2018年全球腦卒中十大研究進展
一. 《NEJM》：正常人服用低劑量阿司匹林可能不能降低心血管事件，而且還會增加出血風險。但是其他研究卻發(fā)現(xiàn)阿司匹林的效果與服藥對象的體重存在關系。
摘要：BACKGROUND:
Aspirin is awell-established therapy for the secondary prevention of cardiovascular events.However, its role in the primary prevention of cardiovascular disease is unclear,especially in older persons, who have an increased risk.
METHODS:
From 2010 through2014, we enrolled community-dwelling men and women in Australia and the UnitedStates who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in theUnited States) and did not have cardiovascular disease, dementia, ordisability. Participants were randomly assigned to receive 100 mg ofenteric-coated aspirin or placebo. The primary end point was a composite ofdeath, dementia, or persistent physical disability; results for this end pointare reported in another article in the Journal. Secondary end points includedmajor hemorrhage and cardiovascular disease (defined as fatal coronary heartdisease, nonfatal myocardial infarction, fatal or nonfatal stroke, orhospitalization for heart failure).
RESULTS:
Of the 19,114persons who were enrolled in the trial, 9525 were assigned to receive aspirinand 9589 to receive placebo. After a median of 4.7 years of follow-up, the rateof cardiovascular disease was 10.7 events per 1000 person-years in the aspiringroup and 11.3 events per 1000 person-years in the placebo group (hazard ratio,0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhagewas 8.6 events per 1000 person-years and 6.2 events per 1000 person-years,respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<>
CONCLUSIONS:
The use oflow-dose aspirin as a primary prevention strategy in older adults resulted in asignificantly higher risk of major hemorrhage and did not result in asignificantly lower risk of cardiovascular disease than placebo. (Funded by theNational Institute on Aging and others; ASPREE ClinicalTrials.gov number,NCT01038583 .).
參考文獻：
1. Effect ofAspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. N Engl JMed. 2018 Oct 18;379(16):1509-1518.
2. Effects ofaspirin on risks of vascular events and cancer according to bodyweight anddose: analysis of individual patient data from randomised trials. Lancet. 2018Aug 4;392(10145):387-399.
二. 《NEJM》：是真的嗎？補充ω-3脂肪酸和維生素D并不能降低心血管疾病和癌癥的發(fā)生風險。
摘要：BACKGROUND:
Higher intake ofmarine n-3 (also called omega-3) fatty acids has been associated with reducedrisks of cardiovascular disease and cancer in several observational studies.Whether supplementation with n-3 fatty acids has such effects in generalpopulations at usual risk for these end points is unclear.
METHODS:
We conducted arandomized, placebo-controlled trial, with a two-by-two factorial design, ofvitamin D3 (at a dose of 2000 IU per day) and marine n-3 fatty acids (at a doseof 1 g per day) in the primary prevention of cardiovascular disease and canceramong men 50 years of age or older and women 55 years of age or older in theUnited States. Primary end points were major cardiovascular events (a compositeof myocardial infarction, stroke, or death from cardiovascular causes) andinvasive cancer of any type. Secondary end points included individualcomponents of the composite cardiovascular end point, the composite end pointplus coronary revascularization (expanded composite of cardiovascular events),site-specific cancers, and death from cancer. Safety was also assessed. Thisarticle reports the results of the comparison of n-3 fatty acids with placebo.
RESULTS:
A total of 25,871participants, including 5106 black participants, underwent randomization.During a median follow-up of 5.3 years, a major cardiovascular event occurredin 386 participants in the n-3 group and in 419 in the placebo group (hazardratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasivecancer was diagnosed in 820 participants in the n-3 group and in 797 in theplacebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In theanalyses of key secondary end points, the hazard ratios were as follows: forthe expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); fortotal stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascularcauses, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths fromcancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause(978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). Noexcess risks of bleeding or other serious adverse events were observed.
