TRACE-III

Published

Xiong Y, et al. "Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy". The New England Journal of Medicine. 2024. 391(3):203-212.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among Chinese adults with stroke onset 4.5 to 24 hours prior with radiographic evidence of salvageable brain tissue, is administration of tenecteplase associated with greater likelihood of 90 day absence of disability when compared with usual care?

Bottom Line

Among Chinese adults with stroke onset 4.5 to 24 hours prior with radiographic evidence of salvageable brain tissue, administration of tenecteplase is associated with greater likelihood of 90 day absence of disability when compared with usual care.

Major Points

Clinical trials including NINDS (1995) and ECASS III reported improved neurological recovery when tPA is given the persons with ischemic stroke up to 4.5 hours. Whether there benefit beyond 4.5 hours was unclear. A 2014 Cochrane review reported possible benefit up to 6 hours. More recently, the 2018 WAKE-UP trial found that tPA improved neurological recovery in persons with unknown time of onset (e.g., persons who woke up with stroke) but had MRI findings consistent with MRI occurring in the prior 4.5 hours. Namely, an ischemic lesion is seen on DWI but not on FLAIR. The 2019 EXTEND trial studied the use of the tPA agent alteplase vs. placebo among persons with stroke with 'salvageable' brain tissue on imaging with onset 4.5 to 9 hours or on awakening. Extend was closed early because of loss of equipoise given the findings in WAKE-UP.

The 2024 Teneteplase [sic] Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) trial randomized 516 Chinese adult patients with ischemic stroke and evidence of salvagable tissue with symptom onset 4.5 to 24 hours prior (including 'wake up' strokes) to tPA in the form of tenecteplase or usual care, as is indicated by Chinese stroke guidelines. Use of tPA was associated with a significant increase in the number of persons without disability at 90 days (modified Rankin score of 0 or 1) when compared with usual care (33% vs 24%; RR 1.37; 95% CI 1.04 to 1.81; P=0.03; NNT=11). In the subgroup analysis, there was no difference when stratifying by duration of time since symptom onset (4.5 to 9 hours, 9 to 24 hours, or 'wake up' stroke).

Together, WAKE-UP, EXTEND, and TRACE-III provide growing evidence for the use of tPA among persons with salvageable brain tissue beyond 4.5 hours.

Guidelines

As of July 2024, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, open label, randomized controlled trial
• N=516
  • Tenecteplase (n=264)
  • Usual care (n=252)
• Setting: 58 centers in China
• Enrollment: 2022-2023
• Follow-up: 90 days
• Analysis: Intention-to-treat
• Primary outcome: Absence of disability

Population

Details taken from the protocol.

Inclusion Criteria

• Aged ≥18 years
• Stroke symptom onset 2.5 to 24 hours prior
  • For those with 'wake up' stroke, this time was the last time seen normal.
• ICA, MCA M1 or M2 stroke
• Pre-stroke modified Rankin score ≤1
• Baseline NIHSS between ranging from 6 to 25
• Salvageable brain tissue on perfusion imaging using the iStroke software package v3.13
  • Specifically, a target mismatch profile on CT or MRI with: Ischemic core volume <70 mL, mismatch ratio ≥1.8, & mismatch volume ≥15 mL
• Informed consent provided

Exclusion Criteria

• Endovascular treatment planned
• Allergy to study medication
• Rapidly improving symptoms
• NIHSS consciousness score 1a being >2, epileptic seizure, Todd's palsy
• Neurological or psychiatric condition preventing cooperation
• BP ≥180/100 even with BP lowering medicaiton
• Hypo or hyperglycemia
• Active bleeding
• At risk for bleeding, including surgery or trauma recently
• Coagulopathy, including warfarin with INR >1.7 or PT >16 seconds or use of DOAC unless able to reverse
• Platelet defector or thrombocytopenia (<100k platelet count)
• Stroke or MI in prior 3 mo
• Prior ICH
• Severe brain injury, brain surgery, or spine surgery in prior 3 months
• Known intracranial malignancy, AVM, or giant aneurysm
• Other illness with life expectancy <1 year
• Unable to get required imaging
• Hypodensity in >1/3 MCA region on non-con CT
• New or old ICH on imaging
• Multiple arterial occlusions
• Pregnancy, nursing, or non-use of effective contraceptives
• Unlikely to adhere to protocol, other conditions that make protocol unsafe, or inclusion in other interventional trials in prior 3 months

Baseline Characteristics

From the tenecteplase group.

