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

Abstract

Background

In acute ischemic stroke, early neurological deterioration following intravenous thrombolysis (IVT) is common and is associated with unfavorable outcomes, necessitating antiplatelet therapy. TREND‐IVT (Trial of Early Aspirin After Intravenous Thrombolysis for Acute Ischemic Stroke) aims to evaluate the safety and efficacy of 300 mg aspirin administered within 3 hours after the initiation of IVT compared with standard antiplatelet therapy for improving functional outcomes in patients with acute ischemic stroke.

Methods

This multicenter, randomized, placebo‐controlled trial in China recruits patients with acute ischemic stroke receiving IVT (alteplase/tenecteplase) who are not scheduled for endovascular therapy. Participants are randomized in a 1:1 ratio to receive either early aspirin or placebo within 3 hours of initiating IVT, followed by guideline‐recommended standard antiplatelet therapy beginning 24 hours after IVT in both groups. The primary outcome is an excellent functional outcome, defined as a modified Rankin Scale (mRS) score 0 to 1 at 90 days. Secondary outcomes will include mRS score 0 to 1 at 30 days, mRS score 0 to 2 at 90 days, ordinal shift analysis of mRS scores at 90 days, and changes in the National Institutes of Health Stroke Scale scores within 7 days. Safety end points will include symptomatic intracerebral hemorrhage, any intracerebral hemorrhage within 48 hours, systemic bleeding, recurrent stroke, other vascular events, mortality, and other adverse events during the 90‐day follow‐up. A sample size of 1184 participants will provide 80% power to detect an 8% intergroup difference in the primary outcome rate (2‐sided α=0.05).

Conclusions

The trial will evaluate the safety and efficacy of early antiplatelet therapy with oral aspirin in patients with acute ischemic stroke treated with IVT and may provide a promising strategy for improving the functional outcomes in this patient population.

Registration

URL: https://www.clinicaltrials.gov; Unique Identifier: NCT06548971.

Nonstandard Abbreviations and Acronyms

AIS

acute ischemic stroke

IVT

intravenous thrombolysis

mRS

modified Rankin Scale

NIHSS

National Institutes of Health Stroke Scale

TREND‐IVT

Trial of Early Aspirin After Intravenous Thrombolysis for Acute Ischemic Stroke

Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt‐PA) is the cornerstone of acute treatment for eligible patients with acute ischemic stroke (AIS) and is designed to restore cerebral blood flow by dissolving thrombi in occluded vessels. ¹ , ² Despite its established efficacy, 20% to 34% of patients experience reocclusion of the recanalized vessel following thrombolysis, leading to neurological deterioration and worse functional outcomes. ³ , ⁴ Augmented platelet activation, which typically peaks within 2 hours after initiating rt‐PA, is the primary mechanism involved in early reocclusion and neurological deterioration. ⁵ , ⁶ Therefore, early antiplatelet therapy following IVT is a promising therapeutic approach to prevent neurological deterioration and improve the functional outcome in this patient population. However, current clinical guidelines recommend delaying the initiation of antiplatelet therapy until 24 hours after rt‐PA administration to minimize the risk of hemorrhagic events, a life‐threatening complication of thrombolysis. ¹ , ⁷

Aspirin is widely used as an antiplatelet agent in patients with cardio‐cerebrovascular disease. Theoretically, administering aspirin shortly after thrombolysis could enhance the therapeutic effects of rt‐PA by stabilizing vessel patency and preventing early thrombus reformation. However, the ARTIS (Antiplatelet Therapy in Combination with rt‐PA Thrombolysis in Ischemic Stroke) trial, published in 2012, reported that 300 mg intravenous aspirin administered within 90 minutes of rt‐PA was associated with a higher risk of symptomatic intracerebral hemorrhage and was prematurely terminated. ⁸

In retrospect, the increased risk of intracerebral hemorrhage observed in the ARTIS study may have been related to the limitations of the treatment methods available at that time. Specifically, endovascular therapy had not yet been recommended, leading many patients with large vessel occlusion, who inherently have a higher risk of intracerebral hemorrhage, to rely mainly on IVT therapy. ⁹ , ¹⁰ Additionally, the study did not require a noncontrast computed tomography scan to rule out intracranial hemorrhage before the administration of aspirin. ¹¹ Therefore, recent advances in stroke management warrant a reevaluation of the risk–benefit of early aspirin administration.

