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. 2021 Oct 22;10(10):CD000024.
doi: 10.1002/14651858.CD000024.pub5.

Anticoagulants for acute ischaemic stroke

Xia Wang  1 , Menglu Ouyang  1 , Jie Yang  2 , Lili Song  3 , Min Yang  4 , Craig S Anderson  1   3
Affiliations

Anticoagulants for acute ischaemic stroke

Xia Wang et al. Cochrane Database Syst Rev. .

Abstract

Background: Stroke is the third leading cause of early death worldwide. Most ischaemic strokes are caused by a blood clot blocking an artery in the brain. Patient outcomes might be improved if they are offered anticoagulants that reduce their risk of developing new blood clots and do not increase the risk of bleeding. This is an update of a Cochrane Review first published in 1995, with updates in 2004, 2008, and 2015.

Objectives: To assess the effectiveness and safety of early anticoagulation (within the first 14 days of onset) for people with acute presumed or confirmed ischaemic stroke. Our hypotheses were that, compared with a policy of avoiding their use, early anticoagulation would be associated with: • reduced risk of death or dependence in activities of daily living a few months after stroke onset; • reduced risk of early recurrent ischaemic stroke; • increased risk of symptomatic intracranial and extracranial haemorrhage; and • reduced risk of deep vein thrombosis and pulmonary embolism.

Search methods: We searched the Cochrane Stroke Group Trials Register (August 2021); the Cochrane Database of Systematic Reviews (CDSR); the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 7), in the Cochrane Library (searched 5 August 2021); MEDLINE (2014 to 5 August 2021); and Embase (2014 to 5 August 2021). In addition, we searched ongoing trials registries and reference lists of relevant papers. For previous versions of this review, we searched the register of the Antithrombotic Trialists' (ATT) Collaboration, consulted MedStrategy (1995), and contacted relevant drug companies.

Selection criteria: Randomised trials comparing early anticoagulant therapy (started within two weeks of stroke onset) with control in people with acute presumed or confirmed ischaemic stroke.

Data collection and analysis: Two review authors independently selected trials for inclusion, assessed trial quality, and extracted data. We assessed the overall certainty of the evidence for each outcome using RoB1 and GRADE methods.

Main results: We included 28 trials involving 24,025 participants. Quality of the trials varied considerably. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition, or reporting bias. Anticoagulants tested were standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. Over 90% of the evidence is related to effects of anticoagulant therapy initiated within the first 48 hours of onset. No evidence suggests that early anticoagulation reduced the odds of death or dependence at the end of follow-up (odds ratio (OR) 0.98, 95% confidence interval (CI) 0.92 to 1.03; 12 RCTs, 22,428 participants; high-certainty evidence). Similarly, we found no evidence suggesting that anticoagulant therapy started within the first 14 days of stroke onset reduced the odds of death from all causes (OR 0.99, 95% CI 0.90 to 1.09; 22 RCTs, 22,602 participants; low-certainty evidence) during the treatment period. Although early anticoagulant therapy was associated with fewer recurrent ischaemic strokes (OR 0.75, 95% CI 0.65 to 0.88; 12 RCTs, 21,665 participants; moderate-certainty evidence), it was also associated with an increase in symptomatic intracranial haemorrhage (OR 2.47; 95% CI 1.90 to 3.21; 20 RCTs, 23,221 participants; moderate-certainty evidence). Similarly, early anticoagulation reduced the frequency of symptomatic pulmonary emboli (OR 0.60, 95% CI 0.44 to 0.81; 14 RCTs, 22,544 participants; high-certainty evidence), but this benefit was offset by an increase in extracranial haemorrhage (OR 2.99, 95% CI 2.24 to 3.99; 18 RCTs, 22,255 participants; moderate-certainty evidence).

Authors' conclusions: Since the last version of this review, four new relevant studies have been published, and conclusions remain consistent. People who have early anticoagulant therapy after acute ischaemic stroke do not demonstrate any net short- or long-term benefit. Treatment with anticoagulants reduced recurrent stroke, deep vein thrombosis, and pulmonary embolism but increased bleeding risk. Data do not support the routine use of any of the currently available anticoagulants for acute ischaemic stroke.

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Conflict of interest statement

Xia Wang: Grants and contracts: investigator grant, post‐doc fellowship (NHMRC National Heart Foundation Australia), "Those grants are for my salary support".

Menglu Ouyang: none known.

Jie Yang: Grants and contracts: funding support (National Natural Science Foundation of China), Grant No. 81870940.

Lili Song: none known.

Min Yang: none known.

Craig Anderson: Grants and contracts: research grants (Takeda China), approximately Aust$1m over 4 grants in as many studies. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events: lecture fees and travel reimbursement (Takeda China), total approximately Aust$10k over 2 years. Payment for a fellowship: research fellowship (National Health and Medical Research Council (NHMRC) of Australia), "pays half my salary". Work as a health professional: "I am a consultant neurologist who manages patients with acute stroke" (Royal Prince Alfred Hospital, Sydney, Australia), clinical academic appointment.

Figures

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Study flow diagram for 2020 update.
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1.1
1.1. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 1: Dead or dependent at end of follow‐up (if > 1 month)
1.2
1.2. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 2: Death from all causes during treatment period
1.3
1.3. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 3: Death from all causes at final follow‐up (if > 1 month)
1.4
1.4. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 4: Deep vein thrombosis during treatment period
1.5
1.5. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 5: Recurrent ischaemic or unknown stroke during treatment period
1.6
1.6. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 6: Symptomatic intracranial haemorrhage during treatment period
1.7
1.7. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 7: Any recurrent stroke or symptomatic intracranial haemorrhage during treatment period or follow‐up (> 1 month)
1.8
1.8. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 8: Symptomatic pulmonary embolism during treatment period
1.9
1.9. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 9: Major extracranial haemorrhage during treatment period
1.10
1.10. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 10: Subgroup analysis by type of anticoagulant agent used: effect on death or dependency
1.11
1.11. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 11: Subgroup analysis by anticoagulant dose: effect on death or dependency
1.12
1.12. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 12: Sensitivity analysis: dead or dependent at end of follow‐up (if > 1 month) in trials with adequate concealment of treatment allocation
1.13
1.13. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 13: Sensitivity analysis: dead or dependent at end of follow‐up (if > 1 month) for patients within 48 hours of stroke onset
1.14
1.14. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 14: Sensitivity analysis: dead or dependent at end of follow‐up (if > 1 month) excluding IST3 trial
1.15
1.15. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 15: Sensitivity analysis: dead or dependent at end of follow‐up (if > 1 month) excluding trial with assessment of primary outcome after only 1 month
1.16
1.16. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 16: Sensitivity analysis: deep vein thrombosis during treatment period restricted to trials where concealment of allocation was secure
1.17
1.17. Analysis
Comparison 1: Anticoagulant vs control in acute presumed ischaemic stroke, Outcome 17: Sensitivity analysis: deep vein thrombosis during treatment period restricted to trials where radiographic assessment was blinded
See this image and copyright information in PMC

