Early antiplatelet treatment for minor stroke following thrombolysis: Insights from the Early Antiplatelet for Minor Stroke following Thrombolysis trial

Early neurological deterioration following intravenous thrombolysis is often attributed to re-occlusion of the recanalized vessel,[1] which presents 6.7% in patients with acute ischemic stroke.[2] Minor stroke, caused by large vessel occlusion and treated with intravenous thrombolysis, has a higher risk of early neurological deterioration.[3] Antiplatelets have a continuous antithrombotic effect on the recanalized vessel to prevent the early neurological deterioration, which is recommended to start 24 h after intravenous thrombolysis by the current guideline, as early antiplatelet treatment may increase the hemorrhagic risk of patients with acute ischemic stroke.[4] Although Antiplatelet therapy in combination with Rt-PA Thrombolysis in Ischaemic Stroke was the first large sample randomized clinical trial to compare the effects of the early addition of intravenous aspirin to standard-dose alteplase, it could not achieve a clear conclusion due to premature termination.[5] Thus, there is a lack of strong evidence to prove the efficacy of early antiplatelet therapy following intravenous thrombolysis in acute ischemic stroke. The Early Antiplatelet for Minor Stroke following Thrombolysis (EAST) trial was designed to investigate the efficacy of early antiplatelet treatment with clopidogrel and aspirin in patients with acute minor ischemic stroke who presented within 6 h after the end of intravenous thrombolysis, which showed early dual antiplatelet treatment was safe but could not improve the excellent functional outcome at 90 days.[6] However, the Advancing Stroke Safety and Efficacy through Early Tirofiban Administration after Intravenous Thrombolysis (ASSET-IT) recently proved that early intravenous tirofiban increased the likelihood of an excellent functional outcome in patients with acute ischemic noncardioembolic stroke who underwent thrombolysis.[7] Different results from two clinical trials raised several concerns about the investigation of early antiplatelet treatment in clinical trials and practice. Patients Selection Patients with acute minor ischemic stroke were included in the EAST trial. Prior evidence has confirmed that patients with minor stroke are the target population who benefit from dual antiplatelet therapy.[8] Furthermore, minor strokes tend to have a lower risk of hemorrhagic transformation but a higher risk of early neurological deterioration due to large vessel occlusion. However, it is difficult to perform vessel examinations for each patient in the emergency department, which will limit the effective screening of patients with large vessel occlusion. Moreover, better functional outcomes were commonly observed in patients with milder neurological deficits,[9] which may introduce a ceiling effect of early antiplatelet treatment. Thus, early antiplatelet treatment should be investigated in patients with a wider range of neurological deficits, such as moderate or severe levels, who are at higher risk of early neurological deterioration due to more severe neurological deficits.[10] Although the ASSET-IT included patients with NIHSS scores ranging from 4 to 25 points, the 6 points of median NIHSS score in the trial still could not represent the efficacy of early antiplatelet treatment in the moderate-to-severe ischemic stroke. Antiplatelet Strategy Dual antiplatelet with aspirin and clopidogrel was selected in the EAST trial as this antiplatelet strategy significantly prevented early neurological deterioration in patients with acute mild-to-moderate ischemic stroke.[11] However, the potential lower sensitivity of Chinese patients to clopidogrel may limit this antiplatelet strategy in clinical routine as there is little time to screen patients who carry CYP2C19 loss-of-function alleles.[12] Other antiplatelet agents such as ticagrelor showed better efficacy in preventing disabling stroke and early neurological deterioration,[13] which were not affected by the metabolism enzyme. It is worth exploring the efficacy of different early antiplatelet strategies following intravenous thrombolysis. For example, the Ticagrelor With Aspirin Dual Antiplatelet Therapy Combined With Intravenous Thrombolysis for Ischemic Stroke (TAPIS; NCT06316570) trial, the Early Tirofiban Administration After Intravenous Thrombolysis in Acute Ischemic Stroke (ADVENT; NCT06045156) trial, and the Early Antiplatelet Administration After Intravenous Thrombolysis for Acute Ischemic Stroke (TREND-IVT; NCT06548971) are three ongoing studies from China, which will investigate the efficacy of early antiplatelet treatment with different antiplatelet strategies in patients with acute ischemic stroke receiving intravenous thrombolysis. Notably, the TREND-IVT will provide evidence of post-thrombolytic early antiplatelet with oral aspirin alone in patients with an NIHSS score of more than 5 points. Stroke Etiology The rationale of the clinical trial, that early antiplatelet treatment contributes to good functional outcome by preventing early neurological deterioration, is critical. Regardless of the functional outcomes at 90 days, neither the EAST trial nor the ASSET-IT trial found that early antiplatelet treatment could prevent the early neurological deterioration or result in early neurological improvement.