To address these unresolved issues, as a component of the TREND (Safety and Efficacy of Tirofiban in Preventing Neurological Deterioration in Acute Ischemic Stroke) research series, the TREND‐IVT trial (Trial of Early Aspirin After Intravenous Thrombolysis for Acute Ischemic Stroke) aims to test the hypothesis that, in patients with AIS treated with IVT, early administration of oral aspirin is safe and may improve functional outcomes compared with standard delayed antiplatelet therapy.

METHODS

Transparency and Openness Promotion

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical Considerations

The study protocol was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University (Approval Number: Clinical Research [2024]117‐003‐Amendment 1) and all participating centers before enrollment. Written informed consent is obtained from the participant or a legal representative before enrollment.

Design

The TREND‐IVT trial is an investigator‐initiated, multicenter, prospective, randomized, placebo‐controlled, double‐blind, phase 3 clinical trial. The trial scheme is illustrated in the Figure. This investigator‐initiated trial was designed solely in compliance with the Declaration of Helsinki and is registered at ClinialTrials.gov (https://clinicaltrials.gov, identifier NCT06548971).

Figure 1. Design and flow diagram of TREND‐IVT trial.

AIS indicates acute ischemic stroke; IVT, intravenous thrombolysis; LVO, large vessel occlusion; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; rt‐PA, recombinant tissue plasminogen activator; TNK, tenecteplase; and TREND‐IVT, Trial of Early Aspirin After Intravenous Thrombolysis for Acute Ischemic Stroke.

Patient Population

Adult patients (age≥18 years) with AIS who received IVT therapy with alteplase or tenecteplase within 4.5 hours of symptom onset and who have undergone cerebral vessel and head imaging examinations will be screened for this trial. Detailed inclusion and exclusion criteria are as follows:

Inclusion Criteria

• Age ≥18 years

• AIS is treated with IVT with alteplase or tenecteplase within 4.5 hours of symptom onset or time last known well, and the study drug can be administered within 3 hours of initiating IVT

• Residual National Institutes of Health Stroke Scale (NIHSS) score >5 points assessed 1 hour after initiation of IVT and before randomization

• Informed consent from the 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 or magnetic resonance angiography), 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 1 week before stroke onset, novel anticoagulant drugs within 48 hours before stroke onset, or treatment with warfarin with an international normalized ratio >1.7

• Prior history of moderate or severe ischemic stroke events with residual neurological disability

• Prestroke modified Rankin Scale (mRS) score>1

• Severe consciousness disturbance with NIHSS item 1a (level of consciousness) ≥2 points

• Postthrombolysis imaging indicating an infarct area larger than one half of the 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 (eg, atrial fibrillation, mechanical heart valve, deep vein thrombosis, pulmonary embolism, antiphospholipid syndrome, hypercoagulable state)

• Presence of malignant tumors, chronic hemodialysis, severe renal insufficiency (glomerular filtration rate<30 mL/min or serum creatinine >220 μmol/L [2.5 mg/dL]), severe hepatic insufficiency (serum alanine aminotransferase >2 times the upper limit of normal, or serum aspartate aminotransferase >2 times the upper limit of normal), severe heart failure (New York Heart Association Functional Classification Class III or IV)

• Severe noncardiovascular complications with an expected survival of <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

Randomization

Randomization will be conducted via a web‐based system on a mobile phone or computer after the patient's eligibility status has been confirmed. Eligible patients will be randomly allocated in a 1:1 ratio to the aspirin or the placebo group. Randomization will be stratified by age (18–65 years or ≥66 years), intravenous thrombolytics (alteplase or tenecteplase), and time from stroke onset to thrombolysis administration (≤3 hours or 3–4.5 hours). Participants will be randomly assigned a unique serial number, and corresponding masked medications will be provided.

Blinding Procedures

All study staff (including investigators, care providers, and outcome assessors) and study participants will remain blinded to treatment assignment. Study medications (oral aspirin or matching placebo) will be labeled, packed, and dispensed by an independent third party (CanPharma Supply Solutions). Placebo will be indistinguishable from the active drug in appearance, texture, and taste. Unblinding will be strictly restricted to authorized investigators under predefined emergency circumstances.

Treatments

Both groups of participants receive guideline‐directed best medical management throughout the study period. ¹ , ¹² In addition, participants randomized to the aspirin group and the control group will receive 3 aspirin enteric‐coated tablets (containing 300 mg aspirin) or 3 placebo tablets within 3 hours of initiating IVT. The tablets should be chewed and administered within 15 minutes of randomization. For patients with swallowing difficulties, the tablets can be crushed and delivered via a nasogastric tube. Beginning 24 hours after IVT, both groups will initiate standard secondary prevention with antiplatelet therapy according to current guidelines, consisting of aspirin (100 mg daily), clopidogrel (75 mg daily), or aspirin–clopidogrel dual therapy when indicated (eg, minor stroke, high‐risk transient ischemic attack, severe stenosis of the culprit artery, or other guideline‐recommended conditions).

