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Date: October 3, 2025

Reference: Doheim et al. Meta-Analysis of Randomized Controlled Trials on IV Thrombolysis in Patients With Minor Acute Ischemic Stroke. Neurology 2025

Guest Skeptic: Dr. Casey Parker is a Rural Generalist, Evidence-based medicine enthusiast and Ultrasound Nerd.

This episode was recorded live, in beautiful Broome, Australia, at the Spring Seminar on Emergency Medicine (SSEM 2025). You can get copies of the slides used in the presentation at this LINK. You can also watch the episode on YouTube.

Case: Dani is a recently retired emergency department (ED) doc who has spent the last year travelling the world, playing banjo & sharing time with family and friends. This morning, whilst eating a breakfast of eggs and ham, Dani had a sudden onset of right-hand weakness and difficulty speaking. Dani’s family called 000 (911 in North America), and she was taken to the ED within one hour. On arrival at your medium-sized rural ED, Dani is assessed by the “Stroke Team aka, you” as having mild motor weakness in the right hand and mild dysarthria. Dani is given an NIHSS score of 4. A rapid CT and CTA is quickly reported as “no acute large vessel occlusion” and “No intracranial bleed and no established cortical infarction”. You know that many centers in the city are offering intravenous tPA for patients with acute ischemic stroke.  You wonder if Dani should get a dose?

 Background: Minor ischemic strokes (MIS), often defined by NIHSS ≤5, are very common, with roughly half of all ischemic strokes presenting with mild deficits. Despite the mild presentation, these strokes are not always benign. About 30% of patients with initially minor stroke symptoms end up significantly disabled (unable to walk independently) at 90 days [1].  In short, a small stroke can still have a big impact on a patient’s life if it isn’t effectively treated or if it progresses.

Dr. Daniel Fatovich

There have been gallons of ink spilled in the discussion of the stroke literature, with much debate on previous SGEM episodes about the relative risks and benefits of IV thrombolytic therapy for acute strokes. Drs. Ken Milne and Danny Fatovich have earned themselves the title of “non-expert EM contrarians” when discussing the literature around acute ischemic stroke management with Neurologists all over the world.

IV thrombolysis (tissue plasminogen activator [tPA], or newer Tenecteplase [TNK]) is a well-established therapy for acute ischemic stroke based on some questionable evidence [2-6]. However, its role in mild strokes has been hotly debated. On one hand, treating early might prevent a minor stroke from evolving or causing hidden disability. On the other hand, tPA carries a risk of intracerebral hemorrhage, and many minor stroke patients recover well without aggressive intervention. Guidelines have wrestled with this nuance: current recommendations endorse tPA for mild strokes that have clearly disabling deficits, but advise against tPA for mild non-disabling strokes [7]. The core controversy is whether the potential functional benefit in MIS is worth the bleeding risk if the patient is already doing okay.

Things changed 10 years ago after Mr. CLEAN was published. It showed that endovascular interventions (EVT) for acute large vessel occlusions (LVOs) could have impressive results (NNT of 7). However, the role of IV thrombolytics for minor stroke syndromes remains unclear and controversial.  Legendary (now-retired) ED Dr. Joe Lex once stated, “If I can kick the syringe outta’ your hand – then don’t give me the tPA!”  Was Joe right?

Before 2019, practice varied widely. Some neurologists treated almost any stroke within the window, reasoning that “time is brain” even for mild deficits, while others were more conservative. Observational studies yielded mixed signals. Several studies suggested that thrombolysis in mild strokes improves the chance of an excellent outcome at discharge or 90 days, while others showed minimal benefit.

The PRISMS trial (2018) was a key randomized study in this area. It compared alteplase vs. aspirin in patients with minor non-disabling strokes (NIHSS ≤5). PRISMS found no difference in 90-day functional outcomes (mRS score 0-1) between the tPA and aspirin groups, but did find an increase in symptomatic intracerebral hemorrhage with tPA [8].