Update of

References

References to studies included in this review

ARGIS‐1 2004 {published and unpublished data}
    1. LaMonte MP, Nash ML, Wang DZ, Woolfenden AR, Schulz J, Hursting MJ, et al. Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1). Stroke 2004;35:1677-82. - PubMed
ARTSS‐2 2017 {published data only}
    1. Barreto AD, Ford GA, Shen L, Pedroza C, Tyson J, Cai C, et al. Randomized, multicenter trial of ARTSS-2 (Argatroban with Recombinant Tissue Plasminogen Activator for Acute Stroke). Stroke 2017;48:1608-10. [PMID: ] - PMC - PubMed
Cazzato 1989 {published and unpublished data}
    1. Cazzato G, Zorzon M, Mase G, Antonutto L, Iona LG. Mesoglycan in the treatment of acute cerebral infarction [Il mesoglicano nelle ischemie cerebrali acute a focolaio]. Rivista di Neurologia 1989;59:121-6. - PubMed
CESG 1983 {published and unpublished data}
    1. Hakim AM, Furlan AJ, Hart RG. Immediate anticoagulation of embolic stroke: a randomized trial. The Cerebral Embolism Study Group. Stroke 1983;14:668-76. - PubMed
    1. Hakim AM, Ryder-Cooke A, Melanson D. Sequential computerized tomographic appearances of strokes. Stroke 1983;14:893-7. - PubMed
Chaudhary 2002 {published data only}
    1. Chaudhry HR, Arora H, Yadav K, Dubey S, Gupta R, Jain R. Low molecular weight heparin In acute ischemic stroke. The Antiseptic 2002;99:31-2.
Dluha 2016 {published data only}
    1. Dluha J, Sivak S, Kurca E, Dusenka R, Kalmarova K, Koprusakova MT, et al. The safety and efficacy of heparin and nadroparin compared to placebo in acute ischemic stroke - pilot study. Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia 2016;160:543-8. [PMID: ] - PubMed
Duke 1983 {published and unpublished data}
    1. Duke RJ, Turpie AGG, Bloch RF, Derby IR, Kronby MH, Bayer NH. Clinical trial of low-dose heparin for the prevention of stroke progression. Circulation 1980;Suppl III:21.
    1. Duke RJ, Turpie AGG, Bloch RF, Trebilcock RG. Clinical trial of low-dose subcutaneous heparin for the prevention of stroke progression: natural history of acute partial stroke and stroke-in-evolution. In: Reivich M, Hurtig HI, editors(s). Cerebrovascular Disease. New York: Raven Press, 1983:399-405.
Duke 1986 {published and unpublished data}
    1. Duke RJ, Bloch RF, Turpie AGG, Trebilcock RG, Bayer N. Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Annals of Internal Medicine 1986;105:825-8. - PubMed
    1. Duke RJ, Bloch RF, Turpie AGG. Heparin in acute partial stable stroke. Annals of Internal Medicine 1987;106:782. - PubMed
    1. Easton JD, Sherman DG, Hart RG. Heparin in acute partial stable stroke. Annals of Internal Medicine 1987;106:781. - PubMed
    1. Loeliger EA. Heparin in acute partial stable stroke. Annals of Internal Medicine 1987;106:781-2. - PubMed
Elias 1990 {published and unpublished data}
    1. Elias A, Milandre L, Lagrange G, Aillaud MF, Alonzo B, Toulemonde F, et al. Prevention of deep venous thrombosis of the leg by a very low molecular weight heparin fraction (CY 222) in patients with hemiplegia following cerebral infarction: a randomized pilot study (30 patients). Revue de Medecine Interne 1990;11:95-8. - PubMed
FISS 1995 {published and unpublished data}
    1. Kay R, Wong KS, Lu YL, Chan YW, Tsoi TH, Ahuja AT, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. New England Journal of Medicine 1995;333:1588-93. - PubMed
    1. Kay R. Fraxiparin in stroke study. Stroke 1994;25:253.
FISS‐bis 1998 {published data only}
    1. Hommel M, for the FISS-bis Investigators Group. Fraxiparine in Ischaemic Stroke Study (FISS bis). Cerebrovascular Diseases 1998;8 Suppl 4:19.
IST 1997 {published data only}
    1. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997;349:1569-81. - PubMed
    1. International Stroke Trial Pilot Study Collaborative Group. Study design of the International Stroke Trial (IST), baseline data, and outcome in 984 randomised patients in the pilot study. Journal of Neurology Neurosurgery and Psychiatry 1996;60:371-6. - PMC - PubMed
    1. Saxena R, Lewis S, Berge E, Sandercock P, Koudstaal P, for the International Stroke Trial Collaborative Group. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischaemic stroke and atrial fibrillation in the International Stroke Trial. Stroke 2001;32:2333-7. - PubMed
Kwiecinski 1995 {published and unpublished data}
    1. Kwiecinski H, Pniewski J, Kaminska A, Szyluk B. A randomized trial of fraxiparine in acute ischaemic stroke. Cerebrovascular Diseases 1995;5:234.
Liu 2020 {published data only}
    1. Liu S, Liu P, Wang P, Zhang F, Wang l, Wang Y, et al. Argatroban increased the basal vein drainage and improved outcomes in acute paraventricular ischemic stroke patients. Medical Science Monitor 2020;26:e924593. - PMC - PubMed
Marshall 1960 {published data only}
    1. Marshall J, Shaw DA. Anticoagulant therapy in acute cerebrovascular accidents: a controlled trial. Lancet 1960;1:995-8. - PubMed