Efficacy Outcomes

The primary efficacy outcome will be the excellent functional outcome with an mRS score of 0 to 1 at 90‐day after randomization. The secondary outcomes include an mRS score of 0 to 1 at 30 days, mRS score of 0 to 2 at 90 days, the ordinal shift analysis of the mRS score at 90 days, neurological improvement (defined as a decrease of ≥2 points in the NIHSS score at 48 hours post thrombolysis compared with the baseline assessment) and early neurological deterioration (defined as an increase of ≥4 points in the NIHSS score within 24 hours of thrombolysis compared with the lowest NIHSS score before deterioration). In addition, the change in NIHSS scores from baseline at 24 hours, 48 hours, and 7 days after thrombolysis will be analyzed as repeated measures to assess early recovery trajectory.

Safety Outcomes

The primary safety outcome will be the incidence of symptomatic intracerebral hemorrhage within 48 hours based on the ECASS III (European Cooperative Acute Stroke Study III) criteria, defined as any extravascular blood into the brain parenchyma due to nontraumatic causes and identified as the predominant cause of clinical deterioration with an increase of ≥4 points in the NIHSS score or that leads to death. ¹³ Other safety end points will include any intracerebral hemorrhage within 48 hours according to the ECASS III criteria, systemic hemorrhage within 90 days according to the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) trial criteria, ¹⁴ recurrent stroke or other vascular events, all‐cause death, and any adverse events during the 90‐day follow‐up period.

Data and Safety Monitoring Board

An external data and safety monitoring board, consisting of 2 stroke neurologists and a statistician who are not involved in the study or affiliated with the sponsor, will review the occurrence of adverse events and make recommendations to the Executive Committee regarding study safety. If the risk of adverse events is significantly higher in the aspirin group compared with the placebo group, the trial will be stopped. The data and safety monitoring board will convene approximately every 6 months. Reports pertaining to safety events will be submitted to the data and safety monitoring board by a statistician at intervals determined by the board.

Sample Size Estimates

The proportion of excellent functional outcomes with mRS scores of 0 to 1 in patients undergoing intravenous alteplase or tenecteplase thrombolysis and standard antiplatelet therapy is assumed to be 0.6 based on previous studies. ¹⁵ , ¹⁶ , ¹⁷ We expect an 8% improvement of the primary outcome in patients receiving early aspirin antiplatelet therapy. ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ To demonstrate the expected treatment effect of an 8% absolute difference between 2 arms with a type‐I error alpha of 0.05 (2 sided) and a power of 80%, a target sample size of 1124 participants (562 in each group) is required if participants are allocated in a 1:1 ratio. The final sample size will be increased to 1184 (592 per treatment group) to allow for a 5% loss to follow‐up, withdrawal of consent, and participants who were randomly assigned but did not receive their assigned treatment due to worsening of their condition. This estimation was performed using Power Analysis and Sample Size version 15 (NCSS LLC, Kaysville, UT, USA; www.ncss.com).

The first patient was enrolled on November 7, 2024, and enrolment is expected to be completed by June 30, 2028.

Statistical Analysis

The analysis will be conducted using both an intention‐to‐treat and a per‐protocol approaches. For comparisons between the 2 groups, all hypothesis tests will be 2 sided. P values <0.05 will be considered statistically significant. We will report the proportions of missing values for all collected variables.

Modified Poisson regression analysis will be used to analyze the primary efficacy outcome, presenting treatment effects with both unadjusted and adjusted estimates with 95% CIs. The analysis will be adjusted for the following prespecified covariates: age, sex (male or female), baseline NIHSS score, thrombolytic agent (alteplase or tenecteplase), time from onset to thrombolysis initiation (≤3 hours or 3–4.5 hours), stroke cause (TOAST [Trial of Org 10 172 in Acute Stroke Treatment] classification), ²⁴ and stroke location (anterior or posterior circulation). Prespecified subgroups by age, sex, history of stroke/transient ischemic attack, type of intravenous thrombolytics (alteplase or tenecteplase), infarct location (anterior or posterior circulation), stroke cause classification, presence of neurological deterioration before treatment, and occurrence of symptomatic intracerebral hemorrhage will be tested for interaction with treatment for the primary efficacy outcome. A comprehensive statistical analysis plan detailing the statistical procedures will be developed separately before the finalization of the trial data.

