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Trial Summaries & Critiques

OPTION

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Publication

  • Title: Tenecteplase for Acute Non–Large Vessel Occlusion 4.5 to 24 Hours After Ischemic Stroke Onset: The OPTION Randomized Clinical Trial
  • Acronym: OPTION
  • Year: 2026
  • Journal published in: JAMA
  • Citation: Ma G, Mo R, Zuo Y, et al. Tenecteplase for Acute Non–Large Vessel Occlusion 4.5 to 24 Hours After Ischemic Stroke Onset: The OPTION Randomized Clinical Trial. JAMA. Published online February 5, 2026.

Context & Rationale

  • Background
    • Non-LVO ischaemic stroke is more common than proximal large vessel occlusion, but late-window reperfusion evidence has historically been dominated by thrombectomy-focused pathways and/or proximal LVO cohorts.
    • Imaging-selected thrombolysis beyond 4.5 hours is biologically plausible (salvageable penumbra persists), yet net benefit is uncertain in heterogeneous non-LVO phenotypes with variable spontaneous recanalisation and recovery.
    • OPTION was prospectively designed as an imaging-selected, late-window intravenous thrombolysis trial in non–large vessel occlusion (non-LVO) stroke, with published rationale and design prior to trial completion.1
    • Tenecteplase offers practical advantages (single IV bolus; longer half-life; greater fibrin specificity) and is increasingly supported as an alteplase alternative in several acute stroke thrombolysis contexts, but late-window non-LVO data were sparse before OPTION.2
  • Research Question/Hypothesis
    • In adults with acute ischaemic stroke due to non-LVO and CT perfusion evidence of salvageable brain tissue, does intravenous tenecteplase (0.25 mg/kg; max 25 mg) administered 4.5–24 hours from time last seen well increase the probability of excellent functional outcome (mRS 0–1) at 90 days compared with standard medical treatment (without thrombolysis)?
    • Hypothesis: late-window tenecteplase would improve functional outcome by promoting reperfusion/recanalisation in selected non-LVO patients, at the cost of increased intracranial haemorrhage risk.
  • Why This Matters
    • If beneficial, tenecteplase could extend reperfusion therapy to a large group currently managed with antiplatelets/supportive care despite demonstrable perfusion mismatch.
    • Clinical decision-making in late-window non-LVO is high stakes because absolute benefit is expected to be modest and the principal countervailing harm (symptomatic intracranial haemorrhage) can be catastrophic.
    • Results interact with rapidly evolving endovascular indications for medium/distal occlusions (MeVO/DVO), creating uncertainty about “best medical therapy” comparators and care pathways.

Design & Methods

  • Research Question: Among imaging-selected non-LVO acute ischaemic stroke presenting 4.5–24 hours from time last seen well, does intravenous tenecteplase improve excellent functional outcome (mRS 0–1) at 90 days versus standard medical treatment?
  • Study Type: Randomised, multicentre (48 centres), open-label, blinded end-point (PROBE) clinical trial; 1:1 allocation via minimisation algorithm; conducted in China; trial registration NCT05752916.
  • Population:
    • Setting: Hyperacute stroke pathways with vascular imaging and CT perfusion selection at 48 hospitals in China.
    • Key inclusion: Acute ischaemic stroke; time last seen well 4.5–24 hours; disabling neurological deficit; non-LVO on vascular imaging; CT perfusion “favourable” profile (ischaemic core volume <50 mL; mismatch ratio ≥1.2; mismatch volume ≥10 mL using Tmax>6 s and relative CBF <30% thresholds).
    • Key exclusions (pragmatic summary): Large vessel occlusion (intracranial internal carotid, proximal middle cerebral artery, vertebral, or basilar artery occlusion); planned endovascular thrombectomy at baseline; premorbid disability; absence of perfusion mismatch; standard contraindications to thrombolysis.
  • Intervention:
    • Intravenous tenecteplase 0.25 mg/kg (maximum 25 mg) as a single bolus over 5–10 seconds, administered immediately after randomisation.
  • Comparison:
    • Standard medical treatment without thrombolysis (including antiplatelet-based management and other guideline-concordant stroke care as clinically indicated).
    • Rescue endovascular thrombectomy was permitted for neurological deterioration despite initial non-thrombectomy intent.
  • Blinding: Open-label treatment delivery; blinded end-point assessment (mRS adjudicated by assessors blinded to treatment allocation; vascular/imaging characterisation assessed by independent core laboratory).
  • Statistics: A total sample size of 568 patients was required to detect a 12% absolute increase in excellent outcome (mRS 0–1 at 90 days: 38% to 50%) with 80% power at a 2-sided α of 0.049 (adjusted for 1 planned interim efficacy analysis at 50% information), allowing for 5% dropout; primary analysis used modified Poisson regression with robust error estimates to report risk ratios (crude analysis prespecified as primary); efficacy analysed in the randomised population without consent withdrawal; per-protocol and sensitivity analyses performed; safety analysed in those receiving any trial treatment.
  • Follow-Up Period: Clinical outcomes to 90 days; symptomatic intracranial haemorrhage assessed within 36 hours; reperfusion and infarct volume assessed at ~24 hours; early neurological outcomes included 24-hour and 7-day NIHSS-based measures.

