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Date: October 6, 2026

Guest Skeptic: Dr. Ryan Stanton, creator of the EM podcast Front Line and the new President of the American College of Emergency Physicians (ACEP).

Reference: Zhou et al. HOPE investigators. Alteplase for Acute Ischemic Stroke at 4.5 to 24 Hours: The HOPE Randomized Clinical Trial. JAMA. 2025

Case: Mr. Wei Zhang is a 73-year-old retired teacher with hypertension and atrial fibrillation (not on anticoagulation), who is brought to the emergency department (ED) at 09:30 after being found by his wife with slurred speech and weakness of the right arm and leg. He was last known well the previous evening at 23:00, when he went to bed. On arrival, he is alert and oriented. The NIHSS score is 12 (moderate stroke; facial droop, dysarthria, right arm and leg weakness). Blood glucose is normal, CT head shows no hemorrhage, CT angiography shows no large-vessel occlusion, and the CT perfusion scan shows an ischemic core 30 mL, penumbra 60 mL (mismatch ratio = 2.0, mismatch volume = 30 mL). He is 10½ hours from last-known-well and not a candidate for thrombectomy .

Background: The use of thrombolytics for acute ischemic stroke (AIS) has been debated in emergency medicine for about three decades. It started with the 1995 NINDS trial of IV alteplase within three hours of symptom onset [1]. That trial became the foundation for thrombolysis in AIS and helped drive the concept that “time is brain.” Alteplase subsequently became incorporated into stroke systems of care and clinical practice guidelines.

That doesn’t mean everyone has agreed on the strength of the evidence. Emergency medicine has had a long and sometimes spirited debate about the benefits and harms of thrombolysis for stroke. Even the catchy phrase “time is brain” deserves some nuance [2]. Dr. Camilo Gómez, who coined the phrase, later argued that collateral circulation and other patient factors mean that ischemic injury does not progress at the same rate in everyone. In other words, time still matters, but the clock doesn’t tell us everything about the brain (Stroke Theory of Relativity).

Then came ECASS III in 2008, extending the alteplase window from three to 4.5 hours [3]. The trial reported improved functional outcomes but also more symptomatic intracranial hemorrhage (sICH), and guidelines subsequently adopted the expanded window. However, ECASS III has also been challenged. Brian Alper and colleagues reanalyzed the patient-level data and raised concerns about the original adjusted analysis and baseline imbalances [4]. Their reanalysis could not confirm a statistically significant efficacy benefit after adjustment, while the increased risk of sICH remained.

The next move was from a clock-based paradigm toward a tissue-based paradigm. WAKE-UP used MRI DWI-FLAIR mismatch to select patients with an unknown time of onset, while EXTEND used perfusion imaging to identify patients with potentially salvageable brain up to nine hours after onset or with wake-up stroke [5, 6]. Both suggested that selected patients might benefit beyond the traditional treatment window, although EXTEND was small, stopped early, and thrombolysis continued to carry an increased risk of sICH.

Things get even more interesting when we stretch the clock to 24 hours. TIMELESS tested tenecteplase (TNK)  from 4.5 to 24 hours in perfusion-selected patients, most of whom subsequently underwent thrombectomy, and did not demonstrate improvement in its primary functional outcome [7]. Current guidelines therefore don’t simply say, see salvageable tissue, give thrombolytics. Patient selection, timing, imaging, and whether thrombectomy is planned all matter.

And this is where things get a little more skeptical. Garg and Brophy recently looked at six randomized trials of imaging-selected extended-window thrombolysis [8]. They found a high probability of improving the traditional dichotomized mRS outcome, but only a 1% probability of a clinically important improvement using a utility-weighted mRS. They also found a 72% probability of at least one additional death per 100 patients treated. They rated the certainty of the evidence as low because every included RCT had a high risk of bias in at least one domain.

So where does that leave us? We have moved from “time is brain” toward “tissue is brain,” but perhaps we should resist replacing one catchy slogan with another. Advanced imaging can identify potentially salvageable brain many hours after stroke onset, but we still don’t know exactly who benefits, how large that patient-important benefit is, or whether it outweighs the harms.

Clinical Question: Does IV alteplase administered 4.5 to 24 hours after acute ischemic stroke onset improve outcomes in patients with salvageable brain tissue and no initial plan for thrombectomy?