CONCLUSIONS:
Supplementationwith n-3 fatty acids did not result in a lower incidence of majorcardiovascular events or cancer than placebo. (Funded by the NationalInstitutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259.).
參考文獻：
1. Marinen-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl JMed. 2018 Nov 10.
2. Vitamin DSupplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med.2018 Nov 10.
三. 《NEJM》：研究揭示TIA和小梗死5年后卒中的發(fā)生風險。
摘要：BACKGROUND:
After a transientischemic attack (TIA) or minor stroke, the long-term risk of stroke and othervascular events is not well known. In this follow-up to a report on 1-yearoutcomes from a registry of TIA clinics in 21 countries that enrolled 4789patients with a TIA or minor ischemic stroke from 2009 through 2011, weexamined the 5-year risk of stroke and vascular events.
METHODS:
We evaluatedpatients who had had a TIA or minor stroke within 7 days before enrollment inthe registry. Among 61 sites that participated in the 1-year outcome study, weselected 42 sites that had follow-up data on more than 50% of their enrolledpatients at 5 years. The primary outcome was a composite of stroke, acutecoronary syndrome, or death from cardiovascular causes (whichever occurredfirst), with an emphasis on events that occurred in the second through fifthyears. In calculating the cumulative incidence of the primary outcome andsecondary outcomes (except death from any cause), we treated death as acompeting risk.
RESULTS:
A total of 3847patients were included in the 5-year follow-up study; the median percentage ofpatients with 5-year follow-up data per center was 92.3% (interquartile range,83.4 to 97.8). The composite primary outcome occurred in 469 patients(estimated cumulative rate, 12.9%; 95% confidence interval [CI], 11.8 to 14.1),with 235 events (50.1%) occurring in the second through fifth years. At 5years, strokes had occurred in 345 patients (estimated cumulative rate, 9.5%;95% CI, 8.5 to 10.5), with 149 of these patients (43.2%) having had a strokeduring the second through fifth years. Rates of death from any cause, deathfrom cardiovascular causes, intracranial hemorrhage, and major bleeding were10.6%, 2.7%, 1.1%, and 1.5%, respectively, at 5 years. In multivariableanalyses, ipsilateral large-artery atherosclerosis, cardioembolism, and abaseline ABCD2 score for the risk of stroke (range, 0 to 7, with higher scoresindicating greater risk) of 4 or more were each associated with an increasedrisk of subsequent stroke.
CONCLUSIONS:
In a follow-up toa 1-year study involving patients who had a TIA or minor stroke, the rate ofcardiovascular events including stroke in a selected cohort was 6.4% in thefirst year and 6.4% in the second through fifth years. (Funded by AstraZenecaand others.).
參考文獻：Five-Year Risk of Stroke after TIA or MinorIschemic Stroke. N Engl J Med. 2018 Jun 7;378(23):2182-2190.
四. 《Lancet》：深度學習算法可快速自動識別頭顱CT中的異常病灶。
摘要：
BACKGROUND:
Non-contrast headCT scan is the current standard for initial imaging of patients with headtrauma or stroke symptoms. We aimed to develop and validate a set of deeplearning algorithms for automated detection of the following key findings fromthese scans: intracranial haemorrhage and its types (ie, intraparenchymal,intraventricular, subdural, extradural, and subarachnoid); calvarial fractures;midline shift; and mass effect.
METHODS:
We retrospectivelycollected a dataset containing 313?318 head CT scans together with theirclinical reports from around 20 centres in India between Jan 1, 2011, and June1, 2017. A randomly selected part of this dataset (Qure25k dataset) was usedfor validation and the rest was used to develop algorithms. An additionalvalidation dataset (CQ500 dataset) was collected in two batches from centresthat were different from those used for the development and Qure25k datasets.We excluded postoperative scans and scans of patients younger than 7 years. Theoriginal clinical radiology report and consensus of three independentradiologists were considered as gold standard for the Qure25k and CQ500 datasets,respectively. Areas under the receiver operating characteristic curves (AUCs)were primarily used to assess the algorithms.