However, that trial was stopped early after only ~1/3 of the planned enrolment (313/948). This was reported due to a lack of funding. There are issues with stopping trials early, which we have discussed on previous SGEM episodes. Stopping PRISMS early meant it lacked the power to definitively settle the question of lysis minor, non-disabling strokes. Consequently, equipoise remained, and actual practice often followed guideline nuance, treating “minor-but-disabling” strokes (for example, isolated aphasia or hemiparesis that significantly limits function) while generally avoiding tPA in trivial or rapidly improving strokes. Viele et al JAMA 2016, Guyatt et al BMJ 2012, Tyson et al Trials 2016

Clinical Question: In adults with minor acute ischemic stroke (generally NIHSS ≤5), does IV thrombolysis (IVT) improve functional outcomes compared with non‑thrombolytic standard care?

Reference: Doheim et al. Meta-Analysis of Randomized Controlled Trials on IV Thrombolysis in Patients With Minor Acute Ischemic Stroke. Neurology 2025

  • Population: Adults (≥18 y) with minor ischemic stroke (NIHSS <6) eligible to receive IVT within 12 hours of onset from RCTs.
    • Excluded: Nonrandomized studies or those without a control arm. Trials included patients with nondisabling and, in some RCTs, mildly disabling symptoms.
  • Intervention: A variety of IV thrombolytic drugs (Alteplase, Tenecteplase, pro-urokinase) given within varying time windows, but most within 3 to 4.5 hours, followed by standard care.
  • Comparison: Non-thrombolytic standard care (NT‑SC), which could include dual or single antiplatelet therapy, anticoagulants, statins, antihypertensives, glucose control, and other risk‑factor–directed treatments.
  • Outcome:
    • Primary Outcome: Excellent functional outcome at ~90 days, defined as mRS 0-1. (For IST‑3 subgroup data, OHS was converted to mRS; where only 6-month data existed, it was used.)
    • Secondary Outcomes: Favourable outcome mRS 0-2, 90-day mortality, recurrent ischemic or hemorrhagic stroke and safety (symptomatic ICH [sICH]and any ICH).
  • Type of Study: Systematic review and meta-analysis or RCTs

 Authors’ Conclusions: “IVT does not confer improved functional outcomes among patients with minor strokes and can be associated with higher odds of sICH and mortality.”     

Quality Checklist for Therapeutic Systematic Reviews: (yes/no/unsure)

  1. Was the clinical question sensible and answerable? Yes
  2. Was the search detailed and exhaustive? Yes
  3. Were primary studies of high methodological quality? Yes
  4. Were the assessments of studies reproducible? Yes
  5. Were the outcomes clinically relevant? Yes
  6. Was there low statistical heterogeneity for the primary outcomes? Unsure
  7. Was the treatment effect large and precise enough to be clinically significant? No 
  8. Who funded the review? No targeted funding reported.
  9. Conflicts of interest declared? Authors report no relevant disclosures. (though not true for the primary trials – most had conflicts/funding by drug companies)

Results: A total of 3,364 patients from four RCTs were included in the primary analysis. The age ranged from ~56 to 80 years across trials. Most had non-disabling deficits. Some RCTs included a minority with disabling symptoms. Trials varied in time windows (≤3 h, ≤4.5 h, ≤12 h) and imaging criteria (TEMPO‑2 required evidence of intracranial occlusion). The typical baseline NIHSS medians ~2 to 4 in the RCT.

Key Results: Compared with non-thrombolytic standard care, IV thrombolysis did not improve excellent 90‑day functional outcome (mRS 0-1) and was associated with higher odds of symptomatic ICH and mortality in patients with minor stroke.

  • Primary Outcome: mRS 0-1 at ~90 days: OR 85 (95% CI 0.70–1.03). No significant benefit of IVT vs NT‑SC. Similar null results across Alteplase, Tenecteplase, and prourokinase subgroups. Null also across disabling and nondisabling presentations. 
  • Secondary Outcomes:
    • mRS 0–2 at ~90 days: OR 71 (95% CI 0.55–0.91). Lower odds of independence with IVT. It became non-significant when post hoc IST‑3 data were added (OR 0.85, 95% CI 0.58–1.24). 
    • Symptomatic ICH: OR 10 (95% CI 2.01–12.96). Increased with IVT. 
    • Any ICH: OR 21 (95% CI 1.63–3.01). Increased with IVT. 
    • 90‑day Mortality: OR 84 (95% CI 1.18–2.89). Increased with IVT. 
    • Recurrent Stroke: OR 01 (95% CI 0.79–1.29). No statistical difference.