Reference: Zhou et al. HOPE investigators. Alteplase for Acute Ischemic Stroke at 4.5 to 24 Hours: The HOPE Randomized Clinical Trial. JAMA. 2025

  • Population: Adults with acute ischemic stroke 4.5–24 hours from onset (or midpoint between last-known-well and recognition if unwitnessed), with salvageable brain tissue on CT perfusion imaging, NIHSS 4–26, baseline mRS 0–1, and no initial plan for thrombectomy.
    • Excluded: Planned endovascular thrombectomy at screening. Guideline-based contraindications to alteplase (aside from time window). Extensive early ischemia (>1/3 MCA territory). Acute or prior ICH, severe comorbidity, or metabolic derangements (glucose <2.8 or >22.2 mmol/L).
  • Intervention: IV alteplase 0.9 mg/kg (max 90 mg): 10% bolus then 90% over 60 minutes
  • Comparison: Standard medical treatment (antiplatelets, statins, supportive care) as per guidelines.
  • Outcomes:
    • Primary Outcome: Functional independence (mRS 0–1 at 90 days).
    • Secondary outcomes: Functional independence defined as mRS 0–2 at 90 days. Distribution (ordinal shift) of mRS at 90 days. Major neurologic improvement (≥8-point NIHSS drop or NIHSS ≤1) at 24h and 7d. Safety: sICH within 36h; parenchymal hematoma ≤36h; all-cause mortality at 90d.
  • Type of Study: Randomized, open-label treatment, blinded endpoint assessment conducted at 26 stroke centers in China.

Authors’ Conclusions: “In patients with acute ischemic stroke with salvageable brain tissue identified by perfusion imaging who did not initially receive thrombectomy, intravenous alteplase administered 4.5 to 24 hours after onset provided functional benefit, despite an increase in symptomatic intracranial hemorrhage.”

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, outcome assessors) were unaware of group allocation. No for patients/clinicians (open‑label); Yes for outcome assessors. 
  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. Unsure
  12. Who funded the study? National Natural Science Foundation of China. Funder had no role in design or analysis.
  13. Any conflicts of interest declared? Some investigators reported relationships with industry, including Genentech/Roche, although these were reported as outside the submitted work. The trial itself was not industry funded.

Results: They screened almost 4,000 patients and randomized 372 (186 alteplase and 186 standard care). The median age was 72 years, 43% were women, and the median NIHSS was 10. About half had a wake-up or unwitnessed stroke.

Key Result: Giving IV alteplase 4.5 to 24 hours after stroke onset in patients with salvageable brain tissue increased the proportion of patients achieving an mRS of 0–1 at 90 days but also increased sICH.

  • Primary Outcome (mRS 0–1 at 90d):
    • 40% alteplase vs 26% control.
    • Adjusted RR 1.52 (95% CI 1.14–2.02); absolute risk difference ~14%.
  • Secondary Outcomes: There was no adjustment for multiple comparisons, so the secondary outcomes should be considered exploratory.
    • mRS 0–2: 55.4% vs 45.7%; aRR 1.20 (95% CI 1.00–1.45), P=0.052
    • Ordinal mRS: adjusted common OR 1.51 (95% CI 1.04–2.18), P=0.03
    • Major neurologic improvement at 24 h: 21.0% vs 12.9%; aRR 1.66 (95% CI 1.03–2.66)
    • Major neurologic improvement at 7 d: 35.5% vs 27.2%; aRR 1.30 (95% CI 0.95–1.77)
    • Mortality: 10.8% vs 10.8%
    • sICH: 3.8% vs 0.5%; absolute difference 3.23% (NNH ≈31)

  1. Open-label: The HOPE trial was randomized but not masked for clinicians or patients, raising concerns about performance bias. Patients and clinicians knew which treatment they received. Outcome assessors were masked, which is good, but the mRS still has some subjectivity. Knowing treatment allocation could also influence other aspects of care. Blinded outcome assessment helps, but it doesn’t completely eliminate the potential for bias.
  2. Imaging Selection: These weren’t just late-presenting stroke patients. They were late-presenting stroke patients with a specific CT-perfusion mismatch. That may identify the patients most likely to benefit, but it also limits external validity. If you don’t have timely CT perfusion, these results aren’t going to help you very much.
  3. Highly Selected Population: Almost 4,000 patients were screened to randomize 372. That does not necessarily introduce selection bias, but it does remind us who these results apply to. These were patients with a prestroke mRS of 0–1, NIHSS 4–26, a specific CT-perfusion mismatch and no initial plan for thrombectomy. The further our patient gets from that population, the less confident we should be applying the HOPE results.
  4. How Much Evidence Do We Really Have Out to 24 Hours? The title says 4.5 to 24 hours, but only 51 patients (14%) had a known onset between 9 and 24 hours. Most patients were treated either between 4.5 and 9 hours or had wake-up/unwitnessed strokes. In the prespecified >9-to-24-hour subgroup, the confidence interval was wide and crossed the null. So be careful interpreting HOPE as strong evidence that alteplase works all the way out to 24 hours.
  5. How You Slice the mRS Matters: The primary outcome was mRS 0–1 versus everything else. That’s easy to report, but dichotomizing an ordinal scale throws away information. Moving from an mRS of 4 to 3 could matter a lot to a patient but doesn’t count as a success. Meanwhile, an mRS of 2 and death both end up on the other side of the primary outcome. This matters when we consider the Garg and Brophy meta-analysis using a utility-weighted mRS.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: HOPE was a positive trial based on its prespecified primary outcome. Where I would pump the brakes a little is how far we take that conclusion. These were highly selected patients, the trial was open-label, and there was more sICH. HOPE gives us more evidence for extended-window thrombolysis, but I don’t think it gives us enough evidence to routinely treat patients out to 24 hours.

