The Hope Trial: Alteplase 4.5–24 Hours After Stroke (CT Perfusion Selected)

Written by Carlton Watson, MD MSc
REBEL Crit, REBEL EM
Medical Category: Neurology
Acute Ischemic Stroke, Alteplase, CT perfusion, HOPE trial, late window stroke, Modified Rankin Scale, perfusion mismatch, symptomatic intracranial hemorrhage, thrombolysis, tissue-based selection, tPA

February 16, 2026

📌 Key Points

🧠🕒 Late-window benefit: Alteplase improved outcomes in patients treated 4.5–24 hours after stroke onset when imaging shows salvageable tissue—supporting a “tissue over time” approach where imaging guides treatment, not the clock.
📈✅⚠️ Benefit–risk tradeoff: Alteplase increased functional independence (40% vs 26%) but also increased symptomatic intracranial hemorrhage; importantly, this did not increase mortality.
🔬🌍➡️ What’s next: More data are needed—tenecteplase comparisons, more diverse populations, and studies across different healthcare systems to confirm whether these results generalize broadly.

📝 Introduction

The cornerstone of acute ischemic stroke (AIS) management involves timely reperfusion of the ischemic brain tissue. Intravenous thrombolysis with alteplase has been the standard of care for AIS within 4.5 hours of symptom onset, based on pivotal trials such as NINDS and ECASS III, which demonstrated improved functional outcomes despite an increased risk of intracerebral hemorrhage.^1,2 However, many patients present outside this narrow therapeutic window, excluding many patients from the potential benefits of thrombolytics. For some, mechanical thrombectomy is an option if their stroke is the result of a medium or large vessel occlusion and is amenable to aspiration or stent retrieval. Recent advances in neuroimaging, particularly perfusion-based techniques, have allowed for the identification of salvageable brain tissue beyond traditional time limits.³ This imaging-guided approach has spurred clinical trials evaluating the safety and efficacy of thrombolysis in the extended and late time windows.

The EXTEND trial suggested a modest functional benefit of alteplase administered between 4.5 and 9 hours in carefully selected patients with perfusion mismatch, though the absolute treatment effect was small and accompanied by increased hemorrhagic risk.⁴ Similarly, the WAKE-UP trial demonstrated improved functional outcomes in patients with unknown onset times selected by MRI-based DWI–FLAIR mismatch, reinforcing a tissue-based approach but with no mortality benefit and a higher risk of intracranial hemorrhage.⁵ Subsequent late-window thrombolysis studies have yielded inconsistent results; trials evaluating tenecteplase such as TIMELESS and TEMPO-2 failed to demonstrate clear clinical benefit and raised concerns regarding futility and safety in certain populations.^6,7 In addition, TRACE-III, conducted exclusively in Chinese patients, may reflect population-specific stroke pathophysiology that limits generalizability.⁸ Against this uncertain and heterogeneous evidence base, the HOPE trial was designed to reassess whether alteplase could provide meaningful functional benefit in patients presenting 4.5 to 24 hours after stroke onset who demonstrate imaging evidence of viable brain tissue.

🧾 Paper

Zhou Y, He Y, Campbell BCV, et al. Alteplase for Acute Ischemic Stroke at 4.5 to 24 Hours: The HOPE Randomized Clinical Trial. JAMA. Published online August 07, 2025. PMID: 40773205

⚙️ What They Did

CLINICAL QUESTION

In acute ischemic stroke patients presenting between 4.5 and 24 hours after symptom onset with evidence of salvageable brain tissue on perfusion imaging and no plan for endovascular mechanical thrombectomy, does the administration of intravenous alteplase compared to standard medical treatment result in improved functional outcomes?

STUDY DESIGN

Phase 3, multi-center, randomized, open-label, blinded endpoint trial across 26 stroke centers in China
Patients with AIS presenting 4.5 to 24 hours after onset (or midpoint if onset unknown)
Salvageable brain tissue
- Ischemic core volume ≤70mL
- A perfusion-core mismatch ratio >1.2
- A perfusion-core mismatch volume of at least 10mL
No initial plan for thrombectomy
The patients were randomized to a 1:1 allocation to alteplase (0.9 mg/kg, max 90 mg) vs standard medical treatment (e.g., antiplatelet therapy, supportive care)
372 patients randomized
- 186 = alteplase
- 186 = control; standard therapy

POPULATION

Inclusion Criteria:

Age ≥ 18 years of age
AIS with CT perfusion (CTP) imaging demonstrating salvageable tissue
Presenting 4.5 to 24 hours after stroke onset
NIHSS >4 and <26
Pre-stroke mRS 0 or 1

Exclusion Criteria:

NIHSS < 4 or > 26
Underwent MT
ICH on CT or prior history of ICH
Thrombolytic treatment at an external hospital
Did not meet the target mismatch profile on CTP
Hypodensity in more than 1/3 of the middle cerebral artery (MCA) territory on non-contrast head CT (NCHCT)
AIS or myocardial infarction within the previous 3 months
Unable to perform or uninterpretable CTP
Any form of coagulopathy
Blood glucose < 50 or >396 mg/dL

INTERVENTION & CONTROL

Intervention:

Intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) was administered to patients who presented between 4.5 and 24 hours after symptoms onset with no initial plan for endovascular thrombectomy.