  • What Goes Into the Sausage Machine: This meta-analysis includes a range of trials with different inclusion, exclusion criteria, differing baselines, geographic/demographic and “standard care” comparators, so it is a bit of an evidentiary fruit salad. It can be hard to know how this data applies to the patient and the drugs/system of care that you are working with in your hospital. To make this decision, we may need to look back at individual cohorts and see if they represent our patients and system of care.

  • Rural Stroke Application: In large tertiary hospitals where access to immediate imaging, stroke teams, and endovascular “clot retrieval” interventions has become the standard of care, all of the options are available. However, in rural or remote hospitals where we often do not have as much information or access to interventional neuro-radiology, we run the risk of delivering “second-class” care to our patients with acute ischemic strokes. This trial gives us some clarification around the role of tPA in our smaller community.  Is it best to transfer patients with large, disabling strokes to a bigger centre, then keep the minor strokes and offer good local care without tPA in this cohort? We find this somewhat empowering as rural doctors, as we can discuss the options with more certainty based on the relative disability at presentation.

  • “Ya Can’t Fix Asymptomatic! (but you can make it worse)”: This cohort largely consisted of patients with “non-disabling stroke symptoms”. So, these are the patients who may or may not turn out to have an actual persistent neurological deficit after the initial treatment window. It is probably expecting a lot from a drug to make a large change to a group who were not too sick in the first place. This means the potential benefits are limited, whereas the harms of IV thrombolytics remain roughly the same, no matter how minimal your symptoms. The scales of potential benefit vs potential harm are tilted towards harm.

  • Not All Minor Strokes are Minor: A minor stroke, as defined by the NIHSS score, is not a uniform group of patients. You can get a low NIHSS score with a facial droop or vertigo, loss of motor in the left hand. Yet for some patients, a small neurological deficit can be a major problem for their lifestyle. One of the core tenets of EBM is to put the patient’s values at the centre of the process.  This can be very difficult to do in the rush of a “Stroke Call,” and the pressure to intervene seems urgent.  However, in light of this data set, are we simply rushing towards harm rather than taking time to discuss the relative severity of the symptoms for the individual in front of us?  Should we rethink our system of “stroke call” to slow down and do the right thing rather than rush to potential harm?

  • Primary Paper Biases: Most of the trials are partly funded by pharmaceutical companies, and we know that there are biases that creep into the data when there is no blinding and there is this conflict. Although mRS seems like an objective outcome, some of the trials used phone follow-up or other subjective/self-assessment means to assess functional outcomes. The fact that the biases were in the direction of finding benefit, and they did not find this, strengthens our confidence in the data.

Comment on Authors’ Conclusion Compared to SGEM Conclusion:  We agree and would state more explicitly for ED care: Do not routinely offer IV thrombolysis to patients with nondisabling minor ischemic stroke.

SGEM Bottom Line: For minor, nondisabling ischemic stroke, IV thrombolysis has no proven functional benefit and increases sICH and mortality compared with non‑thrombolytic care.

Case Resolution: After reviewing the CT and checking Dani again, you discuss the relative risks and benefits of IV tPA or the standard care with antiplatelet agents and early rehabilitation. Specifically, you discuss the risk of potentially making things worse with a roughly 5-fold risk of symptomatic ICH and roughly doubling the 90-day death rate.  This is weighed against the small potential for improved symptoms, which may or may not have a meaningful impact on Dani’s lifestyle and function. After this discussion, Dani decides not to have IV thrombolytics and is referred to the local stroke ward for early physical and speech therapy.

Dr. Casey Parker

Clinical Application: For a patient with minor, nondisabling deficits, this SRMA supports withholding IVT and using evidence-based standard care (ex. DAPT when appropriate), after imaging to exclude hemorrhage and to assess for LVO if clinically suspected. If the symptoms are mildly disabling, the evidence remains uncertain. We suggest engaging in shared decision‑making and considering trial enrollment or expert consultation, balancing potential harm (sICH, mortality) against unproven potential functional benefit.

