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Antithrombotic Management of Ischemic Stroke

  • Kelly L. Sloane
  • Erica C. CamargoEmail author
Cerebrovascular Disease and Stroke (S Silverman, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Cerebrovascular Disease and Stroke

Abstract

Purpose of review

Ischemic stroke describes a condition in which inadequate blood flow leads to lack of oxygenation to the brain tissue and ensuing neuronal death. There are multiple causes of ischemic stroke, each of which may indicate different antithrombotic management strategies. The goal of this review is to provide information about antithrombotic therapies for secondary stroke prevention based on etiology of stroke.

Recent findings

New studies of existing antiplatelet and antithrombotic therapies have demonstrated varied efficacies of treatments based on the underlying risk factor of ischemic stroke.

Summary

Understanding the optimal therapies for secondary stroke prevention can enhance care of stroke patients and lower the incidence of recurrent cerebrovascular ischemia.

Keywords

Ischemic stroke Aspirin Clopidogrel Anticoagulation Warfarin Direct oral anticoagulants 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinical subtypes of cerebral infarction. Lancet. 1991;337:1521–6.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment Investigators. Stroke: a randomized controlled trial (danaparoid), and outcome after acute ischemic low molecular weight heparinoid, ORG 10172. JAMA. 1998;279(16):1265–72.CrossRefGoogle Scholar
  4. 4.
    French Study of Aortic Plaques in Stroke Group, Amarenco P, Cohen A, Hommel M, Moulin T, Leys D, et al. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med. 1996;334(19):1216–21.CrossRefGoogle Scholar
  5. 5.
    Murtagh B, Smalling RW. Cardioembolic stroke. Curr Atheroscler Rep. 2006;8(4):310–6.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Schneider AT, Kissela B, Woo D, Kleindorfer D, Alwell K, Miller R, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke. 2004;35:1552–6.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Sudlow CLM, Warlow CP. Comparable studies of the incidence of stroke and its pathological types. Results from an international collaboration. Stroke. 1997;28:491–9.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852–66.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al. Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13(4):429–38.CrossRefGoogle Scholar
  10. 10.
    den Hartog AG, Achterberg S, Moll FL, Kappelle LJ, Visseren FL, van der Graaf Y, et al. Asymptomatic carotid artery stenosis and the risk of ischemic stroke according to subtype in patients with clinical manifest arterial disease. Stroke. 2013;44(4):1002–7.CrossRefGoogle Scholar
  11. 11.
    Brott TG, Calvet D, Howard G, Gregson J, Algra A, Becquemin JP, et al. Long-term outcomes of stenting and endarterectomy for symptomatic carotid stenosis: a preplanned pooled analysis of individual patient data. Lancet Neurol. 2019;18(4):348–56.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Mott M, Koroshetz W, Wright CB. CREST-2: identifying the best method of stroke prevention for carotid artery stenosis: National Institute of Neurological Disorders and Stroke Organizational Update. Stroke. 2017;48(5):e130–1.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    North American Symptomatic Carotid Endarterectomy Trial Collaborators, Barnett HJM, Taylor DW, Haynes RB, Sackett DL, Peerless SJ, et al. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325(7):445–53.CrossRefGoogle Scholar
  14. 14.
    Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet. 2004;363:915–24.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998;339(20):1415–25.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Taylor DW, Barnett HJ, Haynes RB, Ferguson GG, Sackett DL, Thorpe KE, et al. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators. Lancet. 1999;353(9171):2179–84.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation. 2005;111(17):2233–40.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Adams HP Jr, Bendixen BH, Leira E, Chang KC, Davis PH, Woolson RF, et al. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999;53(1):122–5.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Damania D, Kung NT, Jain M, Jain AR, Liew JA, Mangla R, et al. Factors associated with recurrent stroke and recanalization in patients presenting with isolated symptomatic carotid occlusion. Eur J Neurol. 2016;23(1):127–32.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Ganesh A, Wong JH, Menon BK. Practice current: how do you manage patients with a “hot carotid”? Neurol Clin Pract. 2018;8(6):527–36.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Battistella V, Elkind M. Intracranial atherosclerotic disease. Eur J Neurol. 2014;21(7):956–62.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    White H, Boden-Albala B, Wang C, Elkind MS, Rundek T, Wright CB, et al. Ischemic stroke subtype incidence among Whites, Blacks, and Hispanics: the Northern Manhattan Study. Circulation. 2005;111(10):1327–31.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352(13):1305–16.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993–1003.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Chaturvedi S, Turan TN, Lynn MJ, Derdeyn CP, Fiorella D, Janis LS, et al. Do patient characteristics explain the differences in outcome between medically treated patients in SAMMPRIS and WASID? Stroke. 2015;46(9):2562–7.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Markus HS, Harshfield EL, Compter A, Kuker W, Kappelle LJ, Clifton A, et al. Stenting for symptomatic vertebral artery stenosis: a preplanned pooled individual patient data analysis. Lancet Neurol. 2019;18(7):666–73.