FINDINGS:
The Qure25kdataset contained 21?095 scans (mean age 43 years; 9030 [43%] female patients),and the CQ500 dataset consisted of 214 scans in the first batch (mean age 43years; 94 [44%] female patients) and 277 scans in the second batch (mean age 52years; 84 [30%] female patients). On the Qure25k dataset, the algorithmsachieved an AUC of 0·92 (95% CI 0·91-0·93) for detecting intracranialhaemorrhage (0·90 [0·89-0·91] for intraparenchymal, 0·96 [0·94-0·97] forintraventricular, 0·92 [0·90-0·93] for subdural, 0·93 [0·91-0·95] forextradural, and 0·90 [0·89-0·92] for subarachnoid). On the CQ500 dataset, AUCwas 0·94 (0·92-0·97) for intracranial haemorrhage (0·95 [0·93-0·98], 0·93[0·87-1·00], 0·95 [0·91-0·99], 0·97 [0·91-1·00], and 0·96 [0·92-0·99],respectively). AUCs on the Qure25k dataset were 0·92 (0·91-0·94) for calvarialfractures, 0·93 (0·91-0·94) for midline shift, and 0·86 (0·85-0·87) for masseffect, while AUCs on the CQ500 dataset were 0·96 (0·92-1·00), 0·97(0·94-1·00), and 0·92 (0·89-0·95), respectively.
INTERPRETATION:
Our results showthat deep learning algorithms can accurately identify head CT scanabnormalities requiring urgent attention, opening up the possibility to usethese algorithms to automate the triage process.
參考文獻：Deep learning algorithms for detection ofcritical findings in head CT scans: a retrospective study. Lancet. 2018 Dec1;392(10162):2388-2396.
五. 《NEJM》：長期地中海飲食可以減少主要心血管事件的發(fā)生率
摘要：
BACKGROUND:
Observationalcohort studies and a secondary prevention trial have shown inverse associationsbetween adherence to the Mediterranean diet and cardiovascular risk.
METHODS:
In a multicentertrial in Spain, we assigned 7447 participants (55 to 80 years of age, 57%women) who were at high cardiovascular risk, but with no cardiovascular diseaseat enrollment, to one of three diets: a Mediterranean diet supplemented withextra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or acontrol diet (advice to reduce dietary fat). Participants received quarterlyeducational sessions and, depending on group assignment, free provision ofextra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary endpoint was a major cardiovascular event (myocardial infarction, stroke, or deathfrom cardiovascular causes). After a median follow-up of 4.8 years, the trialwas stopped on the basis of a prespecified interim analysis. In 2013, wereported the results for the primary end point in the Journal. We subsequentlyidentified protocol deviations, including enrollment of household memberswithout randomization, assignment to a study group without randomization ofsome participants at 1 of 11 study sites, and apparent inconsistent use ofrandomization tables at another site. We have withdrawn our previouslypublished report and now report revised effect estimates based on analyses thatdo not rely exclusively on the assumption that all the participants wererandomly assigned.
RESULTS:
A primaryend-point event occurred in 288 participants; there were 96 events in the groupassigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in thegroup assigned to a Mediterranean diet with nuts (3.4%), and 109 in the controlgroup (4.4%). In the intention-to-treat analysis including all the participantsand adjusting for baseline characteristics and propensity scores, the hazardratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterraneandiet with extra-virgin olive oil and 0.72 (95% CI, 0.54 to 0.95) for aMediterranean diet with nuts, as compared with the control diet. Results weresimilar after the omission of 1588 participants whose study-group assignmentswere known or suspected to have departed from the protocol.