Key Results

This trial was not stopped early. A prespecified interim efficacy analysis was not performed because rapid recruitment rendered it operationally unfeasible; no formal efficacy assessment was conducted and no α was spent.

Outcome Tenecteplase Standard medical treatment Effect p value / 95% CI Notes
Excellent functional outcome (mRS 0–1) at 90 days (primary) 123/282 (43.6%) 97/284 (34.2%) RR 1.28 95% CI 1.04 to 1.57; P=0.02 Post hoc risk difference 9.36%; 95% CI 1.37% to 17.46%; number needed to treat 11
Ordinal mRS distribution at 90 days Shift towards lower disability Reference Common OR 1.39 95% CI 1.04 to 1.86; P=0.03 Ordinal analysis; no multiplicity adjustment
Functional independence (mRS 0–2) at 90 days 177/282 (62.8%) 157/284 (55.3%) RR 1.14 95% CI 0.99 to 1.30; P=0.07 Directionally favours tenecteplase; not statistically significant
Reperfusion at 24 hours 95/252 (37.7%) 76/264 (28.8%) RR 1.31 95% CI 1.02 to 1.68; P=0.03 Assessed in patients with baseline non-LVO steno-occlusion and follow-up imaging available
Infarct volume at 24 hours (mL), median (IQR) 5.6 (1.2–19.8) 6.2 (1.2–19.9) Win ratio 1.02 95% CI 0.83 to 1.24; P=0.87 Continuous non-normal outcome analysed with win ratio
Early clinical response at 24 hours 32/280 (11.4%) 14/282 (5.0%) RR 2.30 95% CI 1.26 to 4.22; P=0.007 Denominators reflect available assessments
Change in NIHSS from baseline to day 7, median (IQR) −3 (−5 to −1) −2 (−4 to −1) Win ratio 1.16 95% CI 0.94 to 1.43; P=0.16 Directionally favours tenecteplase
EQ-5D-5L score at 90 days, median (IQR) 0.9 (0.6–1.0) 0.9 (0.6–1.0) Win ratio 1.02 95% CI 0.82 to 1.27; P=0.83 Quality-of-life measure; no clear separation
Symptomatic intracranial haemorrhage within 36 hours (safety) 8/281 (2.8%) 0/284 (0%) Risk difference 2.85% 95% CI 1.16% to 5.54%; P=0.004 RR not estimable due to zero events in control group
Moderate or severe systemic bleeding within 90 days (safety) 2/281 (0.7%) 2/284 (0.7%) RR 1.01 95% CI 0.14 to 7.12; P=0.99 Rare events; wide confidence interval
Death within 90 days (safety) 14/281 (5.0%) 9/284 (3.2%) RR 1.57 95% CI 0.69 to 3.57; P=0.28 Not statistically different; trial not powered for mortality
  • Net effect: Tenecteplase increased excellent outcome at 90 days (43.6% vs 34.2%; RR 1.28; 95% CI 1.04 to 1.57; P=0.02) with a reported number needed to treat of 11.
  • Mechanistic signal: Reperfusion at 24 hours improved (37.7% vs 28.8%; RR 1.31; 95% CI 1.02 to 1.68; P=0.03) alongside higher early clinical response at 24 hours (11.4% vs 5.0%; RR 2.30; 95% CI 1.26 to 4.22; P=0.007).
  • Harm signal and consistency: Symptomatic intracranial haemorrhage increased (2.8% vs 0%; risk difference 2.85%; 95% CI 1.16% to 5.54%; P=0.004); prespecified subgroup analyses showed no evidence of treatment-effect heterogeneity (all interaction P>0.05), with posterior circulation RR 1.59 (95% CI 1.06 to 2.40) and >9–24 hour subgroup RR 1.44 (95% CI 1.01 to 2.05) as notable point estimates.