Protocol Amendments

The initial version approved by the ethics and regulatory authorities was version 3.0.

In version 3.1, the condition that limited NIHSS score improvement to no more than 2 points or decrease to no more than 4 points 1 hour after initiating intravenous thrombolysis, compared with prethrombolysis scores, was dropped. Furthermore, an exclusion criterion was added to exclude patients who had undergone novel anticoagulant therapy within 48 hours before stroke onset or were treated with warfarin with an international normalized ratio >1.7. Additionally, the exclusion criterion pertaining to prior stroke events was changed to include only those with a history of moderate‐to‐severe ischemic events accompanied by residual neurological dysfunction.

DISCUSSION

Early neurological deterioration following intravenous thrombolysis is a multifactorial phenomenon. Although augmented platelet activation and subsequent thrombosis represent a key mechanism, several other pathways may contribute, including collateral circulation failure, blood pressure variability, hyperglycemia‐induced excitotoxicity, and oxidative stress–related reperfusion injury, for which early antiplatelet therapy may not be effective. ²⁵ To maximize potential benefit and minimize bleeding risk, patients with cardioembolic stroke, large vessel occlusion, or other determined causes were excluded, thereby enriching for a population of patients with atherosclerotic stroke, whose early neurological deterioration is more likely thrombotic in origin and theoretically more responsive to antiplatelet therapy in the setting of IVT. ²⁶ This strategy may address a critical unmet need in postthrombolysis care and may provide a foundation for more personalized strategies to prevent early neurological deterioration and improve functional outcomes.

Recent observational studies suggest that the administration of oral aspirin within 24 hours following IVT improves the 3‐month functional outcomes for patients with AIS. ²² , ²³ The TREND‐IVT trial is designed to evaluate the safety and efficacy of early antiplatelet therapy with 300 mg of aspirin administered within 3 hours of initiating intravenous thrombolysis, compared with placebo, in patients with moderate‐to‐severe noncardioembolic ischemic stroke without large vessel occlusion.

The TREND research series is dedicated to exploring antithrombotic strategies for AIS. ²⁷ Recently, the TREND trial demonstrated that in patients with AIS who do not undergo IVT within 24 hours of onset, the use of tirofiban antiplatelet therapy can significantly reduce the risk of neurological deterioration. ²⁸ The intravenous thrombolytic activates the coagulation cascade while promoting fibrinolysis, activating thrombin platelets, and further activating the hemostatic system, which typically peaks within 2 hours after initiating rt‐PA. ⁵ , ⁶ The TREND‐IVT trial is committed to initiating antiplatelet therapy promptly within the peak phase of the coagulation response following IVT and administering aspirin within 3 hours following the initiation of IVT. In addition, the study will use a chewable loading dose of aspirin enteric‐coated tablets to achieve rapid antiplatelet effects, as a previous study demonstrated significant inhibition of platelet aggregation within 15 minutes after chewing a 325‐mg aspirin enteric‐coated tablet. ²⁹

The primary concern regarding in the early use of antiplatelet therapy following IVT is ensuring patients' safety. Unlike the ARTIS study, this trial excludes patients with large vessel occlusive stroke using vascular imaging, patients with intracranial hemorrhage with head imaging before randomization, and patients who recently received antithrombotic therapy before stroke onset. These exclusion criteria were introduced to enhance the safety of the study and reduce the incidence of intracranial hemorrhage. In addition, patients with possible cardioembolic stroke will be excluded from the study owing to the specific pathophysiological mechanisms making patients less prone to benefit from antiplatelet therapy and an inherently higher risk of intracerebral hemorrhage.

CONCLUSIONS

In conclusion, the results of the TREND‐IVT trial will demonstrate whether early aspirin antiplatelet therapy initiated within 3 hours of initiating IVT in patients with AIS is safe and effective at improving functional outcomes at 90 days. This phase 3 trial may provide a promising strategy for enhancing the effectiveness of IVT therapy.

Sources of Funding

The TREND‐IVT trial is sponsored by Xuanwu Hospital, Capital Medical University and received support from the National Natural Science Foundation of China (No. 82422024, No. 82371305), Beijing Natural Science Foundation (JQ22020, Z240021), and National Science and Technology Major Project (2023ZD0505306).

Disclosures

None.