CONCLUSIONS:
In this studyinvolving persons at high cardiovascular risk, the incidence of majorcardiovascular events was lower among those assigned to a Mediterranean dietsupplemented with extra-virgin olive oil or nuts than among those assigned to areduced-fat diet. (Funded by Instituto de Salud Carlos III, Spanish Ministry ofHealth, and others; Current Controlled Trials number, ISRCTN35739639 .).
參考文獻：Primary Prevention of CardiovascularDisease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil orNuts. N Engl J Med. 2018 Jun 21;378(25):e34.
六. 《NEJM》：聯(lián)合應用氯吡格雷和阿司匹林可進一步降低”小”卒中后的卒中再發(fā)生率。
摘要：
Combinationantiplatelet therapy with clopidogrel and aspirin may reduce the rate ofrecurrent stroke during the first 3 months after a minor ischemic stroke ortransient ischemic attack (TIA). A trial of combination antiplatelet therapy ina Chinese population has shown a reduction in the risk of recurrent stroke. Wetested this combination in an international population.
METHODS:
In a randomizedtrial, we assigned patients with minor ischemic stroke or high-risk TIA toreceive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same rangeof doses of aspirin alone. The dose of aspirin in each group was selected bythe site investigator. The primary efficacy outcome in a time-to-event analysiswas the risk of a composite of major ischemic events, which was defined asischemic stroke, myocardial infarction, or death from an ischemic vascularevent, at 90 days.
RESULTS:
A total of 4881patients were enrolled at 269 international sites. The trial was halted after84% of the anticipated number of patients had been enrolled because the dataand safety monitoring board had determined that the combination of clopidogreland aspirin was associated with both a lower risk of major ischemic events anda higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemicevents occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plusaspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo(hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), withmost events occurring during the first week after the initial event. Majorhemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirinand in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32;95% CI, 1.10 to 4.87; P=0.02).
CONCLUSIONS:
In patients withminor ischemic stroke or high-risk TIA, those who received a combination ofclopidogrel and aspirin had a lower risk of major ischemic events but a higherrisk of major hemorrhage at 90 days than those who received aspirin alone.(Funded by the National Institute of Neurological Disorders and Stroke; POINTClinicalTrials.gov number, NCT00991029 .).
參考文獻： Clopidogrel and Aspirin in AcuteIschemic Stroke and High-Risk TIA. N Engl J Med. 2018 Jul 19;379(3):215-225.
七. 《NEJM》：卒中后6~16小時血管內(nèi)取栓可促進卒中的功能恢復。
摘要：
BACKGROUND:
Thrombectomy iscurrently recommended for eligible patients with stroke who are treated within6 hours after the onset of symptoms.
METHODS:
We conducted amulticenter, randomized, open-label trial, with blinded outcome assessment, ofthrombectomy in patients 6 to 16 hours after they were last known to be welland who had remaining ischemic brain tissue that was not yet infarcted.Patients with proximal middle-cerebral-artery or internal-carotid-arteryocclusion, an initial infarct size of less than 70 ml, and a ratio of thevolume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or morewere randomly assigned to endovascular therapy (thrombectomy) plus standardmedical therapy (endovascular-therapy group) or standard medical therapy alone(medical-therapy group). The primary outcome was the ordinal score on themodified Rankin scale (range, 0 to 6, with higher scores indicating greaterdisability) at day 90.
