13] and the extension of the thrombectomy window in 2018 following the publication of DAWN [13] and DEFUSE-3 [15], the standard of care has now shifted to mechanical thrombectomy for large vessel occlusion, though thrombolysis is still used up to 4.5 hours from onset of symptoms.

We have looked at the issue of EVT with or without thrombolytics on the SGEM a few times.

  • SGEM#137: A Foggy Day – Endovascular Treatment for Acute Ischemic Stroke
  • SGEM#292: With or Without You – Endovascular Treatment with or without tPA for Large Vessel Occlusions
  • SGEM#297: tPA Advocates Be Like – Never Gonna Give You Up
  • SGEM#333: Do you Gotta Be Starting Something – Like tPA before EVT?
  • SGEM#349: Can tPA Be A Bridge Over Trouble Waters to Mechanical Thrombectomy?

There have also been several SRMA on this issue [16-21] a few guidelines published on the topic [22-24] and ACEP is currently working on a clinical policy to address this question of EVT +/- thrombolytics.

Following nearly a decade of research into Tenecteplase (TNK), beginning as early as 2012 [25], this agent has supplanted alteplase (tPA)as the preferred thrombolytic agent at both some large stroke centers as well as many community sites designated as primary stroke centers. SGEM#377 covered one of those trials comparing tPA to TNK. The AcT trial was a pragmatic, multicentre, open-label, registry-linked, randomized, controlled, non-inferiority trial [26]. This trial reported that TNK was non-inferior to tPA in stroke patients treated within 4.5 hours of symptom onset.  Studies from the UK [27], Australia and New Zealand [28, 29], and several studies from Norway [30, 31] have similarly shown that it is neither superior to alteplase nor is it inferior.

Perfusion imaging allows more careful patient selection for therapies as it identifies those patients with salvageable ischemic tissue (penumbra) that can be “rescued” if reperfused versus those who have a large burden of infarct (core) that cannot be recovered with reperfusion.  However, this requires advanced software not readily available at most EDs and is generally only found at large, referral centers with comprehensive stroke center designation.  The standard criteria for intervention come from the DEFUSE-3 trial [15] and are reflected in the inclusion criteria for this study.

Clinical Question: Does giving TNK between 4.5 – 24 hours, using perfusion imaging to select patients, improve outcomes after stroke?

Reference: Albers GW et al. TIMELESS Investigators. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection. NEJM Feb 2024

Population: Adults 18 years of age with independent function (mRS 0 – 2) pre-stroke, with an ischemic stroke and could receive the drug/placebo within 4.5 – 24 hours from last known to be well, with NIHSS at least 5, with ICA and/or MCA occlusion on CTA/MRA.  Also, needed core < 70 mL, penumbra ≥ 15 mL, and core:penumbra ratio at least 1.8 (DEFUSE-3 criteria)

Fig 1 from the DEFUSE-3 trial

Exclusions: There were several exclusions published in a separate document [32].

  • Intervention: Tenecteplase 0.25 mg/kg (max 25 mg)
  • Comparison: Placebo
  • Outcome:
    • Primary Outcome: mRS score at Day 90
    • Secondary Outcomes Efficacy:
      • Patients with mRS score of 0–2 at Day 90
      • Angiographic reperfusion at the completion of the angiographic procedure
      • Median NIH stroke scale score at Day 90
      • Patients with a Barthel Index score ≥95 at Day 90
      • Patients with a good recovery based on the Glasgow Outcome Scale at Day 90
      • Reperfusion at 24 h post-randomization*
      • Recanalization at 24 h post-randomization†
    • Secondary Outcomes Safety:
      • Incidence of symptomatic intracranial hemorrhage within 36 h
      • Incidence and severity of adverse events
      • Mortality rate up to Day 30 and Day 90
      • The proportion of patients with parenchymal hematoma type 2 at the 72- to 96-h visit
    • Type of Study: Phase III, multicenter, double-masked, randomized, placebo-controlled trial

*Defined as >90% reduction in time-to-maximum >6 s lesion volume.
†Defined as complete recanalization on computed tomography angiography/magnetic resonance angiography.

