Ticagrelor with aspirin dual antiplatelet therapy combined with intravenous thrombolysis in patients with ischaemic stroke in China (TAPIS): a multicentre, double-blind, randomised controlled trial.

# Ticagrelor with aspirin dual antiplatelet therapy combined with intravenous thrombolysis in patients with ischaemic stroke in China (TAPIS): a multicentre, double-blind, randomised controlled trial *The Lancet 2026* Articles Ticagrelor with aspirin dual antiplatelet therapy combined with intravenous thrombolysis in patients with ischaemic stroke in China (TAPIS): a multicentre, double-blind, randomised controlled trial Anxin Wang*†, Xue Xia*, Ying Tang*, Fan Zhang*, Xinsheng Han*, Jing Li, Xiaoli Zhang, Jing Wang, Yulin Song, Fengyuan Che, Yuzhang Bei, Yong He, Wenji Jing, Junfang Hao, Jinzhao He, Hongqin Yang, Shu Chen, Wei Wu, Ying Li, Hongguo Dai, Chengyan Yang, Zengqiang Sun, Li Li, Yunchao Chen, Philip M Bath, Guillaume Turc, Yilong Wang†, on behalf of the TAPIS Investigators‡ Summary Background Evidence supporting the early addition of antiplatelet therapy to intravenous thrombolysis in patients Lancet 2026; 407: 1919–28 with acute ischaemic stroke remains inconclusive. We aimed to investigate the ecacy and safety of early oral dual Published Online antiplatelet therapy (DAPT), started within 6 h of onset, as an adjunct to intravenous thrombolysis. May 8, 2026 https://doi.org/10.1016/ S0140-6736(26)00757-9 Methods TAPIS was a randomised, double-blind, placebo-controlled trial done in 60 hospitals across China. We enrolled patients treated with intravenous thrombolysis for ischaemic stroke, with a National Institutes of Health See Comment page 1892 Stroke Scale score of 4–10. We randomly assigned (1:1) patients to receive oral aspirin plus ticagrelor (DAPT group) or *Joint first authors corresponding placebo within 6 h of stroke onset, either before, during, or after receiving thrombolysis. Ticagrelor or †Contributed equally to this work and serve as corresponding placebo was continued for days 2–7 in each group, with open-label aspirin administered for days 2–90. Patients, authors clinicians, and investigators were masked to the group assignment. The primary ecacy outcome was an excellent ‡A full list of the TAPIS functional outcome (modified Rankin Scale score 0–1) at 90 days. The primary safety outcome was symptomatic Investigators is provided in intracranial haemorrhage within 36 h. This trial was registered with ClinicalTrials.gov (NCT06316570) and is appendix 1 (pp 4–7) completed. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Findings Between April 3, 2024, and Sept 30, 2025, we randomly assigned 1382 patients to the early DAPT (n=690 Beijing, China [49·9%]) or placebo (n=692 [50·1%]) groups. The median age was 65·6 years (IQR 58·3–72·0), 991 (71·7%) were (Prof A Wang PhD, X Xia PhD, men, and 391 (28·3%) were women. At 90 days, 474 (68·7%) patients in the early DAPT group and 429 (62·0%) in the J Li PhD, X Zhang BS, placebo group achieved excellent functional outcomes (risk ratio 1·11 [95% CI 1·03–1·20; p=0·0089). Symptomatic Prof Y Wang MD); China National Clinical Research intracranial haemorrhage within 36 h occurred in six (0·9%) patients in the early DAPT group versus five (0·7%) in Center for Neurological the control group (risk ratio 1·20 [95% CI 0·37–3·93; p=0.76). Diseases, Beijing Tiantan Hospital, Capital Interpretation Among patients treated with intravenous thrombolysis for moderate ischaemic stroke, initiation of oral Medical University, Beijing, China (Prof A Wang, X Xia, J Li, DAPT within 6 h of onset improved the likelihood of excellent functional outcomes at 90 days. Although no significant X Zhang, Prof Y Wang); between-group dierence in symptomatic intracranial haemorrhage was detected, wide CIs precluded exclusion of a Department of Clinical small increased risk. Epidemiology and Clinical Trial, Capital Medical University, Beijing, China (Prof A Wang, Funding National Natural Science Foundation of China, Capital’s Funds for Health Improvement and Research, X Xia); Department of Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Municipal Science & Epidemiology, Beijing Technology Commission, and the New Cornerstone Science Foundation. Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, Copyright © 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar China (Prof A Wang, X Xia, J Li, technologies X Zhang); Department of Neurology, The First Introduction intravenous thrombolysis do not achieve excellent Affiliated Hospital of Harbin Medical University, Harbin, Early recanalisation of occluded arteries substantially functional outcomes.8,9 Heilongjiang, China improves the prognosis of acute ischaemic stroke. Theoretically, initiating antiplatelet therapy (Prof Y Tang MD, J Wang MM); Intravenous thrombolysis is widely recommended as a concurrently with or soon after intravenous thrombolysis Department of Neurology, Anshan Changda Hospital, standard reperfusion therapy for eligible patients with might inhibit platelet aggregation and prevent Anshan, Liaoning, China acute ischaemic stroke.1–4 However, complete recanali- re-occlusion of recanalised vessels, and thereby improve (F Zhang MM, Y Song MM); sation is achieved in only 14–36% of patients treated functional outcomes. However, the clinical application Neurology Department, with intravenous thrombolysis, and issues such as of antiplatelet therapy is limited by concerns regarding Kaifeng Central Hospital, Kaifeng, He’nan, China macrovascular reocclusion and microvascular throm- the risk of symptomatic intracranial haemorrhage (X Han PhD); Department of bosis after initial recanalisation remain inadequately and uncertain therapeutic ecacy. The ARTIS trial,10 Neurology, Linyi resolved.5–7 Approximately 40–50% of patients treated with recognised as the first large-sample randomised trial People’s Hospital, Linyi, Articles Shandong, China (Prof F Che MD); Department of Research in context Neurology, Liuyang Evidence before this study ongoing. To date, there is a paucity of evidence supporting early Jili Hospital, Liuyang, Changsha, Hunan, China We searched PubMed for randomised trials published from oral antiplatelet therapy for patients with stroke treated with (Y Bei MD, Y He MM); database inception to March 15, 2026, assessing the efficacy of intravenous thrombolysis, particularly those with moderate Department of Neurosurgery antiplatelet therapy within 24 h after