Key Points
Question
Does intravenous tenecteplase administered 4.5 to 24 hours after onset improve clinical outcomes among patients with non–large vessel occlusion acute ischemic stroke and salvageable brain tissue?
Findings
This randomized clinical trial that included 566 patients found that 43.6% of patients receiving tenecteplase and 34.2% of patients receiving standard medical treatment achieved an excellent functional outcome (measured by a modified Rankin Scale score of 0 or 1) at 90 days. This resulted in a risk ratio of 1.28, a difference that was statistically significant.
Meaning
Findings from this study support intravenous tenecteplase given 4.5 to 24 hours after stroke onset for patients with acute non–large vessel occlusion and salvageable brain tissue.
Abstract
Importance
The efficacy and safety of intravenous tenecteplase in non–large vessel occlusion acute ischemic stroke beyond 4.5 hours after symptom onset remain uncertain.
Objective
To assess the efficacy and safety of intravenous tenecteplase administered 4.5 to 24 hours after stroke onset in patients with non–large vessel occlusion and salvageable brain tissue.
Design, Setting, and Participants
This randomized, open-label, blinded end-point clinical trial was conducted at 48 centers in China. A total of 566 patients with non–large vessel occlusion stroke and evidence of potentially salvageable tissue determined on perfusion imaging presenting within 4.5 to 24 hours of the time last seen well were recruited between June 2, 2023, and August 4, 2025 (final follow-up, October 28, 2025).
Interventions
Patients were randomly assigned 1:1 using a minimization algorithm to receive intravenous tenecteplase (0.25 mg/kg; maximum dose, 25 mg; n = 282) or standard medical treatment (n = 284).
Main Outcomes and Measures
The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin Scale at 90 days. Safety outcomes included symptomatic intracranial hemorrhage within 36 hours and mortality within 90 days.
Results
Among the 570 patients randomized, 566 were included in the primary analysis (median age, 68 [IQR, 59-75] years; 196 female [34.6%]). An excellent functional outcome was observed in 123 of 282 patients (43.6%) in the tenecteplase group and 97 of 284 (34.2%) in the control group (risk ratio, 1.28 [95% CI, 1.04-1.57]; P = .02). The incidence of symptomatic intracranial hemorrhage at 2.8% was higher with tenecteplase than with standard medical treatment at 0% (risk difference, 2.85% [95% CI, 1.16%-5.54%]; P = .004), and the mortality at 90 days was 5.0% and 3.2%, respectively (risk ratio, 1.57 [95% CI, 0.69-3.57]; P = .28).
Conclusions and Relevance
Among patients with non–large vessel occlusion acute ischemic stroke and salvageable brain tissue, intravenous tenecteplase administered 4.5 to 24 hours after onset resulted in a greater likelihood of an excellent functional outcome at 90 days than standard care but had an increased risk of symptomatic intracranial hemorrhage.
Trial Registration
ClinicalTrials.gov Identifier: NCT05752916
This trial tests whether intravenous tenecteplase thrombolysis initiated between 4.5 and 24 hours after symptom onset benefits patients with acute ischemic stroke due to non–large vessel occlusion with evidence of salvageable brain tissue.
Introduction
Acute ischemic stroke caused by an occlusion of the internal carotid artery, proximal middle cerebral artery, vertebral artery, or basilar artery (collectively termed large vessel occlusions) is associated with poor functional outcomes and high mortality in the absence of reperfusion.1,2 Endovascular thrombectomy within 24 hours of symptom onset is effective for acute large vessel occlusion stroke in selected patients.1,2,3,4 When thrombectomy is unavailable or not planned, intravenous thrombolysis is effective within 4.5 hours of symptom onset (albeit conferring lesser benefit) and potentially when administered between 4.5 and 24 hours.5,6
Non–large vessel occlusion acute ischemic stroke is more common than stroke due to large vessel occlusion. Such stroke generally arises from medium vessel occlusion, small vessel occlusion (including deep and long pial penetrator vessels), hemodynamic watershed ischemia, and unusual or disseminated conditions.7 Endovascular thrombectomy has generally not been shown to benefit these patients,8,9 and intravenous thrombolysis within 4.5 hours is the standard of care for eligible patients.10,11 Evidence remains scarce from direct comparisons of intravenous thrombolysis vs standard medical treatment for acute ischemic stroke due to non–large vessel occlusion beyond 4.5 hours after onset.
Tenecteplase, a modified human tissue plasminogen activator, has been shown to be noninferior to—and potentially superior to—alteplase within 4.5 hours after stroke onset.12 Therefore, the Tenecteplase for Acute Non–Large Vessel Occlusion in the Extended Time Window (OPTION) trial was designed to test the hypothesis that intravenous tenecteplase thrombolysis initiated between 4.5 and 24 hours after symptom onset would provide a benefit in patients with acute ischemic stroke due to non–large vessel occlusion with salvageable brain tissue.