Internal Validity

  • Randomisation and allocation:
    • 1:1 randomisation via minimisation algorithm, balancing key prognostic variables (including occlusion location, age, baseline NIHSS, and centre), supporting baseline comparability.
    • Allocation occurred at randomisation before treatment; concealment details beyond central assignment were not reported in the main report.
  • Dropout or exclusions (post randomisation):
    • 570 patients randomised; 566 included in the primary analysis (4 excluded due to consent withdrawal, repeated randomisation, or inadvertent randomisation).
    • Primary efficacy outcome data were complete; no imputation was performed.
  • Performance/detection bias:
    • Open-label delivery introduces potential performance bias (e.g., intensity of monitoring, antithrombotic timing, blood pressure targets), particularly relevant when sICH is a major competing harm.
    • Detection bias mitigation was strong for the primary outcome: 90-day mRS was adjudicated by blinded assessors (central blinded raters using audio recordings for 552 patients; local blinded investigators for 6 patients).
  • Protocol adherence and contamination:
    • Safety population suggests near-complete delivery of allocated tenecteplase (281/282 received any trial treatment); standard medical treatment delivered to 284/284.
    • Crossover was uncommon: tenecteplase group 2 crossed over to standard medical treatment; standard medical treatment group 2 received thrombolysis (tenecteplase and alteplase).
  • Baseline characteristics:
    • Median age 68 years (IQR 59–75); 34.6% female; median baseline NIHSS 7 (IQR 4–10) in both groups.
    • Late-window enrolment was substantial: time last seen well to randomisation median 12.4 hours (IQR 8.7–16.8) vs 11.5 hours (IQR 8.3–16.6).
    • Imaging profile reflected small core volumes (median core 0 mL vs 1 mL) with moderate hypoperfusion volumes (median Tmax>6 s volume 34.8 mL vs 37.6 mL).
  • Heterogeneity:
    • Non-LVO encompasses aetiologically and anatomically heterogeneous disease (medium/distal occlusions and stenoses, anterior and posterior circulation, variable collateral status).
    • Subgroup analyses did not demonstrate statistically significant interaction (all interaction P>0.05), but confidence intervals in smaller strata were wide.
  • Timing:
    • Median time from symptom onset to randomisation and treatment was consistent with a late-window paradigm; door-to-needle time was 97.5 minutes (IQR 77.0–132.0) in the tenecteplase group.
    • Operational timing is clinically relevant because longer in-hospital delays could erode benefit, particularly when absolute effect sizes are modest.
  • Dose:
    • Tenecteplase dose (0.25 mg/kg; max 25 mg) aligns with doses widely studied and increasingly recommended for several early-window thrombolysis contexts.
    • Whether the same dose is optimal in a 4.5–24 hour, imaging-selected non-LVO cohort remains uncertain (no dose-finding component).
  • Separation of the variable of interest:
    • Biological separation was demonstrated by higher reperfusion at 24 hours (37.7% vs 28.8%; RR 1.31; 95% CI 1.02 to 1.68).
    • Clinical separation was supported by early response at 24 hours (11.4% vs 5.0%; RR 2.30; 95% CI 1.26 to 4.22).
    • Rescue endovascular thrombectomy occurred in 6/282 (2.1%) vs 1/284 (0.4%), unlikely to explain the overall treatment effect but relevant to pathway interpretation.
  • Outcome assessment:
    • Primary outcome (mRS) is clinically meaningful but partly subjective; blinded central adjudication and structured assessment reduce bias.
    • sICH definitions were prespecified and applied using multiple standard definitions (SITS-MOST, ECASS III, NINDS, IST-3).
  • Statistical rigour:
    • Power calculation was explicit and aligned to a clinically important absolute effect; actual enrolment (570 randomised) closely matched target.
    • Secondary outcomes were not adjusted for multiplicity; interpretation should emphasise the primary endpoint and coherence across outcomes rather than isolated secondary signals.