    1. Marshall J, Shaw DA. Anticoagulant therapy in cerebrovascular disease. In: Proceedings of the Royal Society of Medicine. 1960:547-9. - PMC - PubMed
McCarthy 1977 {published and unpublished data}
    1. McCarthy ST, Turner JJ, Robertson D, Hawkey CJ, Macey DJ. Low dose heparin as a prophylaxis against deep-vein thrombosis after acute stroke. Lancet 1977;ii:800-1. - PubMed
McCarthy 1986 {published and unpublished data}
    1. McCarthy ST, Turner J. Low-dose subcutaneous heparin in the prevention of deep-vein thrombosis and pulmonary emboli following acute stroke. Age and Ageing 1986;15:84-8. - PubMed
NAT‐COOP 1962 {published data only}
    1. Baker RN, Broward JA, Fang HC, Fisher CM, Groch SN, Heyman A, et al. Anticoagulant therapy in cerebral infarction. Report on co-operative study. Neurology 1962;12:823-9.
    1. Miller Fisher C. Anticoagulant therapy in cerebral thrombosis and cerebral embolism. A national cooperative study, interim report. Neurology 1961;11:119-31. - PubMed
Pambianco 1995 {published and unpublished data}
    1. Desmukh M, Bisignani M, Landau P, Orchard TJ. Deep vein thrombosis in rehabilitating stroke patients. Incidence, risk factors and prophylaxis. American Journal of Physical Medicine and Rehabilitation 1991;70:313-6. - PubMed
    1. Pambianco G, Orchard T, Landau P. Deep vein thrombosis: prevention in stroke patients during rehabilitation. Archives of Physical Medicine and Rehabilitation 1995;76:324-30. - PubMed
Pince 1981 {unpublished data only}
    1. Pince J. Thromboses veineuses des membres inferieurs et embolies pulmonaires au cours des accidents vasculaires cerebraux. A propos d'un essai comparitif de traitement preventif (These pour le doctorat d'etat en medecine). Toulouse: Universite Paul Sabatier, 1981.
Prins 1989 {published and unpublished data}
    1. Prins MH, den Ottolander GJH, Gelsema R, Woerkom TCM, Sing AK, Heller I. Deep venous thrombosis prophylaxis with a LMW heparin (KABI 2165) in stroke patients. Thrombosis and Haemostasis 1987;58:117. - PubMed
    1. Prins MH, Gelsema R, Sing AK, Heerde LR, den Ottolander GJ. Prophylaxis of deep venous thrombosis with a low-molecular-weight heparin (Kabi 2165/Fragmin) in stroke patients. Haemostasis 1989;19:245-50. - PubMed
Sandset 1990 {published and unpublished data}
    1. Sandset PM, Dahl T, Abildgaard U. Venous thromboembolic complications in acute thrombotic stroke. Progress report from a randomized trial. Acta Neurologia Scandinavica 1987;76:392.
    1. Sandset PM, Dahl T, Stiris M, Rostad B, Scheel B, Abildgaard U. A double-blind and randomized placebo-controlled trial of low molecular weight heparin once daily to prevent deep-vein thrombosis in acute ischemic stroke. Seminars in Thrombosis and Hemostasis 1990;16 Suppl:25-33. - PubMed
Sarma 2003 {published data only}
    1. Sarma GR, Roy AK. Nadroparin plus aspirin versus aspirin alone in the treatment of acute ischemic stroke. Neurology India 2003;51:208-10. [PMID: ] - PubMed
Tazaki 1986 {published data only}
    1. Tazaki Y, Kobayashi S, Togi H, Ohtomo E, Goto F, Araki G, et al. Therapeutic effect of thrombin inhibitor MD-805 in acute phase of cerebral thrombosis - Phase II double-blinded clinical trial (English translation). Rinsho to Kenkyu (Japanese Journal of Clinical and Experimental Medicine) 1986;63:3047-57.
Tazaki 1992 {published data only}
    1. Tazaki Y, Kobayashi S, Togi H, Ohtomo E, Goto F, Araki G, et al. Clinical usefulness of thrombin inhibitor MD-805 in acute phase of cerebral thrombosis - double blinded comparative study using placebo as a control (English translation). Igaku no Ayumi (Journal of Clinical and Experimental Medicine) 1992;161:887-907.
TOAST 1998 {unpublished data only}
    1. Adams JHP. Trial of Org 10172 in Acute Stroke Treatment (TOAST). Stroke 1994;25:545.
    1. TOAST Investigators. Low molecular weight heparinoid, ORG 10172 (Danaparoid), and outcome after acute ischaemic stroke. JAMA 1998;279:1265-72. - PubMed
Turpie 1987 {published and unpublished data}
    1. Turpie AGG, Levine MN, Hirsh J, Carter CJ, Jay RM, Powers PJ, et al. A double-blind randomized trial of Org 10172 low molecular weight heparinoid in the prevention of deep venous thrombosis in patients with thrombotic stroke. Thrombosis and Haemostasis 1987;58:123. - PubMed
    1. Turpie AGG, Levine MN, Hirsh J, Carter CJ, Jay RM, Powers PJ, et al. Double-blind randomised trial of Org 10172 low-molecular-weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke. Lancet 1987;1:523-6. - PubMed
    1. Turpie AGG. Low molecular weight heparins: deep vein thrombosis prophylaxis in elective hip surgery and thrombotic stroke. Acta Chirurgica Scandinavica Supplementum 1988;543:85-6. - PubMed
Vissinger 1995 {unpublished data only}
    1. Vissinger H, Husted S. Trial of tinzaparin versus placebo in ischaemic stroke. Unpublished work.