Methods
Trial Design and Oversight
We conducted a multicenter, randomized, open-label trial with blinded outcome assessment at 48 Chinese centers. The trial was approved by the institutional review board at Xuanwu Hospital Capital Medical University and all participating centers. The study protocol was published and is available in Supplement 1, and the statistical analysis plan in Supplement 2.13 Written informed consent was obtained from all patients or their legal representatives before randomization.
The trial was designed, conducted, and overseen by the steering committee, with safety monitored by an independent data and safety monitoring board (DSMB). It was conducted in accordance with the principles of the Declaration of Helsinki14 and the International Council for Harmonisation guidelines for Good Clinical Practice. This article followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Participants
Patients were eligible for inclusion if they were 18 years or older; had a prestroke score of 0 or 1 on the modified Rankin Scale (mRS; scores range from 0 [no neurological deficit] to 6 [death]); had an acute ischemic stroke and could receive tenecteplase 4.5 to 24 hours after the time they were last seen well; had a baseline National Institutes of Health Stroke Scale (NIHSS) score of 6 to 25 (scores range, 0-42, with higher scores indicating more severe neurological deficits) or a score of 4 or 5 with a disabling deficit (eg, hemianopia, aphasia, and loss of hand function). The presence of potentially salvageable tissue on penumbral imaging (by automated computed tomographic [CT] perfusion imaging, using CTPdoc software, version 6.11; Shukun Technology Co; a research version of CTPdoc software was provided to the trial sites by Shukun Technology15) was a prerequisite for enrollment (Figure 1 and Table 1). Patients were excluded if there was a large vessel occlusion defined as occlusion of the internal carotid artery, the M1 segment of the middle cerebral artery, or the vertebrobasilar artery, regardless of planned thrombectomy.
Figure 1. Flow of Patients in the OPTION Trial.
aTwo patients in the standard medical treatment group did not receive treatment as randomized, with one receiving tenecteplase and the other alteplase.
bFour patients were excluded due to withdrawal of consent, repeated randomization, and inadvertent randomization.
cFour patients were excluded due to protocol violations, including 2 who had crossed over to the standard medical treatment group, 1 with platelet count lower than 100 × 109/L, and 1 with a serum creatinine level higher than 220 μmol/L (2.26 mg/dL).
dNine patients were excluded due to protocol violations, including 2 who did not receive standard medical treatment, 1 diagnosed with stroke mimic, 3 with large vessel occlusion, 1 with platelet count lower than 100 × 109/L, and 1 who lacked a disabling neurological deficit.
CTP indicates computed tomographic perfusion; OPTION, Tenecteplase for Acute Non–Large Vessel Occlusion in the Extended Time Window.
Table 1. Characteristics of the Patients at Baseline.
| Characteristic | Tenecteplase (n = 282) | Standard medical treatment (n = 284) |
|---|---|---|
| Age, median (IQR), y | 69 (59-75) | 67 (59-74) |
| Sex, No. (%) | ||
| Male | 176 (62.4) | 194 (68.3) |
| Female | 106 (37.6) | 90 (31.7) |
| Medical history, No. (%) | ||
| Hypertension | 211 (74.8) | 200 (70.4) |
| Diabetes | 73 (25.9) | 73 (25.7) |
| Atrial fibrillation | 36 (12.8) | 38 (13.4) |
| Hyperlipidemia | 21 (7.4) | 23 (8.1) |
| NIHSS score at randomization, median (IQR)a | 7 (5-9) | 6 (5-9) |
| Systolic blood pressure, median (IQR), mm Hg | 153 (137-165) | 153 (140-166.5) |
| Serum glucose, median (IQR), mg/dL | 124.0 (104.6-155.5) | 122.9 (101.0-167.0) |
| Modified Rankin Scale score before stroke, No. (%)b | ||
| 0 | 265 (94.0) | 255 (89.8) |
| 1 | 17 (6.0) | 29 (10.2) |
| Circulation with stento-occlusion, No. (%)c | ||
| Anterior circulation | 219 (77.7) | 218 (76.8) |
| Posterior circulation | 63 (22.3) | 65 (22.9) |
| Unknown | 0 | 1 (0.4) |
| Stroke etiology, No (%) | ||
| Large-artery atherosclerosis | 101 (35.8) | 108 (38.0) |
| Cardioembolism | 67 (23.8) | 66 (23.2) |
| Undetermined or other cause | 114 (40.4) | 110 (38.7) |
| Qualifying artery, No. (%)d | ||
| Occlusion | ||
| M2 segment of middle cerebral artery | 86 (30.5) | 93 (32.8) |
| Anterior cerebral artery | 48 (17.0) | 38 (13.4) |
| Posterior cerebral artery | 37 (13.1) | 41 (14.4) |
| M3-M4 segment of middle cerebral artery | 24 (8.5) | 19 (6.7) |
| Other | 18 (6.4) | 11 (3.9) |
| M1 segment of middle cerebral artery | 0 | 3 (1.1) |
| Stenosis | 65 (23.0) | 67 (23.6) |
| No occlusion or stenosis | 4 (1.4) | 12 (4.2) |
| Volume of irreversibly injured ischemic core at initial imaging, median (IQR), mLe | 0 (0-3.7) | 1 (0-4.2) |
| Volume of perfusion lesion at initial imaging, median (IQR), mLf | 34.8 (20.6-58.2) | 37.6 (20.1-67.3) |
| Category of onset of stroke, No. (%) | ||
| Known onset time | 190 (67.4) | 190 (66.9) |
| Stroke on awakening | 91 (32.3) | 90 (31.7) |
| Unwitnessed onset | 1 (0.4) | 4 (1.4) |
| Onset to randomization time, median (IQR), h | 12.4 (8.7-16.8) | 11.5 (8.3-16.6) |
SI conversion factor: To convert glucose from mg/mL to mmol/L, multiply by 0.0555.
