Antiplatelet therapy after intravenous thrombolysis in acute ischemic stroke: No longer one-size-fits-all

Intravenous thrombolysis (IVT) remains the cornerstone of acute ischemic stroke (AIS) treatment within eligible time windows. However, approximately half of patients experience limited improvement or even neurological deterioration after thrombolysis.[1] The underlying pathophysiology is complex and multifactorial, involving symptomatic hemorrhagic transformation, malignant cerebral edema, collateral failure, blood pressure variability, hyperglycemia, oxidative stress, and other metabolic or systemic disturbances.[2] Among these diverse contributors, thrombosis and vessel re-occlusion represent promising targets for therapeutic intervention. Yet, for three decades, guidelines have recommended a 24-h “blanking period,” during which antiplatelet or anticoagulant therapy is withheld to reduce the risk of intracerebral hemorrhage, leaving high-risk patients vulnerable to early re-occlusion or neurological deterioration. The recent Advancing Stroke Safety and Efficacy through Early Tirofiban Administration after IVT (ASSET-IT) trial, a multicenter randomized controlled trial (RCT) conducted in China, published in The New England Journal of Medicine, demonstrated that early administration of tirofiban following IVT did not increase the risk of symptomatic intracranial hemorrhage and improved the proportion of patients achieving favorable functional outcomes.[3] This long-awaited finding represents a pivotal step forward for clinicians, signaling the potential closure of a long-standing therapeutic gap. This commentary aims to appraise the emerging clinical evidence and argue for a paradigm shift–from a rigid, one-size-fits-all delay to an individualized, risk-stratified approach for early antiplatelet strategies following IVT. The 24-h antithrombotic prohibition originated from the Tissue Plasminogen Activator for AIS (NINDS) trial,[4] which was published in 1995 and established the efficacy and safety of IVT within 3 h. To minimize the potential additive risk of intracerebral hemorrhage, the trial protocol explicitly prohibited the use of antithrombotic agents within the first 24 h. Importantly, this conservative approach was rooted in prudence rather than robust randomized evidence. It was a safety-first heuristic adopted in an era lacking safer, rapidly reversible antithrombotic options and sophisticated tools for hemorrhage risk stratification. Paradoxically, thrombolysis itself activates platelets, leading to platelet-rich thrombus formation and vessel re-occlusion; this prothrombotic state peaks within 2 h and persists for over 12 h, significantly influencing functional outcomes.[5] The absence of antithrombotic therapy during this vulnerable window thus created a clinically significant “gray zone” of high-risk neurological deterioration. Over the past three decades, AIS management has evolved dramatically, reshaping the therapeutic paradigm through landmark advancements. The time window of IVT was extended from 3–4.5 h, and in selected patients, up to 9–24 h using advanced imaging.[6,7] Moreover, endovascular therapy (EVT) has become the standard therapy for patients secondary to large vessel occlusions, and its time window was extended from 6–24 h, and its eligible patient population was extended from the anterior circulation to the posterior circulation.[8] Concurrently, secondary prevention and supportive care have become individualized, including precision-time dual antiplatelet therapy and proactive rehabilitation.[9] Despite these monumental advances across other domains of stroke care, the optimal antithrombotic strategy within the first 24 h following IVT has remained a persistent and vulnerable therapeutic void for nearly 30 years. Attempts to breach the 24-h barrier were not absent, but early RCTs yielded disappointing or inconclusive results, inadvertently reinforcing the status quo. Trials such as antiplatelet therapy in combination with Rt-PA thrombolysis in ischemic stroke (ARTIS) and the multiarm optimization of stroke thrombolysis (MOST) evaluated early antiplatelet or anticoagulant initiation post-IVT. The ARTIS trial reported an elevated risk of symptomatic intracerebral hemorrhage (4.3% vs. 1.6%, P < 0.05) when intravenous aspirin (300 mg) was administered within 90 min of thrombolysis.[10] Aspirin was chosen for its established secondary prevention role despite its limited immediate antiplatelet effect and irreversible mechanism of action. In the era preceding the widespread adoption of EVT, the enrolled patients included 24% with large vessel occlusion and 20% with cardioembolic stroke, carried inherently higher baseline hemorrhagic risk, confounding the results.