intravenous neurological severity. (W Jing MD), Department of thrombolysis in patients with acute ischaemic stroke, using the Neurology (J Hao MD), Linfen Added value of this study People’s Hospital, Linfen, terms “antiplatelet”, “intravenous thrombolysis”, and The TAPIS trial, a double-blind, randomised controlled trial Shanxi, China; Brain Disease “ischaemic stroke”. Department, Heyuan enrolling 1382 patients with acute ischaemic stroke from Traditional Chinese Previous randomised trials have reported conflicting findings 60 sites in China, suggests that in patients with acute ischaemic Medicine Hospital, Heyuan, on the efficacy and safety of intravenous antiplatelet agents as stroke with a National Institutes of Health Stroke Scale score Guangdong, China (J He BS); adjunctive therapy to intravenous thrombolysis. The ARTIS trial, of 4–10 who received thrombolysis, early initiation (within 6 h Jiyuan Hospital of TCM, Jiyuan, He’nan, China among the first large-sample randomised clinical trials of symptom onset) of oral dual antiplatelet therapy with (H Yang MD); Department of assessing the efficacy of intravenous aspirin within 90 min after ticagrelor plus aspirin was associated with an improved Neurology, Qixian alteplase treatment, was prematurely terminated because of likelihood of excellent functional outcomes (a modified Rankin People’s Hospital, worse safety outcomes than with alteplase alone. Similarly, the Scale score of 0–1) at 90 days. Moreover, no statistically Kaifeng, He’nan, China (S Chen BS); Department of MOST trial showed no clinical benefit of adjunctive intravenous significant difference in the risk of symptomatic intracranial Neurology, Lingbao First eptifibatide but found increased mortality. By contrast, the haemorrhage was detected between the early dual antiplatelet People’s Hospital, Lingbao, ASSET-IT trial suggested that tirofiban use within 60 min after therapy group and the placebo control group, with wide CIs Sanmenxia, He’nan, China intravenous thrombolysis improved functional outcomes with that did not rule out a modest increase in risk. (W Wu MD); Department of an acceptable risk of symptomatic intracranial haemorrhage. Cerebrovascular Diseases, Sui Implications of all the available evidence County Hospital of Traditional Evidence on oral antiplatelet therapy remains scarce. The EAST Chinese Medicine, Shangqiu, The TAPIS trial showed benefits of ticagrelor–aspirin dual trial showed safety but no additional benefit of antiplatelet He’nan, China (Y Li MD); antiplatelet therapy within 6 h of onset on functional outcomes Emergency Department, Linfen treatment with clopidogrel plus aspirin in patients with mild in patients with acute ischaemic stroke who received Central Hospital, Linfen, neurological deficits treated with intravenous thrombolysis. thrombolysis, providing high-quality evidence that might Shanxi, China (H Dai MM); The TREND-IVT trial, designed to investigate whether patients Department of Neurology, inform clinical decision-making regarding early adjunctive oral Zhalantun City Hospital of with moderate-to-severe ischaemic stroke benefit from a single antiplatelet therapy in this population. Chinese and Mongolian loading dose of oral aspirin adjunctive to thrombolysis, is still Medicine, Zhalantun, Hulunbuir, Inner Mongolia Autonomous Region, China (C Yang MM); Department of comparing early addition of intravenous aspirin to Thrombolysis in Patients with Ischaemic Stroke (TAPIS) Neurology, Zibo intravenous thrombolysis versus intravenous thromboly- trial, we tested the hypothesis that initiation of oral DAPT Municipal Hospital, Zibo, sis alone, was prematurely terminated because of an with ticagrelor plus aspirin within 6 h of symptom onset Shandong, China excess rate of symptomatic intracranial haemorrhage would improve functional outcomes in patients with acute (Prof Z Sun MM); Department of Neurology, The First and a lack of significant clinical benefits. Similarly, the ischaemic stroke receiving intravenous thrombolysis. People’s Hospital of Shenyang, MOST trial11 showed that adjunctive intravenous Shenyang, Liaoning, China eptifibatide failed to reduce post-stroke disability and was Methods (L Li MD); Department of associated with increased mortality. By contrast, the Study design Neurology, Suixian People’s Hospital, Shangqiu, He’nan, ASSET-IT trial12 showed the ecacy of tirofiban, another TAPIS was a multicentre, randomised, double-blind, China (Y Chen MD); Stroke Trials type of glycoprotein IIb/IIIa inhibitor, as an adjunct to parallel-group, placebo-controlled trial done at 60 sites in Unit, Mental Health & Clinical intravenous thrombolysis, despite a modest increase in China and designed to assess the ecacy and safety of Neuroscience, University of the risk of symptomatic intracranial haemorrhage. early add-on oral DAPT with ticagrelor plus aspirin Nottingham, Nottingham, UK (Prof P M Bath MD); Université Given the inconclusive evidence, the 2026 American started within 6 h of ischaemic stroke onset in patients Paris Cité, Institute of Heart Association/American Stroke Association guidel ine treated with intravenous thrombolysis. The trial was Psychiatry and Neurosciences did not support very early use of intravenous aspirin in approved by the ethics committees of Beijing of Paris, INSERM U1266, Paris, conjunction with alteplase,3 and substantial controversy Tiantan Hospital (KY2023-200-03) and each participating France (Prof G Turc MD); Department of Neurology, GHU remains regarding early oral antiplatelet therapy in site. Written informed consent was obtained from the Paris Psychiatrie et patients with ischaemic stroke who undergo intravenous participants or their legally authorised representatives Neurosciences, Paris, France thrombolysis. The Early Antiplatelet for Minor Stroke before enrolment. The trial was done in compliance with (Prof G Turc); Chinese Institute following Thrombolysis (EAST) trial13 confirmed the the Declaration of Helsinki. The trial rationale, design, for Brain Research, Beijing, China (Prof Y Wang); National safety and feasibility of oral dual antiplatelet therapy and methods have been previously published.14 The full Center for Neurological (DAPT) within 6 h after intravenous thrombolysis in details of committee compositions and participating sites Disorders, Beijing, China patients with minor stroke, and highlighted the need for are available in appendix 1 (pp 2–7) and the protocol, (Prof Y Wang); Advanced an optimised DAPT strategy in patients with moderate-to- including statistical analysis plan, is provided in Innovation Center for Human Brain Protection, Capital severe ischaemic stroke. In the Ticagrelor with Aspirin appendix 2. This trial was reported in accordance with Medical University, Beijing, Dual Antiplatelet Therapy Combined with Intravenous the CONSORT 2025 statements. 