Scores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating a more severe neurological deficit.
Scores on the modified Rankin Scale range from 0 to 6, with higher scores indicating more severe disability.
One patient whose posterior circulation stroke was initially described by the investigators at the trial site was later determined to be a stroke mimic.
Other types included occlusion of the anterior or posterior inferior cerebellar artery, and superior cerebellar artery. Stenosis locations were the internal carotid artery, the M1 segment of the middle cerebral artery, the M2 or M3 segment of the middle cerebral artery, the anterior cerebellar artery, the posterior cerebellar artery, and the basilar artery (exact percentages are shown in eTable 2 in Supplement 3). Three patients were identified as having an M1 occlusion by the independent core laboratory.
The volume of irreversibly injured ischemic core was calculated with the use of a threshold for relative cerebral blood flow of less than 30% of that in normal brain tissue as measured with the use of computed tomographic perfusion imaging.
To define the critically hypoperfused tissue, volume of perfusion lesion was calculated as the volume of tissue in which there had been delayed arrival of an injected tracer agent exceeding 6 seconds.
The ischemic core was defined as a region of relative cerebral blood flow less than 30% of that in normal tissue, as measured by CT perfusion imaging.16 The critically hypoperfused tissue was defined by a delayed arrival of the injected tracer agent, as a time to maximum of the residue function exceeding 6 seconds.17 Patients were required to have an ischemic core volume of less than 50 mL, a ratio of the volume of critically hypoperfused tissue to the ischemic core volume of at least 1.2, and a difference in volume between the critically hypoperfused tissue and the ischemic core of at least 10 mL. These criteria indicate potentially salvageable brain tissue by reflecting a mismatch between a small ischemic core and a larger region of critically hypoperfused but viable brain tissue. Additional details regarding inclusion and exclusion criteria are provided in eMethods 1 in Supplement 3.
Randomization
Eligible patients were randomly assigned in a 1:1 ratio via a centralized web-based randomization system to intravenous tenecteplase (CSPC Recomgen Pharmaceutical Co, Ltd) or standard medical treatment. A stochastic minimization algorithm balanced the 2 groups by vessel occlusion location (anterior or posterior circulation), age (<65 or ≥65 years), baseline NIHSS (<16 or ≥16), and center. Treatment assignment was open label. However, the assessment of trial outcomes was performed by qualified physicians who were blinded to the treatment assignments.
Interventions
The tenecteplase group received a bolus of intravenous tenecteplase (0.25 mg/kg; maximum dose, 25 mg) over 5 to 10 seconds immediately after randomization, whereas the control group received antiplatelet therapy. All other treatments followed the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke (2018 updated to 2023 during the trial).18,19 Although patients with planned endovascular thrombectomy during screening were excluded, rescue thrombectomy was permitted for clinical deterioration per local clinician judgment.
Outcomes
The primary efficacy outcome was an excellent functional outcome, defined as mRS score of 0 or 1 at 90 days. The mRS score at 90 days was obtained via structured telephone interview by an assessor who was unaware of the treatment assignment. An independent neurologist, who was unaware of group allocation, reviewed the audio recordings.20 If audio recordings were unavailable, outcomes were assessed in person by local certified investigators, who were also unaware of the treatment assignment.
Secondary efficacy outcomes were the ordinal distribution of the mRS scores at 90 days, functional independence (mRS score, 0-2) at 90 days, reperfusion at 24 hours (defined as >90% reduction in the volume of the lesion in which there had been a delayed arrival of an injected tracer agent of >6 seconds), infarct volume on 24 hours’ follow-up imaging, early clinical response at 24 hours (defined as a reduction from baseline of ≥8 points on the NIHSS or achieving an NIHSS score ≤1), the change from baseline in NIHSS score at 7 days (or at discharge if earlier), and health-related quality of life at 90 days, assessed with the EuroQol Group 5-Dimension 5-Level questionnaire (range, −0.391 to 1.00, with higher scores indicating better quality of life). Baseline and follow-up images were independently adjudicated at an imaging core laboratory (eMethods 2 in Supplement 3).