Conclusion on Internal Validity: Overall, internal validity appears moderate-to-strong given randomisation with balanced groups, complete primary outcome data, and blinded endpoint adjudication; the principal threats are open-label performance bias and the modified intention-to-treat exclusion of a small number of randomised participants.

External Validity

  • Population representativeness:
    • Patients were recruited across 48 centres in China; median NIHSS 7 suggests a mild-to-moderate stroke population rather than the severe end of the spectrum.
    • The cohort was highly selected by advanced imaging (CT perfusion mismatch with small core), limiting applicability to patients without access to rapid perfusion imaging or automated processing.
    • Prestroke disability was uncommon (patients with premorbid disability were a common exclusion at screening), limiting applicability to frailer populations and those with significant baseline dependence.
  • Applicability:
    • Systems with routine CT perfusion and tenecteplase availability can operationalise the approach; resource-limited settings (or those using non-perfusion selection) may not replicate eligibility, timing, or safety profile.
    • Many enrolled patients had medium/distal vessel lesions; evolving endovascular practice (MeVO/DVO thrombectomy) may alter the “standard medical treatment” comparator for subsets of patients.
    • Generalisability beyond an exclusively Chinese population is uncertain, particularly for haemorrhage risk, vascular risk profiles, and imaging characteristics across ethnic groups.

Conclusion on External Validity: External validity is moderate: findings are most applicable to imaging-capable centres managing late-window, non-LVO strokes without planned thrombectomy, but may not extrapolate to broader late-window populations, different ethnic groups, or settings without CT perfusion infrastructure.

Strengths & Limitations

  • Strengths:
    • Large, multicentre randomised trial with near-target enrolment and complete primary outcome data.
    • Blinded adjudication of primary outcome and independent core-lab imaging assessment support methodological robustness.
    • Coherence between primary functional outcome and mechanistic endpoints (reperfusion and early clinical response).
  • Limitations:
    • Open-label design raises the possibility of performance bias in co-interventions and monitoring intensity.
    • Highly selected population (CT perfusion mismatch; small core), limiting generalisability and potentially inflating apparent efficacy compared with unselected practice.
    • Heterogeneous non-LVO phenotypes and evolving endovascular indications (MeVO/DVO) complicate pathway interpretation.
    • Secondary outcomes not corrected for multiplicity; several “positive” signals should be interpreted as supportive rather than definitive.

Interpretation & Why It Matters

  • Clinical practice
    • In imaging-selected late-window non-LVO stroke without planned thrombectomy, tenecteplase increased the probability of excellent outcome, but introduced a clinically meaningful symptomatic intracranial haemorrhage risk (2.8% absolute rate; 0% in controls).
    • The result supports considering late-window tenecteplase where advanced imaging confirms small core and salvageable tissue, with explicit shared decision-making around haemorrhage risk.
  • Trialists & methodologists
    • OPTION demonstrates that PROBE designs with blinded, centralised mRS adjudication can yield interpretable functional outcomes despite open-label delivery in hyperacute pathways.
    • Effect size estimates and safety signals provide a foundation for future trials comparing tenecteplase against alteplase or placebo in late-window non-LVO, and for refining perfusion thresholds (especially posterior circulation).
  • Systems of care
    • Because eligibility hinges on CT perfusion selection and timely workflow, implementation depends on imaging availability, automation, and minimising door-to-needle delays (median 97.5 minutes in OPTION).
    • Overlap with MeVO/DVO lesions implies that evolving thrombectomy evidence may change eligibility, comparators, and optimal reperfusion strategy.