1920 Articles Participants including but not limited to tirofiban, was permitted in China (Prof Y Wang); Beijing Eligible participants were aged 18–80 years, diagnosed cases of neurological deterioration meeting the following Laboratory of Oral Health, with acute ischaemic stroke, had a National Institutes prespecified criteria: an increase in NIHSS score of Capital Medical University, Beijing, China (Prof Y Wang); of Health Stroke Scale (NIHSS) score of 4–10 (range 0–42, 4 points or more from the lowest post-randomisation value Laboratory for Clinical with higher scores indicating greater stroke severity before or a return to the neurological status before intravenous Medicine, Capital Medical intravenous thrombolysis, with at least one point on any thrombolysis, occurring between day 1 and day 7. University, Beijing, China NIHSS limb motor subitem),15 and had received or Otherwise, the use of any other o-protocol antiplatelet (Prof Y Wang) intended to receive intravenous thrombolysis with agents within 7 days after randomisation was strictly Correspondence to: Prof Yilong Wang, Department of alteplase (0·9 mg/kg, maximum dose 90 mg) or prohibited (appendix 1 pp 10–11). Neurology, Beijing Tiantan tenecteplase (0·25 mg/kg, maximum dose 25 mg) within The steering committee designed and oversaw the Hospital, Capital Medical 4·5 h of symptom onset (appendix 1 pp 8–9). conduct of the trial. An independent clinical event University, Beijing 100070, China Randomisation was required to be completed within 6 h adjudication committee, whose members were masked yilong528@aliyun.com of stroke onset (defined as the last-seen-well time). Key to treatment allocation, adjudicated the mRS score or exclusion criteria were planned endovascular therapy, pre- through audio or video recording, as well as symptomatic Prof Anxin Wang, Department of Neurology, Beijing Tiantan existing disability with a score of 2 or higher on the intracranial haemorrhage through neuroimaging. The Hospital, Capital Medical modified Rankin Scale (mRS; ranging from 0 [no progress of the trial was monitored by an independent University, Beijing 100070, China symptoms] to 6 [death]),16 receipt of any antiplatelet data and safety monitoring board (DSMB) to safeguard wanganxin@bjtth.org therapy after symptom onset, pre-existing atrial the wellbeing of patients. See Online for appendices 1 and 2 fibrillation, or use of anticoagulants. Those with previous antiplatelet use, with new-onset atrial fibrillation, or with Outcomes unplanned endovascular therapy after randomisation The primary ecacy outcome was an excellent functional were not excluded and remained in the analyses. Patient outcome at 90 days, defined as a score of 0 or 1 on the sex was indicated from their identity card, recorded as mRS.16 Secondary ecacy outcomes were functional male or female. independence at 90 days, which was characterised by a score of 0–2 on the mRS; an ordinal distribution of scores Randomisation and masking on the mRS at 90 days (shift towards lower disability); The randomisation sequence, in accordance with which neurological improvement at 7 days defined as a decrease the trial medications were packaged, was generated of 4 points or more in NIHSS score from baseline; quality centrally by an independent statistician using a site- of life at 90 days assessed by the EQ-5D 5-level stratified, blocked-randomisation method with a fixed questionnaire (EQ-5D-5L; range from –0·391 to 1, size of four. Once a patient was deemed eligible and with higher scores indicating better quality of life) and written informed consent was obtained, the patient was the EQ-5D visual analogue scale (EQ-5D-VAS; range immediately randomly assigned (1:1) to either the early from 0 to 100, with higher scores indicating better quality DAPT intervention group or the double placebo control of life); 19 independence in activities of daily living at group within 6 h of onset. The trial agents and placebos 90 days defined as a Barthel Index score of 95–100 points were identical in size, shape, colour, taste, and appearance; (ranging from 0 to 100, with higher scores indicating thus, although the randomisation method was publicly greater independence function);20 and recurrent available, complete masking of the patient and all trial ischaemic stroke within 90 days after randomisation. personnel, as well as strict allocation concealment, were The primary safety outcome was symptomatic maintained throughout the entire trial. intracranial haemorrhage within 36 h, defined by the European Cooperative Acute Stroke Study III criteria as Procedures the presence of any apparently extravascular blood in the The initial doses of trial medications were administered brain or within the cranium associated with an increase orally at the time of randomisation within 6 h of symptom in NIHSS score of at least 4 points or death, where onset, before, during, or after intravenous thrombolysis. the haemorrhage was identified as the predominant Patients in the early DAPT group received a loading dose cause of neurological deterioration.9 Secondary safety of 180 mg ticagrelor (90 mg/tablet, two tablets) plus outcomes were symptomatic intracranial haemorrhage 100 mg aspirin (100 mg/tablet, one tablet) on day 1, within 7 days; symptomatic intracranial haemorrhage followed by 90 mg ticagrelor twice daily for days 2–7. with parenchymal haematoma type 2 within 36 h and Patients in the placebo group received two tablets of 7 days defined by the SITS-MOST criteria; 21 any bleeding ticagrelor placebo and one tablet of aspirin placebo on events within 90 days according to the GUSTO criteria;22 day 1, followed by matching ticagrelor placebo for and all investigator-reported adverse events and serious days 2–7. All patients in both groups received open-label adverse events within 90 days. aspirin 100 mg daily for days 2–90. Standard care in accordance with the Chinese Guidelines Statistical analysis for the Diagnosis and Treatment of Acute Ischaemic We calculated that 1380 patients (690 in each group) Stroke was permitted.17,18 Rescue antiplatelet therapy, would yield approximately 90% power to detect a Articles 9% absolute dierence in the proportion of patients treatment, use of prohibited concomitant medications, with excellent functional outcomes at 90 days after and loss to 90-day follow-up visit. The safety population randomisation between treatment groups, assuming the included all patients who received at least one dose of trial proportion in the control group to be 60% and the overall drug and for whom safety was assessed. Missing primary dropout rate to be 10%.8 The significance threshold outcomes were imputed with the last observation carry- for the final analysis was set at 0·048 with the forward estimation, with 60-day, 30-day, or 7-day mRS O’Brien–Fleming α-spending function, accounting for a scores used in descending order of data availability. single interim analysis of the primary ecacy outcome Moreover, deceased patients were analysed using an when 60% of patients completed the trial. However, the NIHSS score of 42, an EQ-5D-5L score of –0·391, an independent DSMB only reviewed overall incidences EQ-5D-VAS score of 0, and a Barthel Index of 0. of safety endpoints in the interim analysis. Given We did unadjusted analyses for both ecacy and safety that 1238 participants had been enrolled by that time, outcomes. For the primary outcome analysis, eects of the independent DSMB recommended cancelling the early DAPT compared with those of placebo were ecacy interim analysis and proceeding with full reported as risk ratios (RRs) with 95% CIs using recruitment and follow-up, and the final significance generalised linear models with a log link and binomial threshold was reset to 0·05. error distribution, along with binary secondary ecacy The primary ecacy analyses were done in the and safety outcomes. The distribution of scores on the intention-to-treat population, defined as all randomly mRS at 90 days was analysed with ordinal logistic assigned patients who completed at least one assessment regression after verification of the proportional-odds on the mRS within 90 days after randomisation. We did assumption using the score test, with the treatment further supportive ecacy analyses in the per-protocol eect presented as a common odds ratio (OR) with a population. The per-protocol population included 95% CI. The median dierence (95% CI) of EQ-5D-5L participants who completed study treatment without and EQ-5D-VAS scores at 90 days (modelled as protocol violations, excluding those with failure to comply continuous variables) was calculated using the Hodges– with inclusion/exclusion criteria, discontinuation of trial Lehmann estimation. The Cox proportional hazards model was used to estimate the hazard ratio of the relative time to recurrent ischaemic stroke by treatment 1382 patients enrolled and randomly assignment, with no violations of the proportional hazard assigned assumption observed. We did subgroup analyses on the primary outcome on the basis of age (<65 years vs ≥65 years), sex, time from 690 assigned to early DAPT 692 assigned to placebo onset to randomisation (<240 min vs ≥240 min, by (ITT population) (ITT population) median), NIHSS score before intravenous thrombolysis (<6 vs ≥6, by median), TOAST classification, thrombolytic agent, history of ischaemic stroke, hypertension, type 2 67 excluded* 69 excluded* 13 met exclusion criteria 22 met exclusion criteria diabetes, and timing of randomisation. We did 3 aged > 80 years 6 aged > 80 years two prespecified sensitivity analyses to test the 1 received intravenous 7 received intravenous thrombolysis beyond 4·5 h thrombolysis beyond 4·5 h robustness of primary findings. First, the adjusted 6 had an NIHSS score >10 or 7 had an NIHSS score >10 or scores on the mRS were applied, under which scenario scored 0 on the fifth and scored 0 on the fifth and any patient receiving prespecified rescue antiplatelet sixth scale sixth scale 2 had a pre-stroke mRS 1 had a pre-stroke mRS therapy was assigned a score of 5 on their subsequent score >1 score >1 visits, unless death had occurred. The number of 1 had a medical history of 1 had brain vascular atrial fibrillation malformation patients who received rescue therapy was further listed 43 discontinued trial treatment 38 discontinued trial treatment by treatment group. Second, we used a mixed-eects 11 intracranial or intraocular 13 intracranial or intraocular model with a random intercept for pooled study sites to haemorrhage haemorrhage 4 adverse events 2 adverse events account for potential site-level clustering. Before 21 investigator decision 12 investigator decision unmasking of treatment groups, sites with fewer than 7 other reasons 11 other reasons 10 had prohibited concomitant 7 had prohibited concomitant 20 participants were pooled within the same geographical medications medications region, ensuring that the pooled sites were of adequate 1 lost to the 90-day follow-up 2 lost to the 90-day follow-up visit visit size for statistical analysis. We did additional sensitivity analyses for the primary outcome excluding patients who received o-protocol antiplatelet agents for reasons 623 included in per-protocol population 623 included in per-protocol population other than rescue therapy, and imputing missing data using worst-case imputation and multiple imputation. Figure 1: Trial profile Secondary outcome analyses and subgroup analyses DAPT=dual antiplatelet therapy. ITT=intention to treat. mRS=modified Rankin Scale. NIHSS=National Institutes were not adjusted for multiple comparisons and should of Health Stroke Scale. *A single reason was recorded in screening logs. Some patients might have had multiple reasons for exclusion. not be interpreted as definitive evidence of treatment 1922 Articles eects. All statistical analyses were done using SAS Early DAPT Placebo (version 9.4). (n=690) (n=692) This trial was registered at ClinicalTrials.gov, Age, years 65·1 66·1 NCT06316570. (57·9–71·9) (59·0–72·1) Sex Role of the funding source Male 495 (71·7%) 496 (71·7%) The funders of the study had no role in study design, Female 195 (28·3%) 196 (28·3%) data collection, data analysis, data interpretation, or BMI, kg/m² 23·7 24·1 writing of the report. (21·9–26·0) (22·0–26·6) Blood pressure, mm Hg Results Systolic 153 (140–166) 153 (140–166) Between April 3, 2024, and Sept 30, 2025, we randomly Diastolic 87 (78–96) 87 (80–96) assigned 1382 