Safety outcomes were symptomatic intracranial hemorrhage within 36 hours after randomization, as defined by the Heidelberg Bleeding Classification (an increase in the NIHSS score of ≥4 points or an increase in a NIHSS subcategory of ≥2 points with any intracranial hemorrhage on imaging),21 moderate or severe systemic bleeding within 90 days (as defined by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO] trial),22 and all-cause mortality within 90 days. Adverse events were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. In post hoc analyses, intracranial hemorrhage was assessed based on the Heidelberg Bleeding Classification, while symptomatic intracranial hemorrhage was defined per the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), the European Cooperative Acute Stroke Study III (ECASS III), the National Institute of Neurological Disorders and Stroke (NINDS), and the Third International Stroke Trial (IST-3) definitions (eMethods 2 in Supplement 3).
Sample Size Calculation
The sample size calculation was based on the occlusion-site subgroup data from a previous meta-analysis,23 assuming a 12% absolute difference in the rate of excellent functional outcome (50.0% in the tenecteplase group and 38.0% in the standard medical treatment group). We calculated that a total sample size of 568 patients would provide 80% power to detect the target difference at a 2-sided α of .049 (after adjustment for 1 interim efficacy analysis when 50% of the target sample size, 284 patients, had reached the 90-day outcome), and a 5% dropout rate. Due to rapid recruitment, a substantial number of additional patients were enrolled during the time it took for the 284th patient to reach the 90-day assessment. Consequently, the original interim analysis plan was deemed unfeasible following a review by the DSMB. No formal efficacy assessment was conducted and no α was spent.
Statistical Analysis
The primary analysis was performed in a population that included all patients who had undergone randomization (no consent withdrawal), analyzed according to randomization group. The efficacy analyses were repeated in the per-protocol population, which included all patients who received the assigned treatment and had no major protocol violations. The safety analyses were performed in the safety population, which consisted of all patients who had undergone randomization and had received any amount of trial treatment, classified according to the treatment they actually received.
The primary efficacy outcome was analyzed by a modified Poisson regression model with robust error estimation to estimate the risk ratio (RR) and 95% CI as a measurement of treatment effect. The crude analysis served as the primary analysis. The post hoc risk difference (RD) was also calculated from analysis of the dichotomized outcomes using a generalized linear model. The number needed to treat for the primary outcome was derived by taking the inverse of the absolute risk reduction. No imputation for missing data was performed because the data for the primary efficacy analysis were complete. The secondary outcome of mRS score at 90 days was analyzed by ordinal logistic regression following confirmation (score test) that the proportional odds assumption was met. Nonnormal continuous secondary efficacy outcomes were analyzed with the win-ratio approach. We also performed prespecified secondary analyses adjusted for 4 prespecified covariates (age, baseline NIHSS score, anterior vs posterior circulation as the location of the stento-occlusion, and time from symptom onset to randomization; eMethods 3 in Supplement 3).
We performed subgroup analysis of the primary outcome by assessing the test for interaction with 7 prespecified subgroup variables including age, time between stroke onset and randomization, NIHSS score, anterior vs posterior circulation as the location of the stento-occlusion, qualifying artery, baseline serum glucose, and baseline systolic blood pressure. A post hoc subgroup variable was stroke etiology. A sensitivity analysis of the primary outcome was conducted to assess the center effect on treatment effect by performing a generalized estimating equation model with center as a cluster effect. In addition to the prespecified analyses, we conducted 2 main post hoc analyses. First, to evaluate the impact of medium or distal vessel occlusion on the primary outcome, we analyzed patients who met the criteria for the Endovascular Treatment to Improve Outcomes for Medium Vessel Occlusions (ESCAPE-MeVO)8 or Endovascular Therapy Plus Best Medical Treatment (BMT) versus BMT Alone for Medium Vessel Occlusion Stroke (DISTAL)9 trials. Second, to remove the effect of rescue endovascular treatment, the primary outcome was multiply imputed based on baseline characteristics for those who received rescue endovascular intervention (eMethods 3 in Supplement 3).
Analyses were performed with a 2-sided α level of .05. Secondary analyses and subgroup analyses were considered exploratory and performed without adjustment for multiplicity. All analyses were performed with SAS software, version 9.4 (SAS Institute Inc), and R software, version 4.1.1 (R Foundation).
Results
Patient Characteristics
From June 2, 2023, to August 4, 2025, a total of 570 patients underwent randomization (eFigure 2 in Supplement 3). Four patients were excluded from all the analyses owing to withdrawal of consent, repeated randomization, and inadvertent randomization, leaving 282 patients assigned to the tenecteplase group and 284 patients to the standard medical treatment group (Figure 1). The enrolled patients were generally representative of the expected study population (eTable 1 in Supplement 3). No patients were lost to follow-up. Two patients in the tenecteplase group crossed over to receive standard medical treatment, whereas 2 patients in the standard medical treatment group received tenecteplase and alteplase, respectively. Rescue thrombectomy was performed in 6 patients in the tenecteplase group and 1 patient in the standard medical treatment group, all of whom had mild symptoms at randomization and experienced neurological deterioration and reassessment before thrombectomy.