Authors’ Conclusions: “Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups.”

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). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, and outcome assessors) were unaware of group allocation. Yes, Yes and 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. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes
  12. Financial conflicts of interest. The trial was funded by the drug manufacturer and authors reported multiple COIs.

Results: They recruited 458 patients into the TIMELESS trial. The median age was early 70’s with slightly more than half being female. The median NIHSS score was 12 and the median duration from time last seen well was 12.5 hours. Around 8% of patients had an internal carotid occlusion, 50% M1 segment and 38% M2. They planned EVT in 87% with 77% having the procedure performed.

Key Results: There was no superiority of TNK over placebo in stroke patients with large vessel occlusions treated between 4.5 and 24 hours last seen well.

  • Primary Outcome:
    • The median score on the mRS scale at 90 days (IQR) was 3 (1–5) in the TNK group and 3 (1–4)
    • Adjusted odds ratio (aOR) was 1.13 (0.82 to 1.57) P=0.45
  • Secondary Outcomes: No statistical difference in functional independence, reperfusion after 24 hours or reperfusion after EVT but greater recanalization at 24 hours with TNK.
    • Functional independence at 90 days 46.0% vs 42.4% aOR 1.18 (0.80 to 1.74)
    • Recanalization at 24 hr 76.7% vs 63.9% aOR 1.89 (1.21 to 2.95)
    • Reperfusion at 24 hr 56.9% vs 57.5% aOR 1.04 (0.69 to 1.57)
    • Reperfusion after endovascular thrombectomy 89.1% vs 85.4% aOR 1.42 (0.75 to 2.67)

  • Secondary Safety Outcomes:
    • Death within 30 days 14.7% vs 15.0%
    • Death within 90 days 19.7% vs 18.2%
    • sICH 3.2% vs 2.3%

1. Conflicts of Interest (COI): This trial was funded by Genentech. The sponsors helped design the study and provided the TNK and placebo. They also were responsible for site monitoring and data management. There were several Genentech employees (green) as authors with two of them providing analysis of the data.Authors who were not employees (yellow) also declared conflicts of interest. There is a literature base that suggests COI can introduce bias into RCTs [33, 34]. However, that does not mean these results suffer from bias, but it should make us more skeptical.

2. Few Patients: This trial was conducted at 112 sites (108 USA and 4 Canadian). It took them 46 months to recruit the 458 patients required based on their power calculation for the primary outcome. This works out to approximately one patient/site/year. It is not clear if that means very few people are eligible for this treatment.

3. Safety: Point estimates for sICH and death were all worse with TNK. The study was not powered for safety but rather for efficacy. All though they were not statistically different you could argue that those additional people who died in the TNK group it was clinically significant. Looking at the RCTs that address this subject of safety with lytics, 5 out of six studies had more bleeding and 4 out of 6 had higher mortality.

  • DIRECT-MT: More bleeds and higher mortality with both
    • sICH 4.3% vs 6.1% RR of 0.70 (95% CI 0.36–1.37)
    • Mortality 17.7% vs 18.8% RR of 0.94 (95% CI 0.68–1.30)
  • DEVIT: More bleeds and higher mortality with both
    • sICH 6.1% vs 6.8% difference -0.8% (95% CI -7.1% to 5.6%)
    • Death 90d 17.2% vs 17.8% difference -0.5% (95% CI -10.3% to 9.2%)
  • SKIP: More bleeds and higher mortality with both
    • sICH 5.9% vs 7.7% difference -1.8% (95% CI -9.7% to 6.1%)
    • Death 90d 7.9% vs 8.7% difference -0.8 (95% CI -9.5% to 7.8%
  • MR CLEAN-NO IV: Less bleeds and less mortality with both
    • sICH 9% and 5.3% (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81)
    • Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30).
  • SWIFT Direct: More bleeds and less mortality with both
    • sICH global (sICHglobal)occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference −1.0%, 95% CI −4.8 to 2.7). From abstract
    • sICHsite 3/201 (1%) vs 10/204 (5%) risk difference -3.4% (95% CI -7.4 to 0.2) p=0.87 (SICHsite was adjudicated by the local investigators if there was radiological evidence of intracranial haemorrhage and the patient had an increase of 4 or more points on the NIHSS compared with immediately before deterioration.)
    • Mortality at 90 days 22/201 (11%) vs 17/207 (9%) Risk difference 2.3% (−3.2 to 7.8) P=0·41
  • Direct Safe: More bleeds and higher mortality with both
    • sICH two (1%) of 146 patients in the direct group and one (1%) of 147 patients in the bridging group (adjusted odds ratio 1.70, 95% CI 0.22–13.04)
    • Death in 22 (15%) of 146 patients in the direct group and 24 (16%) of 147 patients in the bridging group (adjusted odds ratio 0.92, 95% CI 0.46–1.84).

