Early Antiplatelet Administration After Intravenous Thrombolysis for Acute Ischemic Stroke (TREND-IVT)

Official title

Safety and Efficacy of Treatment With Early Antiplatelet Administration After Intravenous Thrombolysis for Acute Ischemic Stroke (TREND-IVT): A Multicenter, Randomized, Placebo-controlled, Clinical Trial

Overview

Stroke is the second leading cause of death worldwide, and ischemic stroke is the most frequent type. Intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 hours of symptom onset is the most effective therapy for patients with acute ischemic stroke. However, ischemic stroke progression and early reocclusion are not an uncommon phenomenon in patients after intravenous thrombolysis, resulting in neurological deterioration, which is associated with unfavorable functional outcomes. The underlying mechanism mainly involves the augmented platelet activation, triggered by the activated coagulation cascade during thrombolysis, which peaks within 2 hours of initiating rt-PA administration. Therefore, early antiplatelet therapy following intravenous thrombolysis represents a promising therapeutic approach to prevent neurological deterioration and improve the functional outcome of patients treated with intravenous thrombolysis. Currently, guidelines recommend initiating antiplatelet therapy 24 hours after intravenous thrombolysis due to the potential risk of increased bleeding. The safety and efficacy of early antiplatelet treatment following intravenous thrombolysis in patients with acute ischemic stroke remain clear. The study aims to test the hypothesis that in patients with acute ischemic stroke treated with intravenous thrombolysis, early administration of oral aspirin will improve functional outcomes without increasing the risk of intracranial hemorrhage.

Interventions

• Drug Aspirin
  Patients in the interventional group will chew 300mg of aspirin enteric-coated tablets as soon as possible after randomization. If swallowing difficulties arise, the tablets can be crushed and administered via a nasogastric tube.
• Drug Placebo
  Patients in the control group will chew 300mg of placebos as soon as possible after randomization. If swallowing difficulties arise, the placebo can be crushed and administered via a nasogastric tube.
• Other Best medical management
  Patients in both groups will receive the best medical management according to the guidelines.

Primary outcome measures

• The proportion of patients with a modified Rankin scale (mRS) score of 0-1 at 90-day follow up. [Time frame: Ninety days after stroke.]

Secondary outcome measures (6)

• The proportion of patients with a modified Rankin scale (mRS) score of 0-1 at 30-day follow up. [Time frame: Thirty days after stroke.]
• The proportion of patients with a modified Rankin scale (mRS) score of 0-2 at 90-day follow up. [Time frame: Ninety days after stroke.]
• The shift analysis in the 90-day modified Rankin scale (mRS) score. [Time frame: Ninety days after stroke.]
• The proportion of patients achieving neurological improvement. [Time frame: Within 48 hours after stroke.]
• The proportion of patients experiencing early neurological deterioration. [Time frame: Within 24 hours after stroke.]
• The changes in the NIHSS score at 24 hours, 48 hours, and 7 days of enrollment as compared with the baseline. [Time frame: Within 7 days after stroke.]

Eligibility criteria

Inclusion criteria

• Age ≥18 years old;
• Acute ischemic stroke treated with intravenous thrombolysis with alteplase or tenecteplase within 4.5 hours of onset or time last known well, and can receive the study drug treatment within 3 hours of initiating intravenous thrombolysis.
• Residual NIHSS score > 5 points assessed 1 hour after initiation of intravenous thrombolysis and prior to randomization.
• Informed consent obtained from patients or an authorized representative.