References to studies excluded from this review

Afshari 2015 {published data only}
    1. Afshari D, Moradian N, Nasiri F, Razazian N, Bostani A, Sariaslani P. The efficacy and safety of low-molecular-weight heparin and unfractionated heparin in the treatment of cerebral venous sinus thrombosis. Neurosciences (Riyadh, Saudi Arabia) 2015;20(4):357-61. - PMC - PubMed
Amarenco 2014 {published data only}
    1. Amarenco P, Davis S, Jones EF, Cohen AA, Heiss WD, Kaste M, et al. Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques. Stroke 2014;45(5):1248-57. - PubMed
Asberg 2018 {published data only}
    1. Asberg S, Hijazi Z, Norrving B, Wester P, Ohagen P, Oldgren J. Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation: the first registry-based randomised controlled stroke trial. European Stroke Journal 2018;3(1):611. - PMC - PubMed
Bergmann 1996 {published data only}
    1. Bergmann JF, Neuhart E. A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute medical illness. Thrombosis and Haemostasis 1996;76:529-34. - PubMed
Bradshaw 1975 {published data only}
    1. Bradshaw P, Brennan S. Trial of long-term anticoagulant therapy in the treatment of small stroke associated with a normal carotid angiogram. Journal of Neurology, Neurosurgery and Psychiatry 1975;38:642-7. - PMC - PubMed
Camerlingo 2005 {published data only}
    1. Camerlingo M, Salvi P, Belloni G, Gamba T, Cesana BM, Mamoli A. Intravenous heparin started within the first 3 hours after onset of symptoms as a treatment for acute non-lacunar hemispheric cerebral infarctions. Stroke 2005;36:2415-20. - PubMed
Carter 1961 {published data only}
    1. Carter AB. Anticoagulant treatment in progressing stroke. BMJ 1961;II:70-3. - PMC - PubMed
    1. Carter AB. Use of anticoagulants in patients with progressive cerebral infarction. Neurology 1961;11:601-9. - PubMed
Chang 2002 {published data only}
    1. Chang KC, Tan TY, Liou CW, Chen SD, Gung C. Nadroparin in moderate acute ischemic stroke trial. Stroke 2002;33:386.
Chen 2019 {published data only}
    1. Chen JH, Zhang C, Zhang CX. Optimal timing to administer non-vitamin K oral anticoagulants (NOACS) and rivaroxaban in patients with acute ischemic stroke and nonvalvular atrial fibrillation. Journal of the American Geriatrics Society 2019;67:S629-S630.
ChiCTR‐OIN‐17013510 {published data only}
    1. ChiCTR-OIN-17013510. Safety and efficacy of intravenous tirofiban in acute ischemic stroke patient without large arterial occlusion. http://www.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-OIN-17013510 (first received 23 November 2017). - PubMed
COU 9116 {unpublished data only}
    1. Oczkowski WJ. A randomised trial of fixed low dose warfarin in the prevention of deep vein thrombosis in patients undergoing rehabilitation after stroke (Cou 9116). Unpublished protocol.
Coutinho 2015 {published data only}
    1. Coutinho JM, Ferro JM, Zuurbier SM, Canhao P, Crassard I, Majoie CB, et al. Thrombolysis or anticoagulation for cerebral venous thrombosis (TO-ACT trial). International Journal of Stroke 2015;10:434-5. - PubMed
Crepin‐leblond 1994 {published data only}
    1. Crepin-leblond T, Moulin T, Ziegler F, Bataillard M, Chopard JL, Chavot D, et al. A randomised trial of heparin therapy in acute ischemic stroke: first results. Cerebrovascular Diseases 1994;4:259.
Czechanowski 1981 {published data only}
    1. Czechanowski B, Heinrich F. Prevention of venous thrombosis in recent ischaemic cerebrovascular accident: double-blind study with heparin-dihydroergotamine. Deutsche Medizinische Wochenschrift 1981;106:1254-60. - PubMed
Dahan 1986 {published data only}
    1. Dahan R, Houlbert D, Caulin C, Cuzin E, Viltart C, Woler M, et al. Prevention of deep vein thrombosis in elderly medical in-patients by a low molecular weight heparin: a randomized double-blind trial. Haemostasis 1986;16:159-64. - PubMed
Dan 2001 {published data only}
    1. Dan G, Gonta A, Serbanescu A, Ionete C. Improvement of outcome in patients with acute ischaemic stroke treated with fragmin. Haemostasis 2001;30 Suppl 2:168-9.
DATAS II 2020 {published data only}
    1. Butcher K, Ng K, Field T, Coutts S, Gioia L, Siddiqui M, et al. The dabigatran following acute transient ischemic attack and minor stroke trial: final results. European Stroke Journal 2018;3(1):3.
    1. Butcher K, Ng K, Sheridan P, Field T, Coutts S, Siddiqui M, et al. Dabigatran treatment for acute noncardioembolic ischemic stroke. Stroke 2020;51:1190-8. - PubMed
    1. Ng KH, Sharma M, Benavente O, Gioia L, Field TS, Hill MD, et al. Dabigatran following acute transient ischemic attack and minor stroke (DATAS II). International Journal of Stroke 2017;12:910-4. - PubMed
Dehen 1994 {unpublished data only}
    1. Dehen H, on behalf of Laboratoire Houde. Double blind placebo controlled study of dermatan sulphate in acute middle cerebral artery infarct [Etude en double aveugle, controlee contre placebo, du dermatane sulfate (RU 54 701) dans le traitement precoce de l'infarctus sylvien]. Unpublished work.
Diener 2005 {published data only}
    1. Diener HC, Ringelstein EB, Kummer R, Harenberg J, Koppenhagen K, Landgraf H, et al. Prevention of thromboembolic complications in acute ischemic stroke by the low-molecular-weight heparin certoparin (PROTECT). Stroke 2005;36:420.
Dong 2003 {published data only}
    1. Dong Q, Lu CZ, Zhen HM. Low-molecular-weight heparin for the treatment of acute ischemic stroke: a randomized controlled trial. Neurology 2003;60:A228.
Donnan 1996 {published data only}
    1. Donnan GA, Davis SM, Gerraty RP, Mitchell PJ, Fitt G, Bladin CF, et al. Australian urokinase stroke trial (AUST). Cerebrovascular Diseases 1996;6 Suppl 2:25.
Dumas 1994 {published data only}
    1. Dumas R, Woitinas F, Kutnowski M, Nikolic I, Berberich R, Adeninpour F, et al. A multicentre, double-blind, randomized study to compare the safety and efficacy of once-daily org 10172 and twice-daily low dose heparin in preventing deep-vein thrombosis in patients with acute ischemic stroke. Age and Ageing 1994;23:512-6. - PubMed
Egan 1999 {published data only}
    1. Egan R, Clark W, Lutsep H, Nesbit G, Barnwell S, Kellogg J. Efficacy of intraarterial thrombolysis of basilar artery stroke. Journal of Stroke and Cerebrovascular Diseases 1999;8:22-7. - PubMed
Egberts 1996 {unpublished data only}
    1. Egberts JFM, Sommer W. Multicentre, randomised, assessor-blind, dose-comparative study of org 10172 (orgaron (r)) in the treatment of acute ischaemic stroke. Unpublished data 1996.
ELAN 2017 {published data only}
    1. Fischer U, Paciaroni M, Strbian D, Seiler S, Ntaios G, Nedeltchev K, et al. Early versus late initiation of direct oral anticoagulation in postischaemic stroke patients with atrial fibrillation (ELAN). European Stroke Journal 2017;2:492-3.
    1. Fischer U, Strbian D, Paciaroni M, Thomalla G, Ntaios G, Bonati L, et al. Early versus late initiation of direct oral anticoagulants in postischaemic stroke patients with atrial fibrillation (ELAN): an international multicentre, randomised-controlled, two-arm, assessor-blinded trial. European Stroke Journal 2019;4:812. - PMC - PubMed
EMT 1992 {unpublished data only}
    1. European Multicenter Team. Randomized pilot study of org 10172 vs. heparin in acute stroke. Unpublished data 1992.
Enger 1965 {published data only}