RESULTS:
The trial wasconducted at 38 U.S. centers and terminated early for efficacy after 182patients had undergone randomization (92 to the endovascular-therapy group and90 to the medical-therapy group). Endovascular therapy plus medical therapy, ascompared with medical therapy alone, was associated with a favorable shift inthe distribution of functional outcomes on the modified Rankin scale at 90 days(odds ratio, 2.77; P<0.001) and="" a="" higher="" percentage="" of="" patients="" who="" werefunctionally="" independent,="" defined="" as="" a="" score="" on="" the="" modified="" rankin="" scale="" of="" 0to="" 2="" (45%="" vs.="" 17%,=""><0.001). the="" 90-day="" mortality="" rate="" was="" 14%="" in="" theendovascular-therapy="" group="" and="" 26%="" in="" the="" medical-therapy="" group="" (p="0.05)," andthere="" was="" no="" significant="" between-group="" difference="" in="" the="" frequency="" ofsymptomatic="" intracranial="" hemorrhage="" (7%="" and="" 4%,="" respectively;="" p="0.75)" or="" ofserious="" adverse="" events="" (43%="" and="" 53%,="" respectively;="" p="">
CONCLUSIONS:
Endovascularthrombectomy for ischemic stroke 6 to 16 hours after a patient was last knownto be well plus standard medical therapy resulted in better functional outcomesthan standard medical therapy alone among patients with proximalmiddle-cerebral-artery or internal-carotid-artery occlusion and a region of tissuethat was ischemic but not yet infarcted. (Funded by the National Institute ofNeurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number,NCT02586415 .).
參考文獻：
1. Thrombectomyfor Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med.2018 Feb 22;378(8):708-718.
2. Thrombectomy 6to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl JMed. 2018 Jan 4;378(1):11-21.
八. 《JAMA》：卵圓孔未閉增加圍手術期腦卒中發(fā)生風險。
摘要：
IMPORTANCE:
Perioperativestroke is a major complication for patients undergoing surgery. Patent foramenovale (PFO) represents a possible anatomical link between venous thrombosis andstroke.
OBJECTIVE:
To determinewhether a preoperatively diagnosed PFO is associated with increased risk ofperioperative ischemic stroke.
DESIGN, SETTING,AND PARTICIPANTS:
Retrospectivecohort study from Massachusetts General Hospital and 2 affiliated communityhospitals between January 1, 2007, and December 31, 2015. Participants were182?393 consecutive adults undergoing noncardiac surgery with generalanesthesia.
EXPOSURES:
Preoperativelydiagnosed PFO.
MAIN OUTCOMES ANDMEASURES:
Perioperativeischemic stroke occurring within 30 days of surgery; stroke subtype byOxfordshire Community Stroke Project classification and stroke severity byNational Institute of Health Stroke Scale (NIHSS).
RESULTS:
Among the 150?198patient cases analyzed (median [SD] age, 55 [16] years), 1540 (1.0%) had adiagnosis of PFO before surgery. A total of 850 (0.6%) ischemic strokesoccurred within 30 days of surgery (49 [3.2%] among patients with PFO and 801[0.5%] among patients without PFO). In adjusted analyses, patients with PFO hadan increased risk of ischemic stroke compared with patients without PFO (oddsratio, 2.66 [95% CI, 1.96-3.63]; P?
CONCLUSIONS ANDRELEVANCE:
Among adultpatients undergoing noncardiac surgery at 3 hospitals, having a preoperativelydiagnosed PFO was significantly associated with increased risk of perioperativeischemic stroke within 30 days after surgery. Further research is needed toconfirm these findings and to determine whether interventions would decreasethis risk.
參考文獻：Association of Preoperatively DiagnosedPatent Foramen Ovale With Perioperative Ischemic Stroke.JAMA. 2018 Feb6;319(5):452-462.
九. 《NEJM》：體細胞KRAS激活突變可能是引起動靜脈畸形的分子機制。
摘要：
BACKGROUND:
Sporadicarteriovenous malformations of the brain, which are morphologically abnormalconnections between arteries and veins in the brain vasculature, are a leadingcause of hemorrhagic stroke in young adults and children. The genetic cause ofthis rare focal disorder is unknown.