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Compter A, van der Worp HB, Schonewille WJ, Vos JA, Boiten J, Nederkoorn PJ, et al. Stenting versus medical treatment in patients with symptomatic vertebral artery stenosis: a randomised open-label phase 2 trial. Lancet Neurol. 2015;14(6):606–14.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 Study. Circulation. 2014;129:837–47.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Ntaios G, Lip GY, Makaritsis K, Papavasileiou V, Vemmou A, Koroboki E, et al. CHADS2, CHA2S2DS2-VASc, and long-term stroke outcome in patients without atrial fibrillation. Neurology. 2013;80(11):1009–17.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J. 2012;33(12):1500–10.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Hicks T, Stewart F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open Heart. 2016;3:e000279.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Baumgartner H, Falk V, Bax J, et al. ESC/EACTS Guidelines for the management of valvular heart disease: The Task Force for the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2017;2017:2939–91.Google Scholar
  33. 33.
    Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med. 2012;366:1859–69.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    •Zannad F, Anker SD, Byra WM, Cleland JGF, Fu M, Gheorghiade M, et al. Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease. N Engl J Med. 2018;379:1332–42 Low ejection fraction has been considered an indication for systemic anticoagulation with warfarin based on the WARCEF trial; this study demonstrates no benefit of rivaroxaban over aspirin in patients with ejection fraction < 40%.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation. 1994;89(2):635–41.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206–14.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Carnicelli AP, De Caterina R, Halperin JL, Renda G, Ruff CT, Trevisan M, et al. Edoxaban for the prevention of thromboembolism in patients with atrial fibrillation and bioprosthetic valves. Circulation. 2017;135(13):1273.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Flaker GC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vabanian A, et al. Risks and benefits of combining aspirin with anticoagulation therapy in patients with atrial fibrillation; an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTF) trials. Am Heart J. 2006;152:967–73.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation; stroke prevention in atrial fibrillation III randomized clinical trial. Lancet. 1996;348:633–8.CrossRefGoogle Scholar
  40. 40.
    Gullov AL, Koeford BG, Petersen P, Petersen TS, Andersen ED, Gottifredsen J, et al. Fixed minidose warfarin and aspirin alone and in combination vs. adjusted-dose warfarin for stroke prevention in atrial fibrillation. Arch Int Med. 1998;158:1513–21.CrossRefGoogle Scholar
  41. 41.
    Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: Executive summary: A report of the american college of Cardiology/American heart association task force on practice guidelines. Circulation. 2014;129:2440–92.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med. 1988;318:1148–52.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991–9.CrossRefGoogle Scholar
  44. 44.
    Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald LA, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368(12):1092–100.CrossRefGoogle Scholar
  45. 45.
    •Mas JL, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377:1011–21 Studies of patent foramen ovale management, including RESPECT and CLOSURE I, previously showed no benefit of PFO closure for secondary stroke prevention. CLOSE, along with REDUCE, DEFENSE-PFO, Long Term Outcomes for RESPECT, have shown that in the right patient population (cryptogenic stroke with PFO), the intervention reduces recurrence of stroke.Google Scholar
  46. 46.
    Sondergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377:1033–42.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Lee PH, Song JK, Kim JS, Heo R, Lee S, Kim DH, et al. Cryptogenic stroke and high-risk patent foramen ovale: the defense-PFO trial. J Am Coll Cardiol. 2018;71:2335–42.CrossRefGoogle Scholar
  48. 48.
    Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017;377(11):1022–32.CrossRefGoogle Scholar
  49. 49.
    Kent DM, Dahabreh IJ, Ruthazer R, Furlan AJ, Weimar C, Serena J, et al. Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis. Eur Heart J. 2015;36(35):2381–9.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    The SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817–25.PubMedCentralCrossRefGoogle Scholar
  51. 51.
    Navi BB, Reiner AS, Kamel H, Iadecola C, Elkind MS, Panageas KS, et al. Association between incident cancer and subsequent stroke. Ann Neurol. 2015;77(2):291–300.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore). 1985;64:16–35.CrossRefGoogle Scholar
  53. 53.
    Zhang YY, Cordato D, Shen Q, Sheng AZ, Hung WT, Chan DK. Risk factor, pattern, etiology and outcome in ischemic stroke patients with cancer: a nested case-control study. Cerebrovasc Dis. 2007;23(2–3):181–7.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Navi BB, Iadecola C. Ischemic stroke in cancer patients: a review of an underappreciated pathology. Ann Neurol. 2018;83:873–83.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146–53.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    ••Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, et al. Edoxaban for cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615–24 Traditionally, hypercoagulability in malignancy has been treated with enoxaparin. This study demonstrated non-inferiority of edoxaban in this patient population.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, et al. Comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36(20):2017–23.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol. 2009;8(11):998–1005.