[6,7] Early neurological deterioration was mainly attributed to re-occlusion of recanalization vessels[1] and associated with poor functional outcomes.[2] We hypothesized that early antiplatelet treatment could improve excellent functional outcome at 90 days by preventing the re-occlusion of recanalization vessels due to its continuous antithrombotic effect. Furthermore, dual antiplatelet treatment was previously found to prevent early neurological deterioration in patients with minor stroke due to large artery atherosclerosis but not large vessel occlusion.[14] Thus, vessel examinations in the screening procedure should be considered in the future study design. On the other hand, several studies showed that antiplatelet treatment may influence the outcomes in patients with intracranial arterial stenosis or large artery atherosclerosis.[15] This further highlights the importance of vessel examinations in the target population selection. In addition, except for re-occlusion of recanalization vessels, early neurological deterioration is also attributed to complex mechanisms such as neuroinflammatory response[16] and oxidative stress-induced blood-brain barrier disruption.[17] Collectively, patient selection based on vessel examination and clear stroke etiology may optimize the efficacy of early antiplatelet treatment in clinical practice as well as in clinical trial design. Thrombolytic Agents With respect to the thrombolytic agents, intravenous thrombolysis with tenecteplase has been proven to be as effective as alteplase in acute ischemic stroke.[18] In two published clinical trials (EAST and ASSET-IT),[6,7] intravenous thrombolysis with tenecteplase or alteplase was both included. Considering the limited statistical power due to small sample size in each subgroup, a future meta-analysis is warranted to evaluate the efficacy of early antiplatelet treatment following each specific agent and to verify the consistency of findings. Initiation Time The time initiating antiplatelet treatment is still the most concerning for clinical physicians as it critically balances efficacy and safety. In the post hoc analysis of the Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke (ATAMIS) trial, patients with acute mild-to-moderate ischemic stroke benefit more from earlier dual antiplatelet treatment.[19] However, whether there is an increasing risk of hemorrhagic transformation along with earlier initiation of antiplatelet treatment following intravenous thrombolysis remains unclear. The investigators should balance the benefits and risks of earlier antiplatelet treatment in clinical design and practice. In addition, the effect of chewable administration of antiplatelet agents on the onset of action warrants exploration, as the administration route is known to impact pharmacokinetics. Previous study demonstrated that an oral aspirin solution showed a significantly shorter t-max than modified release capsules,[20] underscoring the need for further exploration in this area. Future Perspective The neural results of the EAST trial raise multiple aspects to improve future randomized clinical trials. Future studies should aim to enroll acute ischemic stroke participants with a broader spectrum of NIHSS scores, especially those with higher NIHSS scores, which indicate moderate to severe neurological deficits. Vessel examination at admission should be performed for select patients with large artery atherosclerosis etiology, as they are most likely to derive benefit from dual antiplatelet treatment. Furthermore, the subgroup analysis results of the EAST trial, such as time from onset to treatment and comorbidity history, are expected to provide further insights for refining the target population. Except for the EAST and ASSET-IT trials, ongoing studies such as TAPIS, ADVENT, and TREND-IVT trials are expected to provide further validation of the efficacy and safety of early antiplatelet treatment. However, additional robust evidence from other population, including European remains necessary. In clinical practice, physicians should adequately weigh the net benefit of this treatment, as the potential for improved outcomes is accompanied by a parallel increase in hemorrhagic risk. Author contributions Yu Cui wrote the first draft. Hui-Sheng Chen critically revised the manuscript. Ethical policy and institutional review board statement The EAST trial was approved by the ethics committee of the General Hospital of Northern Theater Command [Y(2021)-109]. 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 Nil. Conflicts of interest Prof. Hui-Sheng Chen is an Editorial Board member of Brain Circulation. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.