Baseline demographic and clinical characteristics were balanced between the 2 groups (Table 1; eTable 2 in Supplement 3). The median age was 68 (IQR, 59-75) years, and 196 of the 566 patients (34.6%) were female. The median NIHSS score at randomization was 7 (IQR, 5-9), and the median interval between the time that the patient was last seen well and randomization was 12.0 (IQR, 8.6-16.7) hours. Salvageable brain tissue was present in all patients on CT perfusion imaging. There were 21 patients whose CT hypodensities were larger than the core defined by CT perfusion criteria and were subsequently identified as having a mismatch inconsistency, but they were retained in the analyses. The most common arterial lesions on baseline CT angiography were occlusions of the M2-M4 segments of the middle cerebral artery (39.2% [n = 222]), the anterior cerebral artery (15.2% [n = 86]), or the posterior cerebral artery (13.8% [n = 78]) and cerebral artery stenosis without occlusion (23.3% [n = 132]). Among cases of cerebral artery stenosis without occlusion, the M1-M3 segments of the middle cerebral artery (16.1% [n = 91]) were the most common sites.
Primary Efficacy Outcome
An excellent functional outcome (mRS score, 0 or 1) at 90 days was observed in 123 of 282 patients (43.6%) in the tenecteplase group and in 97 of 284 patients (34.2%) in the standard medical treatment group, yielding an unadjusted RD of 9.46% (95% CI, 1.47%-17.46%) and an unadjusted RR of 1.28 (95% CI, 1.04-1.57; P = .02; Table 2 and Figure 2). The number needed to treat to achieve an excellent functional outcome was 11. The analyses of the primary outcome adjusted for prespecified or post hoc covariates were consistent with the findings in the primary analysis (Table 2; eTable 3 in Supplement 3). The per-protocol analyses yielded similar results (eFigure 3 and eTable 4 in Supplement 3). The primary outcome was assessed by a blinded central rater using audio recordings from 552 patients, including 15 patients who died after discharge and by local blinded investigators for 6 patients. Eight patients died in the hospital.
Table 2. Efficacy and Safety Outcomes.
| Outcome | Tenecteplase (n = 282) | Standard medical treatment (n = 284) | Unadjusted | Adjusteda | |||
|---|---|---|---|---|---|---|---|
| Risk difference (95% CI)b | Treatment difference (95% CI) | P value | Treatment difference (95% CI) | P value | |||
| Primary efficacy outcome | |||||||
| mRS score 0-1 at 90 d, No. (%)c | 123 (43.6) | 97 (34.2) | 9.46 (1.47 to 17.46) | RR, 1.28 (1.04 to 1.57) | .02 | RR, 1.32 (1.08 to 1.61) | .007 |
| Secondary efficacy outcomes | |||||||
| mRS score at 90 d, median (IQR)c | 2 (0 to 3) | 2 (1 to 3) | Common OR, 1.39 (1.04 to 1.86)d | .03 | Common OR, 1.50 (1.12 to 2.01) | .007 | |
| mRS score 0-2 at 90 d, No. (%)c | 177 (62.8) | 157 (55.3) | 7.48 (−0.59 to 15.56) | RR, 1.14 (0.99 to 1.30) | .07 | RR, 1.16 (1.02 to 1.32) | .03 |
| Reperfusion at 24 h, No./total (%)e | 95/252 (37.7) | 76/264 (28.8) | 8.91 (0.81 to 17.01) | RR, 1.31 (1.02 to 1.68) | .03 | RR, 1.31 (1.03 to 1.68) | .03 |
| Infarct volume at 24 h, median (IQR), mLf | 5.6 (1.2 to 19.8) | 6.2 (1.2 to 19.9) | WR, 1.02 (0.83 to 1.24) | .87 | WR, 1.01 (0.83 to 1.24) | .89 | |
| Early clinical response at 24 h, No./total (%)g | 32/280 (11.4) | 14/282 (5.0) | 6.46 (1.96 to 10.97) | RR, 2.30 (1.26 to 4.22) | .007 | RR, 2.37 (1.30 to 4.34) | .005 |
| Change in the NIHSS score at 7 d, median (IQR)h | −3 (−5 to −1) | −2 (−4 to −1) | WR, 1.16 (0.94 to 1.43) | .16 | WR, 1.15 (0.93 to 1.42) | .19 | |
| EQ-5D-5L score at 90 d, median (IQR)i | 0.9 (0.6 to 1.0) | 0.9 (0.6 to 1.0) | WR, 1.02 (0.82 to 1.27) | .83 | WR, 1.08 (0.86 to 1.34) | .52 | |
| Safety outcomes j | |||||||
| Symptomatic intracranial hemorrhage within 36 h, No./total (%)k | 8/281 (2.8) | 0 | 2.85 (1.16 to 5.54)l | .004l | |||
| Moderate or severe systemic bleeding within 90 d, No./total (%)m | 2/281 (0.7) | 2/284 (0.7) | 0.01 (−1.38 to 1.39) | RR, 1.01 (0.14 to 7.12) | .99 | RR,1.02 (0.14 to 7.45) | .98 |
| Death within 90 d, No./total (%) | 14/281 (5.0) | 9/284 (3.2) | 1.81 (−1.45 to 5.07) | RR, 1.57 (0.69 to 3.57) | .28 | RR, 1.48 (0.65 to 3.36) | .35 |
Abbreviations: EQ-5D-5L, EuroQol Group 5-Dimension 5-Level self-report questionnaire; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; RR, risk ratio; WR, win ratio.