    1. Enger E, Boyesen S. Long term anticoagulant therapy in patients with cerebral infarction: a controlled clinical study. Acta Medica Scandinavica 1965;178 Suppl 438:7-61. - PubMed
England 2010 {published data only}
    1. England TJ, Bath PMW, Sare GM, Geeganage C, Moulin T, O'Neill D, et al. Asymptomatic hemorrhagic transformation of infarction and its relationship with functional outcome and stroke subtype: assessment from the Tinzaparin in Acute Ischaemic Stroke Trial. Stroke 2010;41:2834-9. - PubMed
Eriksson 1983 {published data only}
    1. Eriksson S-E, Link H. Evaluation of anticoagulants in patients with cerebral infarction with slight to moderate neurological deficit. Acta Neurologica Scandinavica 1983;68:96-106. - PubMed
Fang 2015 {published data only}
    1. Fang Y, Wenrui J, Ya B, Junliang H, Xueedong L, Guangyun Z, et al. Treatment of rivaroxaban versus aspirin for non-disabling cerebrovascular events (TRACE): study protocol for a randomized controlled trial. BMC Neurology 2015;15:195. - PMC - PubMed
Fassbender 1998 {published data only}
    1. Fassbender K, Eschenfelder C, Hennerici M. Effects of rt-pa thrombolysis and heparin treatment on fibrinolysis and coagulation in acute ischemic stroke. Cerebrovascular Diseases 1998;8 Suppl 4:16.
Field 2017 {published data only}
    1. Field TS, Hill M, Benavente O, Demchuck A, Dowlatshahi D, Honig A. SECRET: safety of rivaroxaban for cerebral venous thrombosis. International Journal of Stroke 2017;12:22.
Fradley 2014 {unpublished data only}
    1. Fradley M. Apixaban for early prevention of recurrent embolic stroke and hemorrhagic transformation. Unpublished data 2014. - PMC - PubMed
Geisler 2017 {published data only}
    1. Geisler T, Poli S, Meisner C, Schreieck J, Zuern CS, Nagele T, et al. Apixaban for treatment of embolic stroke of undetermined source (atticus randomized trial): rationale and study design. International Journal of Stroke 2017;12:985-90. - PubMed
Gelmers 1980 {published data only}
    1. Gelmers HJ. Effects of low-dose subcutaneous heparin on the occurrence of deep vein thrombosis in patients with ischemic stroke. Acta Neurologica Scandinavica 1980;61:313-8. - PubMed
Grond 2000 {published data only}
    1. Grond M, Schneweis S, Heiss WD. Risk of concomitant heparin treatment in systemic thrombolysis of acute ischemic stroke. Stroke 2000;31:2884.
HAEST 2000 {published data only}
    1. Berge E, Abdelnoor M, Nakstad PH, Sandset PM, on behalf of the HSG. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet 2000;355:1205-10. - PubMed
Hillbom 1999 {published data only}
    1. Hillbom M, Erila T, Sotaniemi K, Floschbach CW, Tatlisumak T, Sarna S, et al. Comparison of the efficacy and safety of the low-molecular-weight heparin enoxaparin with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. Blood 1999;94:183a.
Hillbom 2002 {published data only}
    1. Hillbom M, Erila T, Sotaniemi K, Tatlisumak T, Sarna S, Kaste M. Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study. Acta Neurologica Scandinavica 2002;106:84-92. - PubMed
Hossman 1986 {published data only}
    1. Hossman V, Loettgen J, Auel H, Bewermeyer H, Heiss WD. Prophylaxis of deep vein thrombosis in acute stroke. A prospective, randomised double blind study. Haemostasis 1986;16 Suppl 5:54.
Hui 2016 {published data only}
    1. Hui Y. The clinical efficacy research for the treatment among intravenous unfractionated heparin, two antiplatelet agents (clopidogrel and aspirin) and single antiplatelet agent (aspirin) to acute cerebral infarction and transient ischemic attack (TIA). Unpublished data 2016.
IRCT2014020213698N1 {unpublished data only}
    1. IRCT2014020213698N1. The study of the efficacy, safety and tolerability of low molecular weight heparin vs. unfractionated heparin in patients with embolic stroke due to atrial fibrillation. https://www.irct.ir/trial/13492 (first received 2 February 2014). - PMC - PubMed
    1. NCT02159287. Study of the efficacy, safety and tolerability of low molecular weight heparin vs. unfractionated heparin in stroke. https://clinicaltrials.gov/ct2/show/NCT02159287 (first received 9 June 2014).
IRCT201407213106N18 {published data only}
    1. IRCT201407213106N18. Evaluation of different doses administration of clopidogrel in acute ischemic stroke. http://www.who.int/trialsearch/Trial2.aspx?TrialID=IRCT201407213106N18 (first received 5 March 2015).
ISRCTN25644448 {unpublished data only}
    1. Ferro JM, Miranda B. Extending oral anticoagulant treatment after acute cerebral vein thrombosis (EXCOA-CVT): a cluster randomised study. European Stroke Conference 2014.
    1. ISRCTN25644448. The benefit of extending oral blood thinning (anticoagulant) treatment after acute blockage of cerebral veins (cerebral venous thrombosis-CVT) (EX-COA CVT). https://www.isrctn.com/search?q=25644448 (first received 10 April 2014).
Ji 2017 {published data only}
    1. Jin F. A randomized controlled study on the second-level prevention of dabigatran and warfarin in atrial fibrillation associated ischemic stroke/TIA acute phase. Unpublished data 2017.
Jin 2017 {unpublished data only}
    1. Jin F. A randomized controlled study on the second-level prevention of dabigatran and warfarin in atrial fibrillation associated ischemic stroke/TIA acute phase. Unpublsihed data 2017.
JPRN‐UMIN000014405 {published data only}
    1. JPRN-UMIN000014405. Argatroban, aspirin and clopidgrel combination therapy for non-cardioembolic acute ischemic stroke - a prospective, randomized, argatroban and aspirin-controlled study. http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000014405 (first received 27 June 2014).
JPRN‐UMIN000025392 {published data only}
    1. JPRN-UMIN000025392. Optimal antithrombotic therapy in ischemic stroke patients with non-valvular atrial fibrillation and atherothrombosis. http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000025392 (first received 1 February 2017).
Kamel 2018 {published data only}
    1. Kamel H. Atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke. International Journal of Stroke 2019;14:207-14. - PMC - PubMed
Kang 2010 {published data only}
    1. Kang K, Kim DW, Park H-K, Yoon B-W. Optimal dosing of intravenous unfractionated heparin bolus in transient ischaemic attack or stroke. Clinical and Applied Thrombosis/Haemostasis 2010;16(2):126-31. - PubMed
Kario 1995 {published data only}
    1. Kario K, Kodama K, Koide M, Matsuo T. Thrombin inhibition in the acute phase of ischaemic stroke using argatroban. Blood Coagulation and Fibrinolysis 1995;6:423-7. - PubMed
Kataoka 2000 {published data only}
    1. Kataoka S, Hirose G, Hori A, Shirakawa T. Early anticoagulation with heparin in vertebrobasilar occlusive disease. Journal of Stroke and Cerebrovascular Diseases 2000;9(2 Suppl 1):185-6.
Kim 2003 {published data only}
    1. Kim WJ, Lee KM, Park KW, Kim SH, Kim JW, Jeong MH, et al. Changes of platelet activation and clinical outcome in acute atherosclerotic cerebral infarction treated with clopidogrel loading dose (300 mg). Journal of the Korean Neurological Association 2003;21:128-33.
Kobayashi 1997 {published data only}
    1. Kobayashi S, Tazaki Y. Effect of the thrombin inhibitor argatroban in acute cerebral thrombosis. Seminars in Thrombosis and Hemostasis 1997;23:531-4. - PubMed