patients, with 690 (49·9%) assigned to the Current smoking 237 (34·3%) 238 (34·4%) early DAPT group and 692 (50·1%) assigned to the Current drinking 121 (17·5%) 99 (14·3%) placebo group (figure 1) No screening logs were kept. All Previous antiplatelet therapy* 72 (10·4%) 60 (8·7%) patients received at least one dose of trial medication and Medical history underwent at least one assessment on the mRS within Ischaemic stroke 168 (24·3%) 165 (23·8%) 90 days after randomisation and were thus included in Ischaemic heart disease 77 (11·2%) 84 (12·1%) both the intention-to-treat and safety analysis population. Type 2 diabetes 159 (23·0%) 159 (23·0%) The last patient was followed up on Dec 29, 2025, and Hypertension 420 (60·9%) 412 (59·5%) three (0·2%) did not complete the 90-day follow-up. mRS score before stroke onset There were 67 (9·7%) participants in the early DAPT 0 625 (90·6%) 631 (91·2%) group and 69 (9·7%) participants in the placebo group 1 63 (9·1%) 60 (8·7%) with protocol violations; these were excluded from the 2 2 (0·3%) 1 (0·1%) per-protocol analysis. NIHSS score before intravenous 6 (5–7) 6 (6–8) Baseline demographics and clinical characteristics thrombolysis were well balanced between the two treatment Thrombolytic agents groups (table 1). The median age of the patients was Alteplase 340 (49·3%) 321 (46·4%) 65·6 years (IQR 58·3–72·0), 991 (71·7%) were men, and Tenecteplase 350 (50·7%) 371 (53·6%) 391 (28·3%) were women. The two most common causes TOAST classification of stroke were large-artery atherosclerosis (n=569 Large-artery atherosclerosis 284 (41·2%) 285 (41·2%) [41·2%]) and small-artery occlusion (n=736 [53·3%]). Cardioembolic 5 (0·7%) 5 (0·7%) The median time from onset to randomisation was Small-artery occlusion 370 (53·6%) 366 (52·9%) 240 min (IQR 172–297). In the early DAPT group, Other determined cause 13 (1·9%) 10 (1·4%) 113 (16·4%) partici pants were randomly assigned before, Undetermined cause 18 (2·6%) 26 (3·8%) 92 (13·3%) during, and 485 (70·3%) after intravenous Time from onset to randomisation, 240 (172–292) 240 (171–300) thrombolysis. In the placebo group, 107 (15·5%) partici- min† pants were randomly assigned before, 86 (12·4%) during, Time from onset to intravenous 156 (112–210) 155 (110–209) and 499 (72·1%) after intravenous thrombolysis. thrombolysis initiation, min 168 (24·3%) patients in the early DAPT group and Time from intravenous thrombolysis 65 (16–112) 66 (17–111) 165 (23·8%) patients in the placebo group had a initiation to randomisation, min medical history of ischaemic stroke, and the median Timing of randomisation NIHSS scores before intravenous thrombolysis were 6 Before intravenous thrombolysis 113 (16·4%) 107 (15·5%) (IQR 5–7) in the early DAPT group and 6 (6–8) in the During intravenous thrombolysis 92 (13·3%) 86 (12·4%) placebo group. The concomitant medications adminis- After intravenous thrombolysis 485 (70·3%) 499 (72·1%) tered during the treatment period are summarised in Data are n (%) or median (IQR). Percentages might not total 100 because of appendix 1 (pp 12–15). Endovascular therapy was done in rounding. DAPT=dual antiplatelet therapy. mRS=modified Rankin Scale. 14 (2·0%) patients in the early DAPT group and NIHSS=National Institutes of Health Stroke Scale. *Previous antiplatelet therapy in 22 (3·2%) patients in the placebo group. within 1 month before this onset. †The first dose of study medication was administered at the time of randomisation; therefore, time from onset to 23 (3·3%) participants in the early DAPT and 38 (5·5%) in randomisation equals time from onset to study drug administration. the placebo group received anticoagulants. Table 1: Baseline characteristics 62 (9·0%) patients in the early DAPT group and 97 (14·0%) patients in the placebo group received additional antiplatelet therapy within 7 days after indications (appendix 1 pp 12, 23). Despite no restrictions randomisation, including both rescue therapy being placed on the type of antiplatelet agent used for (50 [7·2%] in the early DAPT group vs 81 [11·7%] in the rescue therapy in this study, all patients requiring rescue placebo group) and o-protocol antiplatelet use for other treatment received tirofiban in our study. Articles Early DAPT (n=690) Placebo (n=692) Effect size (95% CI)* p value Primary efficacy outcome mRS score 0–1 at 90 days 474/690 (68·7%) 429/692 (62·0%) 1·11 (1·03–1·20) 0·0089 Secondary efficacy outcomes mRS score 0–2 at 90 days 550/690 (79·7%) 517/692 (74·7%) 1·07 (1·01–1·13) 0·027 Ordinal mRS score at 90 days† ·· ·· 1·24 (1·02–1·50) 0·029 0 222/690 (32·2%) 204/692 (29·5%) ·· ·· 1 252/690 (36·5%) 225/692 (32·5%) ·· ·· 2 76/690 (11·0%) 88/692 (12·7%) ·· ·· 3 87/690 (12·6%) 106/692 (15·3%) ·· ·· 4 23/690 (3·3%) 38/692 (5·5%) ·· ·· 5 11/690 (1·6%) 8/692 (1·2%) ·· ·· 6 19/690 (2·8%) 23/692 (3·3%) ·· ·· NIHSS score decreasing by ≥4 points at 7 days from baseline 400/690 (58·0%) 377/692 (54·5%) 1·06 (0·97–1·17) 0·19 EQ-5D-VAS score at 90 days‡ 90 (78–95) 88 (70–95) 1·00 (0·00–2·00) 0·024 EQ-5D-5L score at 90 days‡ 1·0 (0·9–1·0) 1·0 (0·8–1·0) 0·00 (0·00–0·00) 0·056 Barthel Index 95–100 at 90 days§ 553/689 (80·3%) 514/690 (74·5%) 1·08 (1·02–1·14) 0·011 Recurrence of ischaemic stroke within 90 days¶ 27/690 (3·9%) 24/692 (3·5%) 1·17 (0·67–2·05) 0·57 Safety outcomes Symptomatic intracranial haemorrhage within 36 h|| 6/690 (0·9%) 5/692 (0·7%) 1·20 (0·37–3·93) 0·76 Symptomatic intracranial haemorrhage within 7 days|| 7/690 (1·0%) 6/692 (0·9%) 1·17 (0·39–3·47) 0·78 Symptomatic intracranial haemorrhage with parenchymal 6/690 (0·9%) 5/692 (0·7%) 1·20 (0·37–3·93) 0·76 haematoma type 2 within 36 h** Symptomatic intracranial haemorrhage with parenchymal 6/690 (0·9%) 6/692 (0·9%) 1·00 (0·32–3·10) >0·99 haematoma type 2 within 7 days** Any bleeding within 90 days†† 50/690 (7·2%) 42/692 (6·1%) 1·19 (0·80–1·78) 0·38 Minor 37/690 (5·4%) 33/692 (4·8%) ·· ·· Moderate 2/690 (0·3%) 0/692 (0·0%) ·· ·· Severe or life-threatening 11/690 (1·6%) 9/692 (1·3%) ·· ·· Adverse events within 90 days 109/690 (15·8%) 103/692 (14·9%) 1·06 (0·83–1·36) 0·64 Serious adverse events within 90 days 48/690 (7·0%) 48/692 (6·9%) 1·00 (0·68–1·48) 0·99 Data are n/N (%) or median (IQR), unless otherwise indicated. DAPT=dual antiplatelet therapy. EQ-5D-5L=EuroQoL Group 5-Dimension 5-Level Self-Report Questionnaire. EQ-5D-VAS=EQ-5D Visual Analogue Scale. mRS=modified Rankin Scale. NIHSS=National Institutes of Health Stroke Scale. *The effect size is a risk