Adjusted for age, baseline NIHSS score, circulation with stento-occlusion, and time from symptom onset to randomization. The win ratio was adjusted using the inverse probability of treatment weighting method.
Post hoc analyses were performed to calculate the risk difference using the generalized linear model.
The mRS scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death.
The proportional odds assumption was met (P = .35 by the score test).
Reperfusion was defined as a reduction of greater than 90% in the volume of the lesion in which there had been a delayed arrival of an injected tracer agent exceeding 6 seconds.
The infarct volume was measured on computed tomographic (CT) imaging 24 hours after randomization. Forty-four patients (16 in the tenecteplase group and 28 in the standard medical treatment group) could not be assessed because of severe intracranial hemorrhage or death (3 patients), follow-up CT scan quality (10 patients), or CT was not performed for other reasons (31 patients).
Early clinical response at 24 hours was defined as an improvement (reduction) from baseline of at least 8 points on the NIHSS or an NIHSS score of 1 or lower.
Data were missing for 2 patients (for 1 patient in tenecteplase group and for 1 in the standard medical treatment group).
The EQ-5D-5L is a standard instrument for the measurement of health status. Scores range from −0.391 to 1.00, with higher scores indicating better quality of life and death coded as 0.
The safety population included all patients who underwent randomization, and received any amount of tenecteplase or standard medical treatment.
Symptomatic intracranial hemorrhage was defined by Heidelberg Bleeding Classification. RR values were not calculated due to a 0 denominator in the control group.
Calculated using Fisher exact test.
Moderate or severe systemic bleeding was defined according to the criteria established in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial. Symptomatic intracranial hemorrhage was not included in this category.
Figure 2. Horizontal Stacked Bar Chart Depicting Scores on the Modified Rankin Scale at 90 Days.
Scores on the modified Rankin Scale (mRS) range from 0 (no symptoms) to 6 (death). A score of 1 indicates no clinically meaningful disability (patients are able to perform usual work, leisure, and school activities); 2, slight disability (patients are able to look after their own affairs without assistance but are unable to carry out all previous activities); 3, moderate disability (patients require some help but are able to walk unassisted); 4, moderately severe disability (unable to attend to bodily needs without assistance or unable to walk unassisted); and 5, severe disability (patients are bedridden and require constant care). Percentages may not total 100 because of rounding.
Secondary Efficacy Outcomes
The results for secondary outcomes are shown in Table 2. The common odds ratio for the ordinal distribution of mRS scores at 90 days was 1.39 (95% CI, 1.04-1.86; P = .03) in favor of the tenecteplase group. Functional independence (mRS score, 0-2) at 90 days occurred in 177 patients (62.8%) in the tenecteplase group and 157 (55.3%) in the standard medical treatment group (unadjusted RR, 1.14 [95% CI, 0.99-1.30]; P = .07). Reperfusion at 24 hours was achieved in 95 of 252 (37.7%) of the tenecteplase group vs 76 of 264 (28.8%) of the standard treatment group (unadjusted RR, 1.31 [95% CI, 1.02-1.68]; P = .03).
Subgroup, Sensitivity, and Post Hoc Analyses
The subgroup analyses of the primary outcome are shown in Figure 3. There was no evidence of treatment effect heterogeneity across all 7 baseline features evaluated. The primary findings were supported by the sensitivity analysis for center effects and the post hoc analysis that demonstrated absence of endovascular treatment effect (eTable 5 in Supplement 3). For the post hoc analysis among patients with medium or distal vessel occlusion, the primary outcome occurred in 42.6% of those in the tenecteplase group compared with 33.0% of those in the standard medical treatment group (unadjusted RR, 1.29 [95% CI, 0.995-1.67]; P = .054; eTable 6 in Supplement 3).
Figure 3. Dot Plot Subgroup Analysis of Modified Rankin Scale Score of 0 or 1 at 90 Days.
aThe widths of the CIs have not been adjusted for multiplicity and cannot be used to infer treatment effects.
bThe National Institutes of Health Stroke Scale (NIHSS) score is a measure of the severity of stroke. NIHSS scores range from 0 to 42, with higher scores indicating more severe neurological deficits.
cThe circulation with stento-occlusion and qualifying artery were assessed at an independent core laboratory.
dSubgroup analysis according to stroke etiology was unplanned.
mRS indicates modified Rankin Scale. To convert glucose from mg/dL to mmol/L, multiply by 0.0555.
