SGEM#524: High, High HOPE for Recovery – Alteplase between 4.5 and 24 hours

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: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No for patients/clinicians (open‑label); Yes for outcome assessors. All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Unsure Who funded the study? National Natural Science Foundation of China. Funder had no role in design or analysis. 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) 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. 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. 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,...