SGEM Bottom Line: HOPE suggests a potential functional benefit from alteplase 4.5 to 24 hours after stroke onset in carefully selected patients with salvageable brain tissue and no planned thrombectomy. That potential benefit needs to be balanced against increased sICH and the limitations of the trial.

Case Resolution: After discussing the potential benefits and harms, Mr. Zhang says avoiding significant disability is most important to him and that he is willing to accept the increased bleeding risk. He chooses alteplase.

Dr. Ryan Stanton

Clinical Application: I don’t think HOPE is enough to routinely extend alteplase out to 24 hours. The 2025 Stroke meta-analysis found better functional outcomes with extended-window thrombolysis, but also more sICH and a numerical increase in mortality. Garg and Brophy looked at much of the same evidence through a different lens. Using a utility-weighted mRS, they found only a 1% probability of a clinically important benefit and a 72% probability of at least one additional death per 100 patients treated. Different methods, different conclusions. For now, I think extended-window thrombolysis remains a shared decision rather than a new standard of care.

What Do I Tell the Patient: Your scan suggests there is still some brain tissue that might be saved. Alteplase may increase your chance of recovering with little or no disability, even though your stroke happened more than 4½ hours ago. In this study, about one additional patient achieved that outcome for every seven treated, but serious bleeding in the brain was also about 3% more common. We need to balance that possible benefit against the bleeding risk and decide what matters most to you.

Keener Kontest: Last week’s winner was Dr. Steven Stelts. He knew epinephrine is different from norepinephrine as it has an additional methyl group on the nitrogen that norepinephrine does not have. This structural difference changes the way these molecules bind to the adrenergic receptors.

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
  • SGEM#488: It’s Just A Minor Stroke – Should We Still Lyse?

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. Gomez CR. Time Is Brain: The Stroke Theory of Relativity. J Stroke Cerebrovasc Dis. 2018 Aug;27(8):2214-2227. doi: 10.1016/j.jstrokecerebrovasdis.2018.04.001. Epub 2018 Apr 25. PMID: 29705088.
  3. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29. doi: 10.1056/NEJMoa0804656. PMID: 18815396.
  4. 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.
  5. Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, Cheripelli B, Cho TH, Fazekas F, Fiehler J, Ford I, Galinovic I, Gellissen S, Golsari A, Gregori J, Günther M, Guibernau J, Häusler KG, Hennerici M, Kemmling A, Marstrand J, Modrau B, Neeb L, Perez de la Ossa N, Puig J, Ringleb P, Roy P, Scheel E, Schonewille W, Serena J, Sunaert S, Villringer K, Wouters A, Thijs V, Ebinger M, Endres M, Fiebach JB, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Gerloff C; WAKE-UP Investigators. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018 Aug 16;379(7):611-622. doi: 10.1056/NEJMoa1804355. Epub 2018 May 16. PMID: 29766770.
  6. Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, Kleinig TJ, Wijeratne T, Curtze S, Dewey HM, Miteff F, Tsai CH, Lee JT, Phan TG, Mahant N, Sun MC, Krause M, Sturm J, Grimley R, Chen CH, Hu CJ, Wong AA, Field D, Sun Y, Barber PA, Sabet A, Jannes J, Jeng JS, Clissold B, Markus R, Lin CH, Lien LM, Bladin CF, Christensen S, Yassi N, Sharma G, Bivard A, Desmond PM, Yan B, Mitchell PJ, Thijs V, Carey L, Meretoja A, Davis SM, Donnan GA; EXTEND Investigators. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803. doi: 10.1056/NEJMoa1813046. Erratum in: N Engl J Med. 2021 Apr 1;384(13):1278. doi: 10.1056/NEJMx200014. PMID: 31067369.
  7. Albers GW, Jumaa M, Purdon B, Zaidi SF, Streib C, Shuaib A, Sangha N, Kim M, Froehler MT, Schwartz NE, Clark WM, Kircher CE, Yang M, Massaro L, Lu XY, Rippon GA, Broderick JP, Butcher K, Lansberg MG, Liebeskind DS, Nouh A, Schwamm LH, Campbell BCV; TIMELESS Investigators. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection. N Engl J Med. 2024 Feb 22;390(8):701-711. doi: 10.1056/NEJMoa2310392. Epub 2024 Feb 8. PMID: 38329148.
  8. Garg R, Brophy JM. Extended thrombolysis in acute ischemic stroke: A Bayesian meta-analysis and umbrella review. Am J Emerg Med. 2026 Mar;101:166-172. doi: 10.1016/j.ajem.2025.12.043. Epub 2026 Jan 3. PMID: 41529589.