Exclusion criteria

• Stroke caused by definite large vessel occlusion (including A1/A2 segments of the anterior cerebral artery, M1/M2 segments of the middle cerebral artery, P1/P2 segments of the posterior cerebral artery, intracranial/extracranial segments of the internal carotid artery, basilar artery, and bilateral vertebral artery occlusion) confirmed by vessel imaging (including computed tomography angiography \[CTA\] or magnetic resonance angiography \[MRA\]), or scheduled for endovascular treatment (including mechanical thrombectomy, intra-arterial thrombolysis, and angioplasty).
• Intracranial hemorrhage confirmed by imaging post-thrombolysis.
• Definite or suspected cardioembolic stroke.
• Stroke caused by other determined causes, including nonatherosclerotic vasculopathies (moyamoya disease, artery dissection, arteritis), hypercoagulable states, or hematological disorders.
• Use of antiplatelet therapy within one week prior to stroke onset, novel anticoagulant drugs within 48 hours prior to stroke onset, or treatment with warfarin with an international normalized ratio (INR)>1.7.
• Prior history of moderate or severe ischemic stroke events with residual neurological disability.
• Pre-stroke mRS score > 1.
• Severe consciousness disturbance with NIHSS item 1a (level of consciousness) ≥ 2 points.
• Post-thrombolysis imaging indicates an infarct area larger than 1/2 responsible artery supply area.
• Known contraindications for antiplatelet therapy, such as coagulation disorders, or systemic bleeding
• History of aspirin allergy.
• Anticipated indications for anticoagulant therapy during the study period (e.g., atrial fibrillation, mechanical heart valve, deep vein thrombosis, pulmonary embolism, antiphospholipid syndrome, hypercoagulable state)
• Presence of malignant tumors, chronic hemodialysis, severe renal insufficiency (GFR < 30 mL/min or serum creatinine > 220 μmol/L \[2.5 mg/dL\]), severe hepatic insufficiency (serum alanine aminotransferase \[ALT\] >2 times the upper limit of normal, or serum aspartate aminotransferase \[AST\] >2 times the upper limit of normal), severe heart failure (New York Heart Association \[NYHA\] Functional Classification Class III or IV)
• Severe non-cardiovascular complications with an expected survival of less than 6 months.
• Unavailability for follow-up.
• Presence of dementia, psychiatric disorders, or other known neurological conditions that complicate follow-up.
• Current participation in another therapeutic study with ongoing treatment and follow-up.
• Other conditions that make the patient unsuitable for participation in the study as determined by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 71 centers

• The Third The People's Hospital Of Bengbu — Bengbu
• Suzhou municipal hospital — Suzhou
• Xuanwu Hospital, Capital Medical University — Beijing
• Aerospace central hospital — Haidian
• Beijing Pinggu District Hospital — Pinggu
• Beijing Luhe Hospital affiliated to Capital Medical University — Tongzhou
• Fujian university affiliated provincial hospital — Fuzhou
• The First Affiliated Hospital Of Xiamen University — Xiamen
• … and 63 more centers

Publications

• Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guid PMID 31662037
• Demaerschalk BM, Kleindorfer DO, Adeoye OM, Demchuk AM, Fugate JE, Grotta JC, Khalessi AA, Levy EI, Palesch YY, Prabhakaran S, Saposnik G, Saver JL, Smith EE; American Heart Association Stroke Council and Council on Epidemiology and Prevention. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals PMID 26696642
• Wu C, Sun C, Wang L, Lian Y, Xie N, Huang S, Zhao W, Ren M, Wu D, Ding J, Song H, Wang Y, Ma Q, Ji X. Low-Dose Tirofiban Treatment Improves Neurological Deterioration Outcome After Intravenous Thrombolysis. Stroke. 2019 Dec;50(12):3481-3487. doi: 10.1161/STROKEAHA.119.026240. Epub 2019 Oct 1. PMID 31570084
• Zinkstok SM, Roos YB; ARTIS investigators. Early administration of aspirin in patients treated with alteplase for acute ischaemic stroke: a randomised controlled trial. Lancet. 2012 Aug 25;380(9843):731-7. doi: 10.1016/S0140-6736(12)60949-0. Epub 2012 Jun 28. PMID 22748820
• Zhao W, Li S, Li C, Wu C, Wang J, Xing L, Wan Y, Qin J, Xu Y, Wang R, Wen C, Wang A, Liu L, Wang J, Song H, Feng W, Ma Q, Ji X; TREND Investigators. Effects of Tirofiban on Neurological Deterioration in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurol. 2024 Jun 1;81(6):594-602. doi: 10.1001/jamaneurol.2024.0868. PMID 38648030
• Wang J, Li S, Liu L, Ma Q, Li C, Wu C, Wu L, Song H, Ji X, Zhao W. Safety and Efficacy of Early Aspirin Administration After Intravenous Thrombolysis for Acute Ischemic Stroke (TREND-IVT): Rationale and Design of a Multicenter, Randomized, Placebo-Controlled Clinical Trial. J Am Heart Assoc. 2026 Mar 3;15(5):e045180. doi: 10.1161/JAHA.125.045180. Epub 2026 Feb 20. PMID 41717940

Identifiers

NCT: NCT06548971 · TREND-IVT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