Lee 1994 {published data only}
    1. Lee JH, Seo DC, Kim JS, Lee MC. Therapeutic efficacy of urokinase and heparin in acute ischemic stroke. Stroke 1994;25:268.
Lee 2008 {published data only}
    1. Lee SH, Ahn YM, Ahn SY, Doo HK, Lee BC. Interaction between warfarin and panax ginseng in ischaemic stroke patients. Journal of Alternative and Complementary Medicine 2008;14(6):715-21. - PubMed
Lee 2014 {published data only}
    1. Lee SH, Kim HY, Bae HJ, Yu KH, Kim GM, Kim DE, et al. Clopidogrel and aspirin versus aspirin alone for prevention of recurrent ischemic lesion in acute atherothrombotic stroke: a randomized, double-blind, placebo-controlled trial. Stroke 2014;45:ATP334.
Liu 2015 {published data only}
    1. Liu MC, Li FP, Han YL, Chen HS. Argatroban versus aspirin plus clopidogrel in the treatment of acute ischemic stroke: a pilot, randomised, open-label study. Medical Journal of Chinese People's Liberation Army 2015;40(6):433-9.
Lu 2001 {published data only}
    1. Lu CZ. Low-molecular-weight heparin for the treatment of acute ischemic stroke: a randomized controlled trial. Hong Kong Medical Journal 2001;7:9-10.
Luo 2013 {published data only}
    1. Luo W-L, He Y, Lee M, Ceng W. Safety and effects of using warfarin early in adult patients with cerebral venous and sinus thrombosis. Cerebrovascular Diseases 2013;36 Suppl 1:51.
McCarthy 1993 {unpublished data only}
    1. McCarthy S, McWalter R, Durkin CJ, Hallawi AH, Magnani HN, Pearson J, et al. Org 10172 for the prophylaxis of deep venous thrombosis in the legs (A protocol to establish the efficacy and safety of once or twice daily subcutaneous Org 10172 injections versus placebo in three groups of 60 non-haemorrhagic stroke victims). Unpublished protocol.
McDevitt 1959 {published data only}
    1. Groch SN, McDevitt E, Wright IS. A long-term study of cerebral vascular disease. Annals of Internal Medicine 1961;55:358-67. - PubMed
    1. McDevitt E, Groch SN, Wright IS. A cooperative study of cerebrovascular disease. Circulation 1959;20:215-23. - PubMed
    1. McDowell F, McDevitt E, Wright IS. Anticoagulant therapy: five years' experience with the patient with an established cerebrovascular accident. Archives of Neurology 1963;8:209-14.
    1. McDowell F, McDevitt E. Treatment of the completed stroke with long-term anticoagulant: six and one-half years experience. In: Siekert RG, Whisnant JP, editors(s). Cerebral Vascular Diseases. New York: Grune & Stratton Inc, 1965:185-99.
Melero 2007 {published data only}
    1. Melero MJ, Bergroth B, Contardo DM, Mazzei MM, Ricci S, Celani MG, et al. Prevention of venous thromboembolism after acute ischaemic stroke. Lancet 2007;370:735-7. - PubMed
Meredit 2009 {published data only}
    1. Meredit T, Ahmad O, Harvey I, Hughes A, Lindley R, Neeman T, et al. The Acute Cardioembolic Stroke Trial. International Journal of Stroke 2009;4 Suppl 1:20-1.
Moulin 1994 {published data only}
    1. Moulin T, Crepin-Leblond T. Protocol: Phase III trial using heparin full dose versus low weight heparinoid (preventive dose) in patients with carotid ischemia (< 24 hours). Unpublished data 1994.
Muck 1997 {published data only}
    1. Muck AOHH, Heinrich F. How effective is low molecular weight heparin combined with dihydroergotamine? Prevention of thromboembolism in acute ischemic stroke. Krankenhausarzt 1997;70:359-63.
NAVIGATE ESUS 2014 {published data only}
    1. Ameriso S, Lavados P, Arauz A, Gagliardi RJ, Shoamanesh A, Pater C, et al. NAVIGATE ESUS: phase-III RCT assessing prevention of stroke and systemic embolism in patients with embolic stroke of undetermined source. Journal of the Neurological Sciences 2015;357 Suppl 1:e364-5.
    1. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. New England Journal of Medicine 2018;378:2191-201. - PubMed
    1. Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD, et al. Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: design of the NAVIGATE ESUS randomized trial. European Stroke Journal 2016;1:146-54. - PMC - PubMed
    1. Jin X, Figueroa C, Chen H, Pudov E, Yang Y, Brola W, et al. Rivaroxaban for secondary prevention in patients with embolic strokes of undetermined source: design of the NAVIGATE ESUS randomized trial. European Stroke Journal 2017;2:334-5. - PMC - PubMed
    1. Sharma M, Field T, Teal P, Coutts S, Shuaib A, Stotts G, et al. Navigate ESUS: multicenter, randomized, double-blind, phase III study of prevention of recurrent stroke and systemic embolism in patients with recent embolic stroke of undetermined source. International Journal of Stroke 2015;10:36-7.
NCT01924325 {published data only}
    1. NCT01924325. Apixaban versus Dual-antiplatelet therapy (clopidogrel and aspirin) in Acute Non-disabling Cerebrovascular Events (ADANCE). https://clinicaltrials.gov/ct2/show/NCT01924325 (first received 16 August 2013).
NCT02221102 {published data only}
    1. NCT02221102. Edoxaban for TIA and acute minor stroke. https://clinicaltrials.gov/show/NCT02221102 (first received 20 August 2014).
NCT02283294 {published data only}
    1. NCT02283294. A randomized controlled study on the second-level prevention of dabigatran and warfarin in atrial fibrillation associated ischemic stroke/TIA acute phase. https://clinicaltrials.gov/ct2/show/NCT02283294 (first received 5 November 2014).
NCT03961334 {published data only}
    1. NCT03961334. MidregiOn proatrial natriuretic peptide to guide SEconadry Stroke prevention: the MOSES-study. An international, multicentre, randomised-controlled, two-arm, assessor-blinded trial. https://clinicaltrials.gov/ct2/show/NCT03961334 (first received 23 May 2019).
OPTIMAS 2018 {published data only}
    1. Best J, Bennett K, Caverly E, Cohen H, Dore C, Fenner R, et al. Optimas: a randomised controlled trial to establish the optimal timing of anticoagulation after acute ischaemic stroke. European Stroke Journal 2019;4:810.
PREVAIL 2004 {published data only}
    1. Sherman DG, Albers GW, Bladin C, Fieschi C, Gabbai AA, Kase CS, et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL study): an open-label randomised comparison. Lancet 2007;369:1347-55. - PubMed
RAPID 2005 {published data only}
    1. Chamorro A, Busse O, Obach V, Toni D, Sandercock P, Reverter JC, et al. The Rapid Anticoagulation Prevents Ischemic Damage study in acute stroke - final results from the Writing Committee. Cerebrovascular Diseases 2005;19:402-4. - PubMed
RESPECT CVT 2018 {published data only}
    1. Ferro JM, Coutinho JM, Dentali F, Kobayashi A, Alasheev A, Canhao P, et al. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurology 2019;76:1457-65. - PMC - PubMed
RE‐SPECT ESUS 2019 {published data only}
    1. Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source. New England Journal of Medicine 2019;380:1906-17. - PubMed
    1. Diener HC, Sacco RL, Easton JD, Granger CB, Cronin L, Fraessdorf M, et al. RE-SPECT ESUS, a study of dabigatran versus acetylsalicylic acid for stroke prevention in patients with embolic stroke of undetermined source: baseline predictors of recurrent stroke. European Stroke Journal 2019;4:262-3.
Rha 2001 {published data only}
    1. Rha JH. Acute ischemic stroke trial - oral aspirin vs intravenous. Heparin on stroke progression. Aist-ash 2001.
Rose 2019 {published data only}