Controversies & Subsequent Evidence

  • Positioning within the late-window thrombolysis evidence base:
    • Randomised-trial meta-analyses of thrombolysis beyond 4.5 hours support efficacy in selected patients but consistently highlight increased intracranial haemorrhage, framing OPTION’s benefit–harm trade-off as plausible rather than anomalous.3
    • TRACE-III (tenecteplase 4.5–24 hours in anterior circulation LVO without access to thrombectomy) and HOPE (alteplase 4.5–24 hours, largely proximal LVO) demonstrated benefit in late-window imaging-selected cohorts; OPTION extends late-window thrombolysis evidence specifically to non-LVO patients without planned thrombectomy.45
  • Tenecteplase vs alteplase debate (agent, dose, and generalisability):
    • Pre-OPTION guidance and evidence largely addressed tenecteplase as an alteplase alternative within 4.5 hours and/or in thrombectomy pathways; late-window non-LVO was not a firmly established indication, leaving uncertainty about external uptake and reimbursement decisions.2
    • Early-window meta-analyses comparing tenecteplase vs alteplase inform dose plausibility (0.25 mg/kg) but cannot directly resolve late-window non-LVO efficacy/safety, given different baseline risks and effect modifiers (core size, time-to-treatment, spontaneous recanalisation).6
  • Safety signal interpretation:
    • OPTION’s symptomatic intracranial haemorrhage excess (2.8% vs 0%) is clinically consequential and accentuates the need for strict imaging/clinical selection and haemorrhage-risk mitigation strategies.
    • A meta-analysis of tenecteplase in the 4.5–24 hour window provides broader context for late-window tenecteplase risk–benefit, though treatment effects may vary by occlusion phenotype and imaging criteria.7
  • Interaction with evolving medium/distal thrombectomy evidence:
    • OPTION enrolled patients with medium/distal occlusions and did not exclude dominant M2 occlusions, intersecting with populations studied in ESCAPE-MeVO and DISTAL; changing endovascular evidence may alter the “no planned thrombectomy” comparator for future practice and trials.89
  • Guideline implications (near-term):
    • Contemporary stroke guidelines emphasise imaging-based selection and increasingly delineate tenecteplase’s role; formal incorporation of late-window non-LVO tenecteplase will require guideline updates integrating OPTION alongside the broader late-window thrombolysis evidence.10
  • Key protocol/design considerations surfaced by OPTION:
    • Perfusion thresholds for core/penumbra in posterior circulation remain less validated than in anterior circulation, potentially affecting eligibility accuracy and effect estimates in posterior strokes.
    • On central imaging review, 21 patients had noncontrast CT hypodensity larger than the CT perfusion-defined core (numerically negative mismatch); symptomatic intracranial haemorrhage developed in 2 of these cases, highlighting the need to integrate noncontrast CT infarct signs with automated perfusion metrics in late-window thrombolysis decisions.