Adverse Events
Symptomatic intracranial hemorrhage within 36 hours after treatment occurred in 8 patients (2.8%) in the tenecteplase group vs none in the standard medical treatment group (unadjusted RD, 2.85% [95% CI, 1.16% -5.54%]; P = .004; Table 2; eTables 7, 8, and 9 in Supplement 3 show additional data by intracranial hemorrhage type and using various definitions). Of note, symptomatic intracranial hemorrhage developed in 2 of the 21 patients with CT hypodensities larger than the core defined by CT perfusion scan with post hoc mismatch inconsistency. The incidence of moderate or severe systemic bleeding within 90 days was 0.7% in both groups (unadjusted RR, 1.01 [95% CI, 0.14-7.12]; P = .99; Table 2). Mortality within 90 days was 5.0% (14 of 281) with tenecteplase and 3.2% (9 of 284) with standard medical care (unadjusted RR, 1.57 [95% CI, 0.69-3.57]; P = .28; Table 2; eFigure 4 and eTable 10 in Supplement 3). The results for other adverse events and serious adverse events are provided in eTables 11 and 12 in Supplement 3.
Discussion
Among patients with acute ischemic stroke who had a favorable perfusion-imaging profile detected by automated perfusion imaging and non–large vessel occlusion, treatment with tenecteplase between 4.5 and 24 hours after stroke onset led to a higher proportion of an excellent functional outcome at 90 days than standard medical care. For 1 additional patient to have an excellent functional outcome, the number needed to treat was 11. However, tenecteplase was associated with a higher rate of symptomatic intracranial hemorrhage.
Recent meta-analyses have demonstrated thrombolysis efficacy beyond the 4.5-hour window, advancing understanding of extended thrombolysis.24,25 The Teneteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) trial demonstrated that intravenous tenecteplase administered between 4.5 and 24 hours was beneficial for patients with anterior circulation large vessel occlusion who did not have access to endovascular thrombectomy.26 Also, 81.4% of patients in the TRACE-III trial had intracranial internal carotid artery or the first segment of the middle cerebral artery occlusions. The Treatment With Intravenous Alteplase in Ischemic Stroke Patients With Onset Time Between 4.5 and 24 Hours (HOPE) trial, evaluating intravenous alteplase administered 4.5 to 24 hours in patients with salvageable brain tissue of whom 63% presented with proximal large vessel occlusion, showed improved nondisabled outcomes.27 Unlike these trials, the current study focused on patients with non–large vessel occlusion and excluded candidates for endovascular thrombectomy, providing evidence for tenecteplase use beyond 4.5 hours in this population.
The benefit of the primary outcome in the OPTION trial was corroborated by higher early reperfusion and neurological improvement rates. In line with the Chinese Acute Tissue-Based Imaging Selection for Lysis in Stroke–Tenecteplase II (CHABLIS-T II)28 trial, the current study demonstrated that intravenous tenecteplase at 4.5 to 24 hours increased reperfusion, with comparable reperfusion rates (37.7% reported in OPTION, 33.3% reported in CHABLIS-T II). Despite that, the reperfusion rate was notably lower than that reported in an earlier phase 2b study (79.3% reported in the Tenecteplase versus Alteplase for Acute Ischaemic Stroke [TAAIS] trial).29 Possible explanations include differences in the treatment time window and variations in imaging modality and in the definition for reperfusion assessment.
The OPTION trial used a perfusion-imaging selection strategy analogous to prior late-window thrombolysis trials but excluded patients with acute large vessel occlusion.27,30 Based on this imaging selection approach, the trial enrolled a population in which 68.2% (386 of 566 patients) of patients had medium or distal vessel occlusion, as defined separately in the ESCAPE-MeVO8 and DISTAL9 trials. A post hoc analysis of this subgroup showed rates of excellent functional outcomes at 90 days of 42.6% for the tenecteplase group vs 33.0% for the standard medical treatment group, a 9.6% difference that approached but did not formally achieve statistical significance. Notably, the Tenecteplase vs Alteplase for Stroke Thrombolysis Evaluation (TASTE)31 trial enrolled a nearly identical proportion of patients with non–large vessel occlusion and compared the efficacy and safety of intravenous tenecteplase vs alteplase. In the intention-to-treat population, patients treated with tenecteplase in the TASTE trial had a higher rate of excellent functional outcomes than those in the OPTION trial (57% vs 43.6%), a difference likely attributable to a shorter median onset-to-thrombolysis time (2.5 hours vs 12.8 hours).