    1. Rose DZ, Meriwether JN, Fradley MG, Renati S, Martin RC, Kasprowicz T, et al. Protocol for AREST: apixaban for early prevention of recurrent embolic stroke and hemorrhagic transformation: a randomized controlled trial of early anticoagulation after acute ischemic stroke in atrial fibrillation. Frontiers in Neurology 2019;10:https://doi.org/10.3389/fneur.2019.00975. - PMC - PubMed
Rosin 1994 {unpublished data only}
    1. Rosin A, Abramovitz Z. Preventing deep venous thrombosis following acute strokes. Unpublished protocol.
Shi 2004 {published data only}
    1. Shi J, Zhang Y. The clinical observation of low molecular weight heparin calcium in treating patients with acute cerebral infarction. Pharmaceutical Care and Research 2004;4:258-9.
SOCRATES 2016 {published data only}
    1. Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans S, et al. Ticagrelor vs. aspirin in acute stroke or transient ischemic attack: primary results of the socrates randomized trial. European Stroke Journal 2016;1:708-9.
    1. Wong KSL, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, et al. Efficacy and safety of ticagrelor in relation to prior aspirin usage in the Socrates trial. Stroke 2018;49:1678. - PMC - PubMed
Stiekema 1988 {unpublished data only}
    1. Stiekema JCJ, Egberts J, Voerman J. An open, randomised, rising dose, pilot two-centre study of Org 10172 administered for the purpose of deep vein thrombosis prophylaxis in patients with a non-haemorrhagic stroke on recent onset. Organon International 1988 (SDG Release Report 2244).
TAIST 2001 {published data only}
    1. Investigators Team, Bath PM, editors. Tinzaparin in acute ischaemic stroke trial (TAIST). Unpublished data 2000.
Tan 1998 {published data only}
    1. Tan L, Li TS, Zhao RL. Nardoparin in treating cerebral embolism and thrombosis. Chinese Journal of New Drugs and Clinical Remedies 1998;17:325-6.
Thygesen 1964 {published data only}
    1. Thygesen P, Christensen E, Dyrbye M, Eiken M, Franzen E, Gormsen J, et al. Cerebral apoplexy: a clinical, radiological, electroencephalographic and pathological study with special reference to the prognosis of cerebral infarction and the result of long-term anticoagulant therapy. Danish Medical Bulletin 1964;11:233-57. - PubMed
Tomek 2011 {published data only}
    1. Tomek A, Matoska V, Kumstyrova T, Sramek M, Sarbochova I, Stovickova K, et al. Warfarin loading dose guided by pharmacogenetics is effective and safe in cardioembolic stroke patients. Cerebrovascular Diseases 2011;31 Suppl 2:31.
Toni 2000 {published data only}
    1. Toni D, Argentino C, Fieschi C. Heparin versus aspirin in ischaemic stroke. Lancet 2000;356:504-5. - PubMed
Trencev 2008 {published data only}
    1. Trencev R, Stojanov M, Petrovska-Cvetkovska D, Georgievska A, Baneva N, Radulovic-Bekarovska S. Low-molecular-weight heparin vs aspirin in treatment of cardioembolic stroke. International Journal of Stroke 2008;3:315-6.
Triple AXEL 2015 {published data only}
    1. Hong KS, Choi YJ, Kwon SU. Rationale and design of triple axel: trial for early anticoagulation in acute ischemic stroke patients with nonvalvular atrial fibrillation. International Journal of Stroke 2015;10:128-33. - PubMed
    1. Hong KS, Kwon SU, Lee SH, Lee JS, Kim YJ, Song TJ, et al. Rivaroxaban vs warfarin sodium in the ultra-early period after atrial fibrillation-related mild ischemic stroke: a randomized clinical trial. JAMA Neurology 2017;74:1206-15. - PMC - PubMed
    1. Hong KS, Lee JS, Kim YJ, Kim YD, Kang HG, Park MS, et al. Trial of early anticoagulation with rivaroxaban versus warfarin in patients with and acute cerebral ischemia. European Stroke Journal 2016;1:699-700.
Tsuchiya 1989 {published data only}
    1. Tsuchiya T, Fujikake K, Oku K. Effects of urokinase and heparin on haemorrhagic infarction, recanalisation, recurrence - analysis of 111 cases with middle cerebral artery occlusion on a prospective controlled trial [author's translation]. Japanese Journal of Stroke 1989;11:500-10.
Tsuchiya 1990 {published data only}
    1. Tsuchiya T, Fujikake K, Oku K. A study on clinical effects of urokinase and heparin for acute lacunar infarcts in a prospective controlled trial. Japanese Journal of Stroke 1990;11:177-84.
Turpie 1991 {published data only}
    1. Turpie AGG, Levine MN, Powers PJ, Ginsberg JG, Jay RM, Klimek M, et al. A double blind randomized trial of org 10172 low molecular weight heparinoid versus unfractionated heparin in the prevention of deep venous thrombosis in patients with thrombotic stroke. Thrombosis and Haemostasis 1991;65(6):753.
Turpie 1992 {published data only}
    1. Turpie AGG, Gent M, Cote R, Levine MN, Ginsberg JS, Powers PJ, et al. A low molecular weight heparinoid compared with unfractionated heparin in the prevention of deep vein thrombosis in patients with acute ischemic stroke. Annals of Internal Medicine 1992;117:353-7. - PubMed
VA Study 1961 {published data only}
    1. Baker RN. An evaluation of anticoagulant therapy in the treatment of cerebrovascular disease. Report of the Veterans Administration Cooperative Study of Atherosclerosis, Neurology Section. Neurology 1961;11:132-8. - PubMed
Warach 2003 {published data only}
    1. Warach S. Combination anti-platelet and anti-coagulation treatment after lysis of ischemic stroke trial. Unpublished data 2003.
Wellington 2002 {published data only}
    1. Wellington S. An open-label randomised parallel-group multi-centre study to evaluate the efficacy and safety of enoxaparin versus unfractionated heparin in the prevention of venous thromboembolism in patients following acute ischaemic stroke. Unpublished data 2002.
Wong 2000 {published data only}
    1. Wong WJ, Lo YK, Sheng WY, Hu HH. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in progressive ischemic stroke. Journal of Stroke and Cerebrovascular Diseases 2000;9(2 Suppl 1):183-4.
Yamaguchi 2004 {published data only}
    1. Yamaguchi T. Edaravone and argatroban stroke therapy study for acute ischemic stroke (EAST). Unpublished data 2004.
Yang 2016 {published data only}
    1. Yang L, Zhao P, Zhao J, Wang J, Shi L, Wang X. Effects of ezetimibe and anticoagulant combined therapy on progressing stroke: a randomized, placebo-controlled study. Journal of Neurology 2016;263:2438-45. - PubMed
Yi 2015 {published data only}
    1. Yi X, Chi W, Wang C, Zhang B, Lin J. Low-molecular-weight heparin or dual antiplatelet therapy is more effective than aspirin alone in preventing early neurological deterioration and improving the 6-month outcome in ischemic stroke patients. Journal of Clinical Neurology 2015;11(1):57-65. - PMC - PubMed
Zhang 2005 {published data only}
    1. Zhang DJ, Zhu SW, Cui QX, Li YZ, Zhang HM, Xia ZL, et al. Clinical study of low molecular weight heparin calcium and aspirin therapy on acute cerebral infarction. Clinical Pharmacology 2005;40:634-6.
Zhu 2014 {published data only}
    1. Zhu X, Wang J, Cheng Y. Argatroban in Chinese patients with acute cerebral infarction: a randomized, double-blind, positive-controlled study. Latin American Journal of Pharmacy 2014;33:903-7.
Zuo 2017 {published data only}
    1. Zuo FT, Liu H, Wu HJ, Su N, Liu JQ, Dong AQ. The effectiveness and safety of dual antiplatelet therapy in ischemic cerebrovascular disease with intracranial and extracranial arteriostenosis in chinese patients. Medicine 2017;96:e5497. - PMC - PubMed