Control:

Patients received standard medical therapy for acute ischemic stroke, which is not explicitly stated but includes aspirin, clopidogrel, blood pressure control, and statin administration.

OUTCOMES

Primary Outcome:

Modified Rankin Scale (mRS) score of 0 or 1 at 90 days

Secondary Outcomes:

Safety
- Symptomatic intracranial hemorrhage (sICH) within 36 hours after randomization
- 90-day all-cause mortality
Functional
- mRS 0 to 2 at 90 days
- mRS 0 to 3 at 90 days
- Distribution of mRS at 90 days
- Improvement of at least 8 points on the NIHSS at 24 hours and 7 days
- NIHSS less than 1 at 24 hours and 7 days

📈 Results

OUTCOMES

DEMOGRAPHICS

OUTCOMES

DEMOGRAPHICS

💥 Critical Results

Primary efficacy (mRS 0–1 at 90 days): 40.3% (75/186) with alteplase vs 26.3% (49/186) with standard therapy → RR 1.52 (95% CI 1.14–2.02); absolute difference +13.98%; p = 0.004.
Symptomatic ICH within 36 hours: 3.8% (7/185) vs 0.5% (1/182) → RR 7.34 (95% CI 1.54–34.84); absolute difference +3.23%; p = 0.01.
90-day mortality: 10.8% vs 10.8% (no difference).
Secondary functional outcome (mRS 0–2 at 90 days): 55.4% vs 45.7% → RR 1.20 (95% CI 1.00–1.45); absolute difference +9.68%; p = 0.052 (borderline).
Early neurologic improvement (NIHSS):
- Major neurologic improvement at 24h: 21.0% vs 12.9% → RR 1.66; p = 0.04.
- Major neurologic improvement at 7 days: 35.5% vs 27.2% → RR 1.30; p = 0.10.

💪 Strengths

Randomized controlled multi-center trial design ensures a high level of internal validity for comparing treatments.
Patient-centered outcomes by utilizing mRS 0-1 at 90 days as the primary efficacy outcome, as a longer follow-up increases the validity of the intervention’s benefit.
Investigators performed and intention to treat analysis.
Baseline demographics were equal across both groups, including between age and gender.
Baseline characteristics were well-matched between groups, reducing the risk of confounding.
Blinded mRS outcome assessment reduced bias despite the open-label nature of the trial
Meaningful clinical outcome focused on functional independence and is patient-centered.
Tissue-based selection using perfusion imaging to guide eligibility shifts the paradigm away from rigid time windows toward identifying salvageable brain tissue.
Comprehensive secondary outcomes provide additional insight into neurologic recovery and safety.
Real-world relevance was achieved through the use of perfusion imaging, which facilitated broad inclusion and increased generalizability.
Approximately 50% of patients had an NIHSS score >10, which is a moderate stroke burden

⚠️ Limitations

The open-label design introduces a potential performance bias, as the treating clinicians were not blinded to the therapy.
A single-country (China) setting reduces generalizability to non-Chinese populations and international practice settings.
Safety trade-off in that alteplase significantly increased the rate of symptomatic intracranial hemorrhage (3.8% vs 0.5%), raising concerns about disability from hemorrhage, even if overall mortality did not differ.
Short safety follow-up for sICH (within 36 hours) may miss later-occurring adverse events.
Exclusion of thrombectomy candidates eliminates a large subset of patients who may benefit from alteplase and recannulization.
Exclusion of very high stroke severity (NIHSS > 26) may reduce the relevance to patients with severe strokes.
Out of the total 372 patients, 180 patients were enrolled from a single site, minimizing external validity

🗣️ Discussion

What HOPE Adds

The HOPE trial randomized 372 perfusion-selected patients to IV alteplase (0.9 mg/kg) vs standard care 4.5–24 hours after onset and found improved mRS 0–1 at 90 days (40% vs 26%).
The trial used a tissue-based perfusion mismatch selection strategy rather than a strict time cutoff, consistent with the paradigm established by EXTEND and WAKE-UP.4,5
HOPE demonstrated a clinically meaningful absolute benefit (~14% risk difference) but also a higher rate of symptomatic intracranial hemorrhage (3.8% vs 0.5%).
Mortality was unchanged between arms, suggesting bleeding events increased morbidity more than mortality in this cohort.
EXTEND previously showed benefit up to 9 hours with perfusion selection; HOPE extends that concept to 24 hours in selected patients.4
Trials of tenecteplase in late windows (eg, TIMELESS/TNK trials) have had mixed results, and some late-window tenecteplase trials did not show consistent benefit, leaving uncertainty about the optimal agent.6,7