METHODS:
We analyzed tissueand blood samples from patients with arteriovenous malformations of the brainto detect somatic mutations. We performed exome DNA sequencing of tissuesamples of arteriovenous malformations of the brain from 26 patients in themain study group and of paired blood samples from 17 of those patients. Toconfirm our findings, we performed droplet digital polymerase-chain-reaction(PCR) analysis of tissue samples from 39 patients in the main study group (21 withmatching blood samples) and from 33 patients in an independent validationgroup. We interrogated the downstream signaling pathways, changes in geneexpression, and cellular phenotype that were induced by activating KRASmutations, which we had discovered in tissue samples.
RESULTS:
We detectedsomatic activating KRAS mutations in tissue samples from 45 of the 72 patientsand in none of the 21 paired blood samples. In endothelial cell-enrichedcultures derived from arteriovenous malformations of the brain, we detectedKRAS mutations and observed that expression of mutant KRAS (KRASG12V) inendothelial cells in vitro induced increased ERK (extracellularsignal-regulated kinase) activity, increased expression of genes related toangiogenesis and Notch signaling, and enhanced migratory behavior. Theseprocesses were reversed by inhibition of MAPK (mitogen-activated proteinkinase)-ERK signaling.
CONCLUSIONS:
We identifiedactivating KRAS mutations in the majority of tissue samples of arteriovenousmalformations of the brain that we analyzed. We propose that thesemalformations develop as a result of KRAS-induced activation of the MAPK-ERKsignaling pathway in brain endothelial cells. (Funded by the Swiss CancerLeague and others.).
參考文獻：Somatic Activating KRAS Mutations inArteriovenous Malformations of the Brain. N Engl J Med. 2018 Jan18;378(3):250-261.
十. 《NEJM》：三聯(lián)抗血小板加強治療對改善預后無進一步助益，反而增加出血風險。
摘要：
BACKGROUND:
Intensive antiplatelettherapy with three agents might be more effective than guideline treatment forpreventing recurrent events in patients with acute cerebral ischaemia. We aimedto compare the safety and efficacy of intensive antiplatelet therapy (combinedaspirin, clopidogrel, and dipyridamole) with that of guideline-basedantiplatelet therapy.
METHODS:
We did aninternational, prospective, randomised, open-label, blinded-endpoint trial inadult participants with ischaemic stroke or transient ischaemic attack (TIA)within 48 h of onset. Participants were assigned in a 1:1 ratio using computerrandomisation to receive loading doses and then 30 days of intensiveantiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, anddipyridamole 200 mg twice daily) or guideline-based therapy (comprising eitherclopidogrel alone or combined aspirin and dipyridamole). Randomisation wasstratified by country and index event, and minimised with prognostic baselinefactors, medication use, time to randomisation, stroke-related factors, andthrombolysis. The ordinal primary outcome was the combined incidence andseverity of any recurrent stroke (ischaemic or haemorrhagic; assessed using themodified Rankin Scale) or TIA within 90 days, as assessed by central telephonefollow-up with masking to treatment assignment, and analysed by intention totreat. This trial is registered with the ISRCTN registry, numberISRCTN47823388.
FINDINGS:
3096 participants(1556 in the intensive antiplatelet therapy group, 1540 in the guidelineantiplatelet therapy group) were recruited from 106 hospitals in four countriesbetween April 7, 2009, and March 18, 2016. The trial was stopped early on therecommendation of the data monitoring committee. The incidence and severity ofrecurrent stroke or TIA did not differ between intensive and guideline therapy(93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95%CI 0·67-1·20, p=0·47). By contrast, intensive antiplatelet therapy wasassociated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI2·05-3·16, p<>
INTERPRETATION:
Among patientswith recent cerebral ischaemia, intensive antiplatelet therapy did not reducethe incidence and severity of recurrent stroke or TIA, but did significantlyincrease the risk of major bleeding. Triple antiplatelet therapy should not beused in routine clinical practice.
參考文獻：Antiplatelet therapy with aspirin,clopidogrel, and dipyridamole versus clopidogrel alone or aspirin anddipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised,open-label, phase 3 superiority trial. Lancet. 2018 Mar 3;391(10123):850-859.
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