References to ongoing studies

ChiCTR1800018313 {published data only}
    1. ChiCTR1800018313. A multicenter trial for revascularization pretreated with argatroban for acute ischemic stroke. https://www.chictr.org.cn/showproj.aspx?proj=30871 (first received 11 September 2018).
ISRCTN76741621 {published data only}
    1. ISRCTN76741621. Endovascular treatment for acute ischemic stroke; the use of periprocedural heparin or antiplatelet agents. https://www.isrctn.com/search?q=ISRCTN76741621 (first received 6 December 2017).
NCT03506009 {published data only}
    1. NCT03506009. Argatroban Plus r-tPA for Posterior Circulation Infarction (AR-PCI). https://clinicaltrials.gov/ct2/show/NCT03506009 (first received 23 April 2018).
NCT03570281 {published data only}
    1. NCT03570281. Edoxaban for the treatment of coagulopathy in patients with active cancer and acute ischemic stroke: a pilot study (ENCHASE study). https://clinicaltrials.gov/ct2/show/NCT03570281 (first received 26 June 2018).
NCT03735979 {published data only}
    1. NCT03735979. Multi-arm optimization of stroke thrombolysis (MOST). https://clinicaltrials.gov/ct2/show/NCT03735979 (first received 8 November 2018).
NCT03740958 {published data only}
    1. NCT03740958. Argatroban plus R-tPA for acute ischemic stroke. https://clinicaltrials.gov/ct2/show/NCT03740958 (first received 14 November 2018).
NCT04275180 {published data only}
    1. NCT04275180. Clinical study of argatroban in the treatment of acute progressive ischemic stroke. https://clinicaltrials.gov/ct2/show/NCT04275180 (first received 19 February 2020).
NCT04304508 {published data only}
    1. NCT04304508. Study to gather information about proper dosing and safety of the oral fxia inhibitor bay 2433334 in patients following a recent non cardioembolic ischemic stroke which occurs when a blood clot has formed somewhere in the human body (but not in the heart) travelled to the brain. https://clinicaltrials.gov/ct2/show/NCT04304508 (first received 11 March 2020).

Additional references

AHA Guidelines 2019
    1. William P, Alejandro AR, Teri A, Opeolu MA, Nicholas CB, Kyra B, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019;50:e344-e418. [DOI: ] - PubMed
Altman 1996
    1. Altman DG, Matthews JNS. Interaction 1: heterogeneity of effects. BMJ 1996;313:486. - PMC - PubMed
APT 1994
    1. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106. - PMC - PubMed
ATC 2002
    1. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86. - PMC - PubMed
Bamford 1990
    1. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. A prospective study of acute cerebrovascular disease in the community: The Oxfordshire Community Stroke Project 1981-1986. 2. Incidence, case fatality and overall outcome at one year of cerebral infarction, primary intracerebral haemorrhage and subarachnoid haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 1990;53:16-22. - PMC - PubMed
Boutron 2021
    1. Boutron I, Page MJ, Higgins JT, Altman DG, Lundh A, Hróbjartsson A. Chapter 7. Considering bias and conflicts of interest among the included studies. In: Higgins JT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.
CLOTS‐3 2013
    1. CLOTS (Clots in Legs Or sTockings after Stroke) Trials Collaboration. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet 2013;382:516-24. - PubMed
Collins 1988
    1. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. New England Journal of Medicine 1988;318:1162-73. - PubMed
Coutinho 2011
    1. Coutinho J, Bruijn SFTM, deVeber G, Stam J. Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database of Systematic Reviews 2011, Issue 8. Art. No: CD002005. [DOI: 10.1002/14651858.CD002005] - DOI - PMC - PubMed
Davenport 1996
    1. Davenport R, Dennis M, Wellwood I, Warlow C. Complications after acute stroke. Stroke 1996;27:415-20. - PubMed
Deeks 2021
    1. Deeks JJ, Higgins JT, Altman DG (editors). Chapter 10. Analysing data and undertaking meta-analyses. In: Higgins JT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.
Egger 1997
    1. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34. - PMC - PubMed
Feigin 2009
    1. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009 Feb 21;8:355-69. [PMID: ] - PubMed
Feigin 2014
    1. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014;383(9913):245-54. - PMC - PubMed
Guyatt 2008
    1. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924. - PMC - PubMed
Hao 2012
    1. Hao Z, Liu M, Counsell C, Wardlaw JM, Lin S, Zhao X. Fibrinogen depleting agents for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No: CD000091. [DOI: 10.1002/14651858.CD000091] - DOI - PMC - PubMed
Higgins 2011
    1. Higgins JT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.handbook.cochrane.org. [COCHRANE: www.training.cochrane.org/handbook.]
Kyu‐2018
    1. Kyu HH, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet 2018;392:1859–922. [PMID: ] - PMC - PubMed
Lederle 2011
    1. Lederle FA, Zylla D, MacDonald R, Wilt T. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Annals of Internal Medicine 2011;155:602-15. - PubMed
Lindley 1993
    1. Lindley RI. Are very large trials of promising treatments for acute stroke feasible?. Newcastle Upon Tyne: University of Newcastle Upon Tyne, 1993.
Lyrer 2010
    1. Lyrer P, Engelter S. Antithrombotic drugs for carotid artery dissection. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No: CD000255. [DOI: 10.1002/14651858.CD000255] - DOI - PMC - PubMed
Odgaard‐Jensen 2011
    1. Odgaard-Jensen J, Vist GE, Timmer A, Kunz R, Akl EA, Schünemann H, et al. Randomisation to protect against selection bias in healthcare trials. Cochrane Database of Systematic Reviews 2011, Issue Issue 4. Art. No: MR000012. [DOI: 10.1002/14651858.MR000012.pub3] - DOI - PMC - PubMed
PREVAIL 2007
    1. Sherman DG, Albers GW, Bladin C, Fieschi C, Gabbai AA, Kase CS, et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL study): an open-label randomised comparison. Lancet 2007;369:1347-55. - PubMed
RevMan 2014 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Sandercock 2008
    1. Sandercock PAG, Counsell C, Tseng MC. Low molecular weight heparin or heparinoids versus standard unfractionated heparin for acute ischemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No: CD000119. [DOI: 10.1002/14651858.CD000119.pub3] - DOI - PubMed
Saxena 2001
    1. Saxena R, Lewis S, Berge E, Sandercock P, Koudstaal, P, the International Stroke Trial Collaborative Group. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke 2001;32:2333-7. - PubMed
Wardlaw 2014
    1. Wardlaw JM, Murray V, Berge E, Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No: CD000213. [DOI: 10.1002/14651858.CD000213] - DOI - PMC - PubMed
Warlow 2008
    1. Warlow C, Bamford J, Dennis M, Rothwell P, Rinkel G, Sandercock P, et al. Stroke: Practical Management. 3rd edition. Blackwells Scientific, 2008.
Whiteley 2013
    1. Whiteley W, Adams HP, Bath PMW, Berge E, Sandset PM, Dennis M, et al. Targeted use of heparin, heparinoids, or low-molecular weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials. Lancet Neurology 2013;12:539-45. - PMC - PubMed

References to other published versions of this review

Gubitz 2004
    1. Gubitz G, Sandercock P, Counsell C. Anticoagulants for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No: CD000024. [DOI: 10.1002/14651858.CD000024.pub2] - DOI - PubMed
Sandercock 1993
    1. Sandercock PAG, den Belt AGM, Lindley RI, Slattery J. Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials. Journal of Neurology, Neurosurgery and Psychiatry 1993;56:17-25. - PMC - PubMed

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