Summary

  • In imaging-selected non-LVO acute ischaemic stroke presenting 4.5–24 hours from time last seen well, tenecteplase increased excellent functional outcome (mRS 0–1) at 90 days (43.6% vs 34.2%; RR 1.28; 95% CI 1.04 to 1.57; P=0.02).
  • Mechanistic endpoints supported biological plausibility, with higher 24-hour reperfusion (37.7% vs 28.8%; RR 1.31; 95% CI 1.02 to 1.68; P=0.03) and greater early clinical response (11.4% vs 5.0%; RR 2.30; 95% CI 1.26 to 4.22; P=0.007).
  • Tenecteplase increased symptomatic intracranial haemorrhage (2.8% vs 0%; risk difference 2.85%; 95% CI 1.16% to 5.54%; P=0.004), with no statistically significant difference in mortality (5.0% vs 3.2%; RR 1.57; 95% CI 0.69 to 3.57; P=0.28).
  • Internal validity is supported by randomisation, complete primary outcome data, and blinded endpoint adjudication, but open-label delivery leaves potential for performance bias.
  • External validity is constrained by advanced imaging selection, a Chinese-only cohort, and evolving thrombectomy indications for medium/distal occlusions that may change clinical pathways.

Further Reading

Other Trials

Systematic Review & Meta Analysis

Observational Studies

Guidelines

Overall Takeaway

OPTION provides high-level evidence that, in a carefully selected late-window non-LVO population with CT perfusion mismatch and small core, intravenous tenecteplase improves the likelihood of excellent functional recovery compared with standard medical treatment. The clinical signal is accompanied by a clear symptomatic intracranial haemorrhage penalty, underscoring that late-window thrombolysis is a precision intervention requiring rigorous imaging selection, rapid delivery, and explicit risk–benefit framing in a landscape where MeVO/DVO thrombectomy evidence is rapidly evolving.

Overall Summary

  • Tenecteplase 0.25 mg/kg (max 25 mg) improved mRS 0–1 at 90 days in late-window, imaging-selected non-LVO stroke.
  • Benefit was accompanied by increased symptomatic intracranial haemorrhage (2.8% vs 0%).
  • Implementation depends on CT perfusion infrastructure, rapid workflow, and careful integration of noncontrast CT infarct signs with automated perfusion outputs.

Bibliography

  • 1Ma G, Mo R, Zuo Y, et al. A multicenter, prospective, randomized, open-label, blinded endpoint trial of intravenous thrombolysis with tenecteplase for acute non-large-vessel occlusion in extended time window (OPTION): Rationale and design. J Transl Int Med. 2025;13(5):472-479. Link
  • 2Alamowitch S, Turc G, Palaiodimou L, et al. European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke. Eur Stroke J. 2023;8(1):8-54. Link
  • 3Günkan A, Ferreira MY, Vilardo M, et al. Thrombolysis for ischemic stroke beyond the 4.5-hour window: a meta-analysis of randomized clinical trials. Stroke. 2025;56(3):580-590. Link
  • 4Xiong Y, Campbell BCV, Schwamm LH, et al; TRACE-III Investigators. Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy. N Engl J Med. 2024;391(3):203-212. Link
  • 5Zhou Y, He Y, Campbell BCV, et al; HOPE investigators. Alteplase for acute ischemic stroke at 4.5 to 24 hours: the HOPE randomized clinical trial. JAMA. 2025;334(9):788-797. Link
  • 6Palaiodimou L, Katsanos AH, Turc G, et al. Tenecteplase vs alteplase in acute ischemic stroke within 4.5 hours: a systematic review and meta-analysis of randomized trials. Neurology. 2024;103(9):e209903. Link
  • 7Wang Z, Li J, Wang X, Yuan B, Li J, Ma Q. Tenecteplase for acute ischemic stroke at 4.5 to 24 hours: a meta-analysis of randomized controlled trials. Stroke. 2026;57(1):50-62. Link
  • 8Goyal M, Ospel JM, Ganesh A, et al; ESCAPE-MeVO Investigators. Endovascular treatment of stroke due to medium-vessel occlusion. N Engl J Med. 2025;392(14):1385-1395. Link
  • 9Psychogios M, Brehm A, Ribo M, et al; DISTAL Investigators. Endovascular treatment for stroke due to occlusion of medium or distal vessels. N Engl J Med. 2025;392(14):1374-1384. Link
  • 10Prabhakaran S, Ruff I, Bernstein RA, et al. 2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association. Stroke. Published online January 26, 2026. Link