ratio unless otherwise indicated. The widths of CIs for difference or risks for secondary outcomes were not adjusted for multiple comparisons, so no conclusions can be drawn from these data. †The common odds ratio (95% CI) is provided for ordinal score on the mRS at 90 days. ‡The median difference (95% CI) is provided for EQ-5D-VAS and EQ-5D-5L scores at 90 days. Data on the EQ-5D-VAS and EQ-5D-5L scores at 90 days were missing for three patients (one in the early DAPT group and two in the placebo group). §Data on the Barthel Index at 90 days were missing for three patients (one in the early DAPT group and two in the placebo group). ¶The hazard ratio (95% CI) is provided for recurrence of ischaemic stroke within 90 days. ||Symptomatic intracranial haemorrhage was defined according to the ECASS-III criteria. **Symptomatic intracranial haemorrhage with parenchymal hematoma type 2 was defined by the SITS-MOST criteria. ††A bleeding event was defined according to the GUSTO criteria. Table 2: Efficacy and safety outcomes in the intention-to-treat population For the primary outcome, excellent functional assumption satisfied (p=0·44). 553 (80·3%) patients in outcomes (scores of 0 or 1 on the mRS) at 90 days were the early DAPT group and 514 (74·5%) patients in the reported for 474 (68·7%) of 690 patients in the early placebo group had a Barthel index of 95–100 at 90 days DAPT group and 429 (62·0%) of 692 patients in the (RR 1·08 [1·02–1·14]; p=0·011). All other secondary placebo group in the intention-to-treat population ecacy outcomes are reported in table 2. The results of (RR 1·11 [95% CI 1·03–1·20]; p=0·0089; table 2). the per-protocol analysis were consistent with those of Regarding secondary outcomes, 550 (79·7%) patients the intention-to-treat analysis, with an RR of 1·10 in the early DAPT group and 517 (74·7%) patients in the (1·02–1·19; p=0·016) for the primary ecacy outcome placebo group had an mRS score of 0–2 at 90 days (appendix 1 pp 16–19, 31). (RR 1·07 [95% CI 1·01–1·13]; p=0·027). The ordinal No significant between-group dierence was detected distribution of scores on the mRS at 90 days is shown in in the risk of symptomatic intracranial haemorrhage figure 2. The common OR (95% CI) of early DAPT (table 2). Specifically, the primary safety outcome of compared with placebo for a favourable shift towards symptomatic intracranial haemorrhage within 36 h, as lower disability on the mRS at 90 days was 1·24 (95% CI defined by the ECASS-III criteria, occurred in 1·02–1·50]; p=0·029), with the odds proportionality six (0·9%) patients in the early DAPT group and 1924 Articles five (0·7%) patients in the control group (RR 1·20 [95% CI 0·37–3·93]; p=0·76). 50 (7·2%) patients in the early DAPT group and 42 (6·1%) in the placebo group had 2·8% any bleeding according to the GUSTO criteria (RR 1·19 1·6% 3·3% [0·80–1·78]; p=0·38). Adverse events within 90 days were Early DAPT reported in 109 (15·8%) patients in the early DAPT group 32·2% 36·5% 11·0% 12·6% (n=690) and 103 (14·9%) patients in the placebo group; serious adverse events were reported in 48 (7·0%) patients in the early DAPT group and 48 (6·9%) in the placebo group (RR 1·00 [0·68–1·48]; p=0·99; appendix 1 pp 20–22). In subgroup analyses, we found no evidence for eect Placebo modification (figure 3). 50 (7·2%) patients in the early (692) 29·5% 32·5% 12·7% 15·3% 5·5% DAPT group and 81 (11·7%) patients in the placebo 1·2% group received rescue antiplatelet therapy within 7 days 3·3% after randomisation. The results of sensitivity analyses 0 25 50 75 100 done using mRS scores adjusted by rescue therapy use were consistent with the primary findings for excellent functional outcomes at 90 days (RR 1·15 [95% CI Figure 2: Distribution of mRS scores at 90 days in the intention-to-treat population DAPT=dual antiplatelet therapy. mRS=modified Rankin Scale. Percentages might not amount to 100% because of 1·06–1·25]; p=0·0008; appendix 1 pp 23–24). rounding. Furthermore, multivariable analyses that incorporated a mixed-eects term for pooled study sites yielded a similar focused on injectable antiplatelet agents and evidence on RR of 1·11 (1·02–1·19; p=0·010) for the primary ecacy early oral antiplatelet therapy in this setting is rather scare. outcome (appendix 1 pp 25–29). Findings from additional The EAST trial, done in patients with minor ischaemic sensitivity analyses were also consistent with the primary stroke, first showed that early oral administration of results (appendix 1 pp 30). clopidogrel plus aspirin following intravenous thrombolysis was safe but failed to improve excellent Discussion functional outcomes at 90 days. In addition to the ceiling In this trial of patients with acute ischaemic stroke who eect attributable to mild baseline neurological deficits underwent intravenous thrombolysis within the (median NIHSS score of 3),24 we hypothesised that the conventional therapeutic time window of 4·5 h, a greater chosen DAPT strategy might also contribute to the neutral percentage of patients in the early DAPT group, who findings observed in the EAST trial. The high prevalence received oral ticagrelor plus aspirin within 6 h of of CYP2C19 loss-of-function alleles among Asian patients symptom onset (before, during, or after intravenous partially attenuated the antiplatelet ecacy of clopidogrel thrombolysis), had an excellent functional outcome used in the EAST trial.25 Moreover, the single loading dose (defined as a score of 0 or 1 on the mRS) at 90 days of clopidogrel plus aspirin administered within 6 h after than those in the placebo group (68·7% vs 62·0%). intravenous thrombolysis might also have been Symptomatic intracranial haemorrhage within 36 h was insucient to enhance long-term functional outcomes. rare in both treatment groups, although the wide CIs By contrast, in our trial, we used a dierent DAPT necessitate cautious interpretation regarding a potential regimen comprising ticagrelor and aspirin. Unlike modest increased risk. clopidogrel, ticagrelor directly blocks platelet P2Y Although several studies before the TAPIS trial receptors without the need for metabolic activation, explored the ecacy and safety of antiplatelet agents as theoretically conferring more potent inhibition of platelet early adjunctive therapy for intravenous thrombolysis, aggregation. Furthermore, the DAPT duration in the findings regarding early initiation of antiplatelet therapy TAPIS trial was set to 7 days to balance