[11] The MOST trial, evaluating argatroban and eptifibatide initiated within 75 min of thrombolysis, was prematurely terminated due to increased 90-day mortality without functional benefits.[12] Notably, 44% of enrolled patients underwent EVT. Broad, heterogeneous enrollment without adequate risk stratification likely diluted potential benefits while amplifying the risks, and low-risk patients gained little, while high-risk subgroups were underrepresented. More recently, the early antiplatelet for minor stroke following thrombolysis trial, which investigated the administration of clopidogrel and aspirin within 6 h after IVT in patients with minor stroke, also failed to demonstrate improvement in 3-month functional outcomes of the proportion of excellent outcome assessed by modified Rankin scale score of 0–1. This null result may be largely attributable to the ceiling effect for recovery in patients with mild deficits and the relatively high prevalence of clopidogrel resistance in the Chinese population. These early setbacks were instructive, highlighting the need for rapid-acting, potent, and rapidly reversible agents, such as glycoprotein IIb/IIIa inhibitors, and precise patient selection, guided by advanced imaging (e.g., cerebrovascular imaging and perfusion imaging) to ensure imperatives of effective early intervention and acceptable hemorrhagic safety. The era of precision medicine calls for individualized antiplatelet strategies after IVT. Current evidence allows identification of high-risk patients mainly based on vascular pathology and baseline stroke severity, including those with large artery atherosclerosis, small vessel occlusion, severe initial neurological deficits, or no prior antiplatelet therapy.[13] For these patients, rigid adherence to the 24-h antiplatelet delay may forgo meaningful functional benefits. The challenge remains balancing ischemic prevention with hemorrhagic safety, requiring careful selection of agents and optimal timing. The preferred agents for such early intervention should exhibit a rapid onset and a favorable safety profile. Glycoprotein IIb/IIIa inhibitors (e.g., tirofiban) currently represent the best-supported option; however, their administration requires continuous intravenous infusion, which may limit convenience and widespread applicability. During this exploratory phase, rigorous clinical monitoring is essential, including serial neurological assessments, strict blood pressure management, and prompt evaluation for hemorrhagic complications. Several ongoing RCTs are investigating early post-IVT antiplatelet strategies. The effectiveness and safety of early combined treatment with tirofiban following IVT in AIS (RESCUE BT-3, ChiCTR2400080653) trial assesses the safety and efficacy of early tirofiban in disabling strokes. In addition, the safety and efficacy of early aspirin administration after IVT for AIS (TREND-IVT, NCT06548971) trial investigates early administration of aspirin, either as chewable tablets or through a nasogastric tube, at 300 mg within 3 h of IVT initiation. This approach is particularly appealing, as rapid-acting aspirin may bridge the critical gap until standard secondary prevention becomes effective, a strategy analogous to acute coronary syndrome management. The key completed and ongoing trials are summarized in Table 1.Table 1: Clinical studies of the early antiplatelet therapy after intravenous thrombolysisIn conclusion, the ASSET-IT trial provides pivotal evidence challenging the long-standing 24-h antiplatelet-free period and the traditional one-size-fits-all antiplatelet regime. While caution remains warranted, the paradigm is shifting towards individualized, risk-adapted antithrombotic strategies. It is imperative to conduct high-quality, mechanism-informed, and precisely targeted trials to refine patient selection, optimize therapeutic agents and timing, and integrate early antithrombotic therapy within comprehensive stroke care, including bridging to EVT. These advances mark the beginning of a new era in early postthrombolysis management, offering the potential to substantially improve outcomes in patients treated with IVT. Author contributions Dr. Jing Wang drafted the article; Dr. Wenbo Zhao revised it critically for important intellectual content. Ethical policy and institutional review board statement Not applicable. Data availability statement Data sharing is not applicable to this article as no datasets were generated and/or analyzed during the current study. Financial support and sponsorship The research was supported by the National Natural Science Fund of China (82422024) and the Beijing Natural Science Fund for Outstanding Young Scholars (JQ22020). Conflicts of interest Dr. Wenbo Zhao is an Associate Editor of Brain Circulation. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editor and their research groups.