What Do I Tell the Patient? We do not know if there is any clear benefit to IV tPA in patients with minor strokes.  The relative benefit of IV tPA is dependent upon the impact that the stroke symptoms will have on the patient’s lifestyle.  We do know that there is a risk of intracranial bleeding leading to worse functional outcomes and a small increase in mortality with this therapy. However, good medical and physical therapy can also produce good functional outcomes in people with smaller strokes.

Keener Kontest: Last week’s winner was Dr. Cindy Bitter from St. Louis. She knew 988 is administered by SAMHSA – the Substance Abuse and Mental Health Services Administration, part of the Department of Health & Human Services. The number 988 was launched in 2022.

Listen to the SGEM podcast this week to hear the trivia question. If you know the answer, send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.  

Other SGEM Episodes on Stroke:

  • SGEM#29: Stroke Me, Stroke Me
  • SGEM#70: The Secret of NINDS
  • 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 Xtra: Thrombolysis for Acute Stroke
  • SGEM Xtra: Walk of Life
  • SGEM#297:tPA Advocates Be Like – Never Gonna Give You Up
  • SGEM Xtra: Here Comes the NINDS Again
  • SGEM Xtra: Are tPA Stroke Trials Really Fragile?
  • SGEM#325: Thin Ice – Subgroup Analysis of the THAWS Trial
  • SGEM#333: Do you gotta be starting something – like tPA before EVT?
  • SGEM#349: Can tPA Be A Bridge Over Troubled Waters to Mechanical Thrombectomy?
  • SGEM#377: You Don’t Have to “AcT” that Way – TNK for Acute Ischemic Stroke?
  • SGEM#436: For the Longest Time – To Give TNK for an Acute Ischemic Stroke
  • SGEM#455: Harmony 5000 – Prehospital Detection of Large Vessel Occlusion Strokes

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

References:

[1] Moawad MHED, Salem T, Alaaeldin A, Elaraby Y, Awad PD, Khalifa AA, Naggar AE, Mohamed KA, Elhalal M, Badr M, Abdelnaby R. Safety and efficacy of intravenous thrombolysis: a systematic review and meta-analysis of 93,057 minor stroke patients. BMC Neurol. 2025 Jan 22;25(1):33. doi: 10.1186/s12883-024-04000-8. PMID: 39844066; PMCID: PMC11752810.

[2] Garg R, Mickenautsch S. Risk of selection bias assessment in the NINDS rt-PA stroke study. BMC Med Res Methodol. 2022 Jun 15;22(1):172. doi: 10.1186/s12874-022-01651-4. PMID: 35705913; PMCID: PMC9202115.

[3] 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.

[4] Garg R, Torrealba-Acosta G, Mickenautsch S, Berger VW. A methodological assessment of randomization integrity in alteplase for acute ischemic stroke individual patient data meta-analyses. PLoS One. 2025 Mar 19;20(3):e0315342. doi: 10.1371/journal.pone.0315342. PMID: 40106441; PMCID: PMC11922233.

[5] Garg R. Methodological survey of missing outcome data in an alteplase for ischemic stroke meta-analysis. Acta Neurol Scand. 2022 Sep;146(3):252-257. doi: 10.1111/ane.13656. Epub 2022 Jun 2. PMID: 35652287; PMCID: PMC9541760.

[6] Alper BS, Foster G, Thabane L, Rae-Grant A, Malone-Moses M, Manheimer E. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evid Based Med. 2020 Oct;25(5):168-171. doi: 10.1136/bmjebm-2020-111386. Epub 2020 May 19. PMID: 32430395; PMCID: PMC7548536.

[7] Warner JJ, Harrington RA, Sacco RL, Elkind MSV. 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. Stroke. 2019 Dec;50(12):3331-3332. doi: 10.1161/STROKEAHA.119.027708. Epub 2019 Oct 30. PMID: 31662117.

[8] Khatri P, Kleindorfer DO, Devlin T, Sawyer RN Jr, Starr M, Mejilla J, Broderick J, Chatterjee A, Jauch EC, Levine SR, Romano JG, Saver JL, Vagal A, Purdon B, Devenport J, Pavlov A, Yeatts SD; PRISMS Investigators. Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial. JAMA. 2018 Jul 10;320(2):156-166. doi: 10.1001/jama.2018.8496. PMID: 29998337; PMCID: PMC6583516.