the ischaemic remain unclear.10–12,23 By contrast with the ARTIS trial benefit against the risk of haemorrhage.26 Eligible and the MOST trial, which did not show ecacy patients in our trial had an NIHSS score of 4–10 (with a of intravenous aspirin and eptifibatide as adjunctive median score of 6 in the randomly assigned participants); therapy to intravenous thrombolysis,10,11 the ASSET-IT we further excluded patients with a history of atrial trial showed that early tirofiban administration within fibrillation because such patients would typically be 1 h after intravenous thrombolysis completion was managed with anticoagulation therapy. These eligibility associated with improved functional outcome at 90 days criteria contributed to a substantially lower proportion of among patients with moderate stroke deficits who patients with cardioembolic stroke than the general might have less injured tissue at risk for haemorrhagic stroke population, who were at increased risk of transformation than those with more severe stroke. 12 symptomatic intracranial haemorrhage. Therefore, Compared with intravenous agents, oral antiplatelet although no post-intravenous thrombolysis imaging was agents oer superior administration convenience in most requested before the initiation of DAPT, symptomatic clinical settings; however, most previous clinical trials have intra cranial haemorrhage events were rare in our trial. puorG mRS score 0 1 2 3 4 5 6 mRS 0–1 at 90 days Risk ratio 1·11 (95% CI 1·03–1·20); p=0·0089 Patients (%) Articles Early DAPT group Placebo group Risk ratio (95%CI) p interaction Age (years) <65 261/342 (76·3%) 209/321 (65·1%) 1·17 (1·06–1·29) 0·11 ≥6 5 213/348 (61·2%) 220/371 (59·3%) 1·03 (0·92–1·16) Sex Female 134/195 (68·7%) 113/196 (57·7%) 1·19 (1·02–1·39) 0·26 Male 340/495 (68·7%) 316/496 (63·7%) 1·08 (0·99–1·18) Time from onset to randomisation (min) <240 239/332 (72·0%) 227/335 (67·8%) 1·06 (0·96–1·17) 0·26 ≥240 235/358 (65·6%) 202/357 (56·6%) 1·16 (1·03–1·31) NIHSS score before intravenous thrombolysis <6 133/174 (76·4%) 115/163 (70·6%) 1·08 (0·95–1·23) 0·74 ≥6 341/516 (66·1%) 314/529 (59·4%) 1·11 (1·01–1·22) TOAST classification Large-artery atherosclerosis 185/284 (65·1%) 168/285 (58·9%) 1·11 (0·97–1·26) Small-artery occlusion 268/370 (72·4%) 237/366 (64·8%) 1·12 (1·01–1·23) 0·84 Others 21/36 (58·3%) 24/41 (58·5%) 1·00 (0·68–1·45) Thrombolytic agent Alteplase 233/340 (68·5%) 195/321 (60·7%) 1·13 (1·01–1·26) 0·68 Tenecteplase 241/350 (68·9%) 234/371 (63·1%) 1·09 (0·98–1·21) History of ischaemic stroke No 372/522 (71·3%) 339/527 (64·3%) 1·11 (1·02–1·20) 0·96 Yes 102/168 (60·7%) 90/165 (54·5%) 1·11 (0·93–1·34) Type 2 diabetes No 376/531 (70·8%) 340/533 (63·8%) 1·11 (1·02–1·21) 0·94 Yes 98/159 (61·6%) 89/159 (56·0%) 1·10 (0·92–1·32) Hypertension No 191/270 (70·7%) 189/280 (67·5%) 1·05 (0·94–1·17) 0·21 Yes 283/420 (67·4%) 240/412 (58·3%) 1·16 (1·04–1·29) Timing of randomisation Before intravenous thrombolysis 80/113 (70·8%) 77/107 (72·0%) 0·98 (0·83–1·16) During intravenous thrombolysis 63/92 (68·5%) 53/86 (61·6%) 1·11 (0·89–1·38) 0·33 After intravenous thrombolysis 331/485 (68·2%) 299/499 (59·9%) 1·14 (1·04–1·25) Overall 474/690 (68·7%) 429/692 (62·0%) 1·11 (1·03–1·20) 0·5 1·0 1·5 Favours placebo Favours early DAPT Figure 3: Subgroup analysis of the primary efficacy outcome in the intention-to-treat population Data are n/N (%), unless otherwise indicated. Comparisons are unadjusted for multiplicity. Effect sizes are shown by prespecified subgroups. DAPT=dual antiplatelet therapy. NIHSS=National Institutes of Health Stroke Scale. Collectively, the moderate severity of ischaemic stroke patients with moderate stroke deficits. Similarly, the of the target population and the moderate duration of oral TAPIS trial also targeted patients with moderate DAPT with ticagrelor and aspirin might have contributed neurological severity. Taken together, there might be a to the positive findings in the TAPIS trial. Nevertheless, range of stroke severity where early adjunctive antiplatelet these findings should be interpreted within the context of therapy provides the greatest net benefit. Moreover, previous trials showing neutral or negative results, given although the antiplatelet eects of ticagrelor and aspirin the interstudy heterogeneity probably reflects variations provide a biological rationale for preventing post- in patient enrolment criteria, stroke pathophysiology, and thrombolysis re-occlusion, we did not perform systematic therapeutic protocols. For example, the neutral or vascular imaging after thrombolysis and could not negative results of previous trials might be explained, at directly assess whether the improved functional outcomes least in part, by dierences in stroke severity. The patients were mediated by reduced re-occlusion. Thus, the positive with higher median NIHSS scores in the ARTIS trial and finding in TAPIS should not be viewed as definitive proof the MOST trial might have contributed to an increased of treatment benefit across all settings but rather as a risk of haemorrhagic transformation, potentially contribution to the evolving evidence base. The ongoing osetting benefits from early antiplatelet therapy. TREND-IVT trial (NCT06548971) might further clarify Conversely, a ceiling eect in the EAST trial enrolling whether patients with moderate-to-severe ischaemic patients with mild stroke might have obscured the ability stroke receiving intravenous thrombolysis could benefit to detect a treatment benefit. By contrast, the ASSET-IT from a single loading dose of oral aspirin, an issue not trial, which showed benefit with early tirofiban, enrolled addressed in the present trial. 