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132(13):1365–71.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Engelter ST, Grond-Ginsbach C, Metso TM, Metso AJ, Kloss M, Debette S, et al. Cervical artery dissection: trauma and other potential mechanical trigger events. Neurology. 2013;80(21):1950–7.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Kennedy F, Lanfranconi S, Hicks C, Reid J, Gompertz P, Price C, et al. Antiplatelets vs anticoagulation for dissection: CADISS nonrandomized arm and meta-analysis. Neurology. 2012;79(7):686–9.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Chowdhury MM, Sabbagh CN, Jackson D, Coughlin PA, Ghosh J. Antithrombotic treatment for acute extracranial carotid artery dissections: a meta-analysis. Eur J Vasc Endovasc Surg. 2015;50(2):148–56.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    •Markus HS, Levi C, King A, Madigan J, Norris J, Cervical Artery Dissection in Stroke Study (CADISS) Investigators. Antiplatelet Therapy vs Anticoagulation Therapy in Cervical Artery Dissection: The Cervical Artery Dissection in Stroke Study (CADISS) Randomized Clinical Trial Final Results. JAMA Neurol. 2019;76(6):657–64 Practice patterns have varied regarding therapy for acute cervical arterial dissection, ranging from single antiplatelet to dual antiplatelet to anticoagulation with warfarin. This study found no difference in direct comparison of aspirin and warfarin for prevention of stroke after cervical arterial dissection, potentially sparing patients from unnecessary anticoagulation.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Metso TM, Metso AJ, Helenius J, Haapaniemi E, Salonen O, Porras M, et al. Prognosis and safety of anticoagulation in intracranial artery dissections in adults. Stroke. 2007;38(6):1837–42.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Ono H, Nakatomi H, Tsutsumi K, Inoue T, Teraoka A, Yoshimoto Y, et al. Symptomatic recurrence of intracranial arterial dissections: follow-up study of 143 consecutive cases and pathological investigation. Stroke. 2013;44(1):126–31.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001;345(20):1444–51.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Longstreth WT Jr, Kronmal RA, Thompson JL, Christenson RH, Levine SR, Gross R, et al. Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke. 2013;44(3):714–9.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    ••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. N Engl J Med. 2019;380(20):1906–17 In many patients with embolic stroke of undetermined source, the suspicion for atrial fibrillation is high, but it remains undetected. Given that atrial fibrillation is such a strong indication for anticoagulation, prior to this study (along with NAVIGATE), it was uncertain whether or not patients with suspected cardioembolic source should be placed on systemic anticoagulation. This trial demonstrates non-superiority of anticoagulation over aspirin in the management of patients with cerebral embolism of uncertain etiology.Google Scholar
  69. 69.
    Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med. 2018;378(23):2191–201.CrossRefGoogle Scholar
  70. 70.
    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(7329):71.CrossRefGoogle Scholar
  71. 71.
    Hennekens CH, Sechenova O, Hollar D, Serebruany VL. Dose of aspirin in the treatment and prevention of cardiovascular disease: current and future directions. J Cardiovasc Pharmacol Ther. 2006;11(3):170–6.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Johnson ES, Lanes SF, Wentworth CE 3rd, Satterfield MH, Abebe BL, Dicker LW. A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med. 1999;159(11):1248–53.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329–39.CrossRefGoogle Scholar
  74. 74.
    Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375(1):35–43.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006;367(9523):1665–73.CrossRefGoogle Scholar
  76. 76.
    Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359(12):1238–51.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    ••Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018;379(3):215–25 While previous studies had suggested that dual antiplatelet therapy conferred a high risk of intracranial hemorrhage for the benefit of stroke risk reduction, this study demonstrated that short-term use of aspirin and clopidogrel in patients with minor stroke or transient ischemic attack can be safe and effective.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11–9.Google Scholar
  79. 79.
    ••Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial. Lancet Neurol. 2019;18(6):539–48 Previous studies of dual antiplatelet therapy have primarily used aspirin, clopidogrel or ticagrelor and have shown high risk of bleeding complications with long-term use. This study reveals benefit of stroke risk reduction without increased bleeding complications in long-term dual antiplatelet therapy using cilostazol.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    •Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377(14):1319–30 This study demonstrates that combination of low-dose rivaroxaban plus aspirin conferred a lower ischemic stroke risk than high-dose rivaroxaban plus aspirin or aspirin alone in patients with cardiovascular disease requiring antithrombotic therapy.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Sharma M, Hart RG, Connolly SJ, Bosch J, Shestakovska O, Ng KKH, et al. Stroke outcomes in the COMPASS Trial. Circulation. 2019;139(9):1134–45.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423–34.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107–15.PubMedCrossRefPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Department of NeurologyMassachusetts General HospitalBostonUSA
  2. 2.Harvard Medical SchoolCambridgeUSA

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