4. Per-Protocol Analysis: Using this type of analysis tends to bias results towards finding superiority. Despite this potential bias they still did not find TNK superior to placebo in these patients.

5. Endovascular Therapy (EVT): Most patients underwent EVT (77.3%) in this trial. The subgroup analysis did not support the use of TNK for those undergoing EVT. The evidence is mixed on the efficacy of bridging therapy in these patients. The authors provided several possible explanations for why they did not observe superiority in the patients who did receive EVT with TNK.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We tend to agree with the authors that based on these data, there does not appear to be a benefit to administering Tenecteplase in this patient population.

SGEM Bottom Line: There continues to be a lack of evidence to support the use of thrombolytics beyond 4.5 hours in acute ischemic stroke.

Case Resolution: Thrombolysis was not offered to the patient, and she was taken urgently for mechanical thrombectomy. TICI 3 recanalization was achieved (full reperfusion) and she was admitted to the neurocritical care unit for post-procedure monitoring.

Dr. Vasisht Srinivasan

Clinical Application: This study adds to the literature base that shows the “longest time” for thrombolytics remains <4.5 hours. While no superiority for thrombolysis beyond the 4.5-hour window with a suggestion of increased harm.  Patients with LVOs should preferentially be directed toward thrombectomy without delays.

We will not re-hash the strength/weakness of the evidence for thrombolytics in acute ischemic stroke in under 4.5 hours. People can read more about my thoughts on the CJEM debate with Dr. Eddy Lang [35], The Lown Institute article with Dr. Daniel Fatovich [36] and the NNT assessment with Dr. Justin Morgenstern [37].

What Do I Tell the Patient?  It looks like you are having a stroke. Because it has been more than 4.5 hours, the “clot-busting drugs” have not been shown to work, and because a big artery is blocked, we need to do a procedure to take the clot out quickly.  The stroke team is arranging this, and it will happen shortly.

Keener Kontest: The last episode was another win for Dr. Cindy Bitter. She knew the oldest alcohol was found in pottery excavated in a neolithic village in the Yellow River Valley, Henan province, China – dating back to 7000 BC.

Listen to the SGEM podcast for this week’s question. If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer 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. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-7. doi: 10.1056/NEJM199512143332401. PMID: 7477192.
  2. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med. 2009 Sep;54(3):329-36, 336.e1-35. doi: 10.1016/j.annemergmed.2009.03.019. Epub 2009 May 23. PMID: 19464756.
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  36. Milne WK and Fatovich D. Will it take 50-100 years to get the right answer about tPA for stroke? July 20, 2020. https://lowninstitute.org/will-it-take-50-100-years-to-get-the-right-answer-about-tpa-for-stroke/  Accessed April 3, 2024
  37. Milne WK and Morgenstern J. Tissue Plasminogen Activator (tPA) For Acute Ischemic Stroke. April 21, 2021. https://thennt.com/nnt/tissue-plasminogen-activator-tpa-acute-ischemic-stroke/  Accessed April 3, 2024