• Demographics: Age 67 years, male sex 69%
• Medical problems: Hypertension 67%, DM 26%, AF 19%, HLD 31%, prior stroke/TIA 28%, CHD 21%
• Meds: Antiplatelets 14%, anticoagulation 2%, lipid-lowering medication 9%, glucose lowering 15%, BP lowering 46%
• Volume of perfusion mismatch: 97 mL
• Mismatch ratio 7
• Occlusion site: ICA 33%, M1 45%, M2 22% (proximal M2 98%)
• Modified Rankin scale prior to stroke: Zero 87%, one 13%
• NIHSS at randomization: 11
• Timing:
  • Known onset of stroke: 54%
  • Unwitnessed 8%
  • On awakening 38%
• Volume on initial imaging:
  • Of irreversibly injured ischemic core: 16 mL
  • Of perfusion lesion: 199 mL
• Symptom onset to treatment: 12.4 hours
  • ≤9 hours: 22%
  • >9 hours: 39%
  • Wake-up stroke: 38%

Interventions

• Participants were randomized to a group in open-label fashion:
  • Tenecteplase - Administered as bolus of 0.25 mg/kg, up to 25 mg.
  • Usual care - Antiplatelet therapy at investigator discretion, and other treatment per 2018 Chinese Guidelines. Note: The WJC editors were unable to find an English translation of these guidelines. The trial protocol includes some commentary about how these guidelines were incorporated into the study design.
• Rescue thrombectomy could be performed at the treating clinician's discretion.

Outcomes

Presented as tenecteplase vs. usual care. RR is relative rate.

Primary Outcome

Absence of disability at 90 days

Defined as score ≤1 on modified Rankin scale

33% vs 24% (RR 1.37; 95% CI 1.04 to 1.81; P=0.03; NNT=11)

Secondary Outcomes

Distribution of modified Rankin score

Across distributions: OR 1.33; 95% CI 0.98 to 1.81

0: 10% vs 7%

1: 23% vs. 18%

2: 11% vs. 9%

3: 17% vs. 23%

4: 22% vs. 23%

5: 4% vs. 8%

6: 13% vs. 13%

Score ≤2 at 90 days

44% vs. 33% (RR 1.31; 95% CI 1.05 to 1.63)

Major neurologic improvement at 72h

Defined as reduction in NIHSS ≥8 points or total NIHH score ≤1

16% vs. 6% (RR 2.66; 95% CI 1.51 to 4.69

Reperfusion at 24h

Defined as >90% reduction in volume of lesion that had ≥6 second arrival of tracer agent

20% vs. 12% (RR 1.70; 95% CI 1.10 to 2.64)

Change in NIHSS score at 7 days

WJC editor note: it is unclear from the primary publication what the ranges follow -4 and -2 are. They are possibly IQRs or 95% CIs. It is also unclear what the effect size of -1.47 represents, but this is probably a difference between -4 and -2.

-4 (-6 to -1) vs. -2 (-5 to 0) (-1.47; 95% CI -2.30 to -0.64)

Other Outcomes

Rescue endovascular treatment

1.5% vs. 2%

Adverse Events

Symptomatic ICH in first 36h

3% vs. 0.8% (RR 3.82; 95% CI 0.82 to 17.87)

All-cause mortality at 90 days

13.3% vs. 13.1% (RR 1.01; 95% CI 0.65 to 1.58)

Moderate or severe systemic bleeding at 90 days

1.9% vs. 0.8% (RR 2.36; 95% CI 0.46 to 12.09)

Any adverse event

51% vs. 51% (RR 0.99; 95% CI 0.84 to 1.17)

Serious: 20% vs. 17% (RR 1.18; 95% CI 0.82 to 1.69)

Subgroup Analysis

The primary outcome was similar by age, NIHSS score, and time from onset or stroke on awakening. There might have been greater benefit among males and among M1 and M2 sites of occlusion over ICA occlusion.

Primary outcome by sex

Male: 26% vs. 37% (RR 1.42; 95% CI 1.03 to 1.95)

Female: 21% vs. 25% (RR 1.18; 95% CI 0.68 to 2.06)

Occlusion site

ICA: 27% vs. 29% (RR 1.04; 95% CI 0.64 to 1.69)

M1: 23% vs. 33% (RR 1.43; 95% CI 0.95 to 2.15)

M2: 21% vs. 40% (RR 1.89; 95% CI 0.94 to 3.82)

Criticisms

• Open label design.
• Only enrolled in 1 country (China). Per the authors, in China there is greater prevalence of intracranial atherosclerosis and lower prevalence of AF than Western countries.
• The authors note that strokes were less severe than in other studies. The WJC editors note that this isn't universally true across tPA studies as the NIHSS scores at baseline were similar to ECASS III.

Funding

Chinese public funding sources.