Reperfusion Completion Via Local Arterial Infusion of Tenecteplase After Incomplete Mechanical Thrombectomy

Effectiveness and Safety of Intra-arterial Tenecteplase Bridging Therapy Following Incomplete Recanalization After Mechanical Thrombectomy for Acute Anterior Circulation Large Vessel Occlusion: A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

To evaluate the efficacy and safety of intra-arterial TNK bridging therapy following incomplete recanalization (2b ≤ eTICI < 3) after mechanical thrombectomy for acute anterior circulation large vessel occlusion.

Stroke is a group of diseases characterized by neurological deficits resulting from ischemic or hemorrhagic damage to brain tissue. It has high rates of incidence, disability, and mortality, making it the leading cause of disability and a significant cause of death among residents in China, imposing a heavy disease burden on families and society. According to the "China Stroke Center Report 2020", there are approximately 17.8 million stroke survivors among people aged over 40 in China, with 3.4 million new cases annually. Among these, Acute Ischemic Stroke (AIS) accounts for up to 80%. Current common clinical treatment strategies for AIS include Standard Medical Therapy (SMT), which involves Intravenous Thrombolysis (IVT), and Endovascular Thrombectomy (EVT). Extensive clinical evidence has fully confirmed a significant positive correlation between reperfusion quality and patient prognosis, suggesting that adopting more aggressive strategies to optimize reperfusion may be of great significance.

Incomplete reperfusion may result from various causes, including distal microthrombi occluding the microvasculature, residual occlusion unreachable by mechanical devices during EVT, and the formation of new emboli. As these situations are typically not amenable to mechanical thrombectomy, intra-arterial thrombolytic therapy has emerged as a potential option to further improve reperfusion in ischemic tissue. The CHOICE study was the first international randomized controlled trial (RCT) on EVT bridging with intra-arterial thrombolysis. Its results indicated that the group receiving successful mechanical thrombectomy combined with intra-arterial alteplase had improved neurological outcomes in AIS patients with anterior circulation large vessel occlusion compared to the control group (90-day mRS 0-1, 59% vs. 40.0%, P=0.047), with no significant difference in bleeding risk between the two groups.

Subsequently, several other important related studies were published, including the PEARL study (also using alteplase), the ANGEL-TNK, POST-TNK, and DATE studies (using tenecteplase, TNK), and the POST-UK study (using urokinase). Due to differing patient selection criteria, the results varied. However, a careful comparison reveals that studies whose inclusion criteria comprised patients with eTICI 2b grade (i.e., incomplete recanalization) all yielded positive conclusions, including CHOICE, PEARL, and ANGEL-TNK. More importantly, a subgroup analysis of the ANGEL-TNK study clearly found that in the eTICI 2b group, patients receiving intra-arterial TNK had significantly better clinical outcomes than those in the medical therapy group (90-day mRS 0-1, 42.3% vs. 21.8%, RR=2.08, 95%CI 1.35-3.20, P<0.001), whereas no significant difference was observed between the two groups in the eTICI 2c/3 group. This suggests that intra-arterial TNK therapy may offer greater benefits in the population failing to achieve complete recanalization.

TNK, a genetically engineered variant of alteplase, features amino acid modifications at three key sites, which significantly prolong its half-life and enhance its fibrin-binding specificity. In recent years, it has emerged as one of the most promising novel thrombolytic agents in the field of stroke thrombolysis. Studies have found that in patients with LVO identified on baseline CTA, TNK thrombolysis achieves significantly higher recanalization rates compared to alteplase, indicating TNK's unique advantage for large vessel occlusion. Therefore, the therapeutic effect of EVT combined with intra-arterial TNK thrombolysis holds great potential for AIS patients with anterior circulation large vessel occlusion, particularly those with incomplete recanalization after EVT, but this requires further investigation and confirmation.

This study aims to evaluate the efficacy and safety of intra-arterial TNK bridging therapy following incomplete recanalization (2b ≤ eTICI < 3) after mechanical thrombectomy for acute anterior circulation large vessel occlusion, using a prospective, multicenter, randomized, double-blind, placebo-controlled trial design.

Inclusion Criteria:

1. Age ≥ 18 years;
2. Time from symptom onset or last known well to randomization within 24 hours;
3. Clinical diagnosis of acute ischemic stroke caused by acute occlusion of the intracranial anterior circulation large vessels confirmed by CTA/MRA/DSA, including occlusion of the intracranial segment of the internal carotid artery, the M1 or M2 segments of the middle cerebral artery, with or without concomitant occlusion of the ipsilateral extracranial segment of the internal carotid artery;
4. NIHSS score ≥ 6, and meeting the current guidelines for mechanical thrombectomy;
5. Anterior circulation large vessel stroke due to occlusion of the intracranial ICA, MCA M1, or M2 segments;
6. Pre-stroke mRS score ≤ 1;
7. ASPECTS score ≥ 6;
8. Post-mechanical thrombectomy status with 2b ≤ eTICI < 3, and the operator has decided not to attempt further mechanical recanalization of the occluded vessel;
9. No more than 3 passes with the thrombectomy device;
10. Signed informed consent obtained from the patient or their legal guardian.

Exclusion Criteria:

1. Contraindications to intravenous thrombolysis (excluding time-based criteria);
2. DSA post-thrombectomy indicating dissection of the occluded artery, or intra-procedural flat-panel CT suggesting local hemorrhage or significant contrast extravasation;
3. Baseline NIHSS score not obtained;
4. Severe allergy or absolute contraindication to iodinated contrast media;
5. Systolic blood pressure ≥ 185 mmHg or diastolic blood pressure ≥ 110 mmHg, refractory to antihypertensive medication;
6. Blood glucose < 50 mg/dL (2.8 mmol/L) or > 400 mg/dL (22.2 mmol/L);
7. Platelet count < 50 × 10⁹/L, or APTT > 40 s, or PT > 15 s;
8. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; or current use of oral anticoagulants with INR > 1.7;
9. Severe renal failure, defined as serum creatinine > 3.0 mg/dL (or 265.2 μmol/L) or glomerular filtration rate [GFR] < 30 mL/min, or requiring hemodialysis or peritoneal dialysis;
10. Patient unlikely to complete the 90-day follow-up (e.g., no fixed address, palliative care patient, etc.);
11. Suspected vasculitis or septic embolism;
12. Suspected aortic dissection;
13. Pre-existing neurological or psychiatric disease that would interfere with the assessment of outcomes;
14. Pregnancy or lactation;
15. Current participation in another clinical trial that could interfere with this study;
16. Any other condition deemed by the investigator to make the patient unsuitable for participation or to pose a significant risk to the patient.