The incidence of symptomatic intracranial hemorrhage was higher with tenecteplase regardless of the definition used to denote this complication. This finding is consistent with data from the pooled analysis of extended time window thrombolysis.24,25
Limitations
The trial has several limitations. First, it used an open-label design, although all outcomes were adjudicated by assessors blinded to treatment assignment. Second, some patients were not enrolled in the trial and instead treated with endovascular thrombectomy, but there were only 11 such individuals. Third, the trial did not exclude patients with occlusions of the dominant M2 segment of middle cerebral artery—a subgroup for which thrombectomy has shown a trend toward benefit in prior trials.1 Fourth, the optimal perfusion threshold for ischemic core and penumbra volume in posterior circulation strokes are not well established, which may have resulted in the inclusion of patients with inaccurate penumbral assessment; however, these patients showed homogeneous benefit with patients with anterior circulation. Fifth, on central imaging review, we identified 21 patients whose CT hypodensities were larger than the core defined by CT perfusion criteria and led to the numerically negative mismatch, with symptomatic intracranial hemorrhage developing in 2 of these cases. Therefore, careful evaluation of noncontrast CT hypodensity is advisable when considering late-window thrombolytic therapy. Finally, this study was performed in a Chinese population, and findings may not fully generalize to populations of other races or ethnicities.
Conclusions
Intravenous tenecteplase administered 4.5 to 24 hours after stroke onset in patients with non–large vessel occlusion and salvageable brain tissue resulted in a higher likelihood of an excellent functional outcome than standard medical care, although an increased risk of symptomatic intracranial hemorrhage existed. These results support extending the thrombolysis time window in this patient population.
Trial Protocol
Statistical Analysis Plan
eAppendix 1. Participating Centers and Primary Investigators
eAppendix 2. Steering Committee
eAppendix 3. Executive Committee
eAppendix 4. Data Safety and Motoring Board
eAppendix 5. Clinical Events Committee
eAppendix 6. Imaging Core Laboratory
eAppendix 7. Trial Funding
eMethod 1. Patient Selection Criteria
eMethod 2. Imaging Core Laboratory Review
eMethod 3. Additional Statistical Section
eFigure 1. Number of Patients Enrolled at the Participating Centers
eFigure 2. Enrollment Rate/Progress of OPTION Trial over Trial Period
eFigure 3. Distribution of Modified Rankin Scale in Per-Protocol Population
eFigure 4. Kaplan-Meier Estimates of the Survival Probability in Patients
eTable 1. Representativeness
eTable 2. Additional Clinical Characteristics
eTable 3. Post-hoc Adjusted Analysis for the Efficacy and Safety Outcomes
eTable 4. Efficacy Outcomes in the Per-Protocol Population
eTable 5. Sensitivity Analysis for Primary Efficacy Outcome: Intention-To-Treat Population
eTable 6. Post-hoc Analysis in the Medium or Distal Vessel Occlusion Population (Primary Outcome) According to ESCAPE-MeVO or DISTAL Definition
eTable 7. Overview of Types of Intracranial Hemorrhages (Core-lab Assessment): Safety Population
eTable 8. Overview of Definitions for Symptomatic Intracranial Hemorrhage (Core-lab Assessment): Safety Population
eTable 9. Details of Symptomatic Intracranial Hemorrhage (Core-lab Assessment): Safety Population
eTable 10. Details of All Deaths
eTable 11. Number of Patients with Adverse Events up to 90-day Visit: Safety Population
eTable 12. Number of Patients with Serious Adverse Events up to 90-day Visit: Safety Population
eReferences
Nonauthor Collaborators
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
Statistical Analysis Plan
eAppendix 1. Participating Centers and Primary Investigators
eAppendix 2. Steering Committee
eAppendix 3. Executive Committee
eAppendix 4. Data Safety and Motoring Board
eAppendix 5. Clinical Events Committee
eAppendix 6. Imaging Core Laboratory
eAppendix 7. Trial Funding
eMethod 1. Patient Selection Criteria
eMethod 2. Imaging Core Laboratory Review
eMethod 3. Additional Statistical Section
eFigure 1. Number of Patients Enrolled at the Participating Centers
eFigure 2. Enrollment Rate/Progress of OPTION Trial over Trial Period
eFigure 3. Distribution of Modified Rankin Scale in Per-Protocol Population
eFigure 4. Kaplan-Meier Estimates of the Survival Probability in Patients
eTable 1. Representativeness
eTable 2. Additional Clinical Characteristics
eTable 3. Post-hoc Adjusted Analysis for the Efficacy and Safety Outcomes
eTable 4. Efficacy Outcomes in the Per-Protocol Population
eTable 5. Sensitivity Analysis for Primary Efficacy Outcome: Intention-To-Treat Population
eTable 6. Post-hoc Analysis in the Medium or Distal Vessel Occlusion Population (Primary Outcome) According to ESCAPE-MeVO or DISTAL Definition
eTable 7. Overview of Types of Intracranial Hemorrhages (Core-lab Assessment): Safety Population
eTable 8. Overview of Definitions for Symptomatic Intracranial Hemorrhage (Core-lab Assessment): Safety Population
eTable 9. Details of Symptomatic Intracranial Hemorrhage (Core-lab Assessment): Safety Population
eTable 10. Details of All Deaths
eTable 11. Number of Patients with Adverse Events up to 90-day Visit: Safety Population
eTable 12. Number of Patients with Serious Adverse Events up to 90-day Visit: Safety Population
eReferences
Nonauthor Collaborators
Data Sharing Statement