Inside The Numbers

Primary benefit (functional independence): mRS 0–1 at 90 days occurred in 40.3% of patients treated with alteplase (75/186) vs 26.3% with standard therapy (49/186) → Absolute risk difference: +13.98%; RR 1.52 (95% CI 1.14–2.02); p = 0.004.
Number needed to treat (NNT): ~8 patients treated to achieve 1 additional excellent functional outcome (mRS 0–1) at 90 days (NNT = 8).
Key harm (symptomatic ICH): sICH within 36 hours occurred in 3.8% of alteplase patients (7/185) vs 0.5% of controls (1/182) → Absolute risk difference: +3.23%; RR 7.34 (95% CI 1.54–34.84); p = 0.01.
Number needed to harm (NNH): ~31 patients treated to cause 1 additional symptomatic intracranial hemorrhage (NNH = 31).
Mortality: No difference in 90-day all-cause mortality (10.8% vs 10.8%).

State of the Evidence

The HOPE trial adds to the existing body of evidence evaluating IV alteplase in an extended time window for patients presenting with acute ischemic stroke. Although EXTEND and WAKE-UP demonstrated that tissue-guided thrombolysis with IV alteplase could be beneficial beyond the conventional 4.5-hour window (up to ~9 hours or in wake-up strokes) using perfusion or MRI-based mismatch selection, the HOPE trial pushes this boundary dramatically further, showing a significant increase in 90-day functional independence when alteplase is given as late as 24 hours after onset in perfusion-selected patients.

Future Direction

Current major guidelines (AHA/ASA) emphasize time- and tissue-based selection (and recommend thrombectomy for LVOs within guideline windows); HOPE may prompt guideline reappraisal for alteplase in imaging-selected late-window patients.
HOPE is highly relevant where thrombectomy access is limited, but extrapolation to thrombectomy-rich systems requires caution because many patients had LVOs, and the trial excluded those already planned for EVT.
Operational barriers remain: routine perfusion imaging and standardized mismatch thresholds are not universally available, and variability in CT perfusion processing could alter eligibility and outcomes.
Head-to-head late-window comparisons of alteplase vs tenecteplase, integration with early/bridging EVT strategies, and cost-effectiveness analyses are needed before widespread adoption.

📘 Author's Conclusion

“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”

💬 Our Conclusion

The HOPE trial investigated the use of alteplase outside the current standard treatment window in patients with salvageable brain tissue on CTP imaging. The findings demonstrated a significant functional benefit with a respectable hemorrhage risk. These results support shifting the paradigm from “time is brain” to “tissue over time,” and the consideration of extending treatment windows for eligible patients. However, more evidence in large, diverse settings is needed before extending the window.

🚨 Clinical Bottom Line

Perfusion-selected AIS patients treated with IV alteplase 4.5–24 hours after onset had better 90-day functional outcomes, with higher sICH but no mortality difference.

📚 References

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. PMID: 7477192
Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329. PMID: 18815396
Campbell BCV, Mitchell PJ, Kleinig TJ, et al; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018. PMID: 25671797
Ma H, Campbell BCV, Parsons MW, et al; EXTEND Investigators. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380(19):1795-1803. PMID: 31067369
Thomalla G, Simonsen CZ, Boutitie F, et al; WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611-622. PMID: 29766770
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. PMID: 38329148
Coutts, Shelagh B Salluzzi, Marina et al.;Tenecteplase versus standard of care for minor ischemic stroke with proven occlusion (TEMPO-2): a randomized, open label, phase 3 superiority trial. The Lancet, Volume 403, Issue 10444, 2597-2605. PMID: 38768626
Yang P, Zhang Y, Zhang L, et al; TRACE-III Investigators. Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med. 2023;388(19):1791-1803. PMID: 32374959
Albers GW, Campbell BC, Lansberg MG, Broderick J, Butcher K, Froehler MT, Schwamm LH, Nouh AM, Liebeskind DS, Toy F, Yang M, Massaro L, Schoeffler M, Purdon B. A Phase III, prospective, double-blind, randomized, placebo-controlled trial of thrombolysis in imaging-eligible, late-window patients to assess the efficacy and safety of tenecteplase (TIMELESS): Rationale and design. Int J Stroke. 2023 Feb;18(2):237-241. PMID: 35262424
Campbell BCV, Majoie CBLM, Albers GW, et al; TIMELESS Investigators. Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy: the TIMELESS randomized clinical trial. JAMA. 2023;330(19):1887-1897.

Post Peer Reviewed By: Mark Ramzy, DO (X: @MRamzyDO), and Marco Propersi, DO (X: @Marco_Propersi)

👤 Guest Author

Carlton Watson

MD, MSc

Neurocritical Care Fellow North Shore University Hospital, Manhasset, NY

Meet The Team

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Cite this article as: Carlton Watson, MD MSc, "The Hope Trial: Alteplase 4.5–24 Hours After Stroke (CT Perfusion Selected)", REBEL EM blog, February 16, 2026. Available at: https://rebelem.com/the-hope-trial-alteplase-4-5-24-hours-after-stroke-ct-perfusion-selected/.