1926 Articles The high proportion of male patients included in our other racial backgrounds with distinct genetic profiles. trial was consistent with the epidemiological profile of Additionally, some important subpopulations were ischaemic stroke in China.8,27,28 Although subgroup excluded, such as those with more severe stroke, and analyses suggested a numerically larger treatment those who planned to receive endovascular therapy. benefit in female than in male patients, no significant Further confirmatory clinical trials across diverse settings interaction was observed. Likewise, interaction tests for are warranted to validate the generalisability of these other prespecified subgroups were also not statistically findings. Moreover, the rate of protocol violation in our significant, with CIs for eect estimates crossing unity in trial was approximately 10%, which might introduce several subgroups. Because the subgroup analyses were potential bias. Although the consistency between the per- exploratory, unadjusted for multiple comparisons, and protocol analyses and the intention-to-treat analyses limited by small sample sizes in some subgroups, these indicated minimal eect, the presence of protocol findings should be interpreted cautiously. Further studies violation still should be considered when interpreting the specifically powered to assess treatment eects in key results. subpopulations are warranted to confirm the consistency In this trial involving Chinese patients with moderate of early DAPT benefits. stroke deficits (NIHSS score of 4–10) who were treated In addition to better functional outcomes defined by the with intravenous thrombolysis within 4·5 h of symptom mRS, we also observed suggestive improvements in onset and who were not scheduled to receive endovascular independence in activities of daily living and EQ-5D-VAS therapy, early initiation of oral DAPT with ticagrelor plus score at 90 days, whereas no significant dierences aspirin within 6 h of onset was associated with an increased were observed in other secondary ecacy endpoints. incidence of excellent functional outcomes at 90 days. These findings suggest the potentially increased ecacy The overall risk of symptomatic intracranial haemorrhage of early DAPT on the overall subjective quality of was low in each treatment group, although cautious life, although these findings should be interpreted interpretation is warranted because of limited statistical as hypothesis-generating rather than as definitive precision. evidence of treatment eects. Notably, although death Contributors was recorded as part of safety outcomes, this outcome YW and AW proposed the study conception and study design. PMB and was not assessed as a separate secondary ecacy outcome GT supervised the study design. AW, XX, YT, FZ, and XH prepared the in our trial, given the low mortality among patients with first draft of the report. PMB, GT, and YW provided essential revisions, and all coauthors reviewed and revised the Article. YT, FZ, XH, JW, YS, mild-to-moderate stroke, which provided insucient FC, YB, YH, WJ, JHa, JHe, HY, SC, WW, YL, HD, CY, ZS, LL, and YC statistical power to draw firm conclusions. Moreover, a were involved in trial conduct, patient management, and data collection. somewhat large proportion of patients received XX, JL, and XZ supported data management, prepared the statistical analysis plan, and conducted statistical analyses. YW, AW, XX, YT, FZ, antiplatelet agents (including rescue antiplatelet therapy), and XH accessed and verified the underlying data reported in the anticoagulants, or endovascular therapy in the placebo manuscript. All authors had full access to all the data in the study and group, which to some extent attenuated the ecacy of the corresponding authors (YW and AW) had the final responsibility to early DAPT with ticagrelor and aspirin because the submit the publication. placebo group might receive more active intervention for Declaration of interests neurological deterioration than the early DAPT group. YW reports grants from the National Natural Science Foundation of China, the Noncommunicable Chronic Diseases-National Science and Nonetheless, the benefits of early antiplatelet therapy Technology Major Project, the Beijing Municipal Science & Technology were still significant despite this treatment imbalance, Commission, and the New Cornerstone Science Foundation. AW reports and further benefits were observed in the prespecified a grant from the Capital’s Funds for Health Improvement and Research. sensitivity analyses using the modified functional PMB reports grants or contracts from the National Institute for Health and Care Research Health Technology Assessment programme and the outcomes adjusted for rescue antiplatelet therapy use. British Heart Foundation; consulting fees from CoMind and DiaMedica; The TAPIS trial has several limitations. First, this study stock or stock options in CoMind and DiaMedica; membership of the was done exclusively in China, where approximately data safety monitoring board for the AVERT Dose and ECS’T-2 trials; 60% of patients carry CYP2C19 loss-of-function serving as co-chair of the Industry Roundtable at the World Stroke Organization; and receipt of device support from Phagenesis for the alleles, which might have contributed to the benefits PhEAST trial. All other authors declare no competing interests. from early DAPT with ticagrelor and aspirin. Moreover, Data sharing the distribution of stroke mechanisms in our trial, De-identified individual participant data can be available on reasonable predominantly large-artery atherosclerosis and small- request to the corresponding authors YW or AW and after signing artery occlusion, reflects the high burden of intracranial appropriate data sharing agreements. Such requests must be approved atherosclerotic disease in east Asian populations and by the respective ethics boards and appropriate data custodians. might partially account for the observed treatment Acknowledgments benefit, given that DAPT is especially eective against This trial was supported by grants from the National Natural Science Foundation of China (82425101), the Capital’s Funds for Health platelet-mediated thrombosis in atherosclerotic disease. Improvement and Research (CFH2024-2-2045), the Noncommunicable Our findings therefore cannot necessarily be generalised Chronic Diseases-National Science and Technology Major Project to populations with a higher proportion of cardioembolic (2023ZD0504800, 2023ZD0504801, 2023ZD0504802, 2023ZD0504803, stroke or to patients with acute ischaemic stroke of and 2023ZD0504804), the Beijing Municipal Science & Technology Articles Commission (Z231100004823036), and the New Cornerstone Science 15 National Institute of Neurological Disorders and Stroke rt-PA Foundation. We sincerely acknowledge the CSPC Pharmaceutical Stroke Study Group. Tissue plasminogen activator for acute Group, which provided aspirin, ticagrelor, and their placebo at no cost ischemic stroke. N Engl J Med 1995; 333: 1581–87. and with no restrictions. We also thank all the patients and their relatives 16 Saver JL, Chaisinanunkul N, Campbell BCV, et al. 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