Antithrombotic Management of Ischemic Stroke
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.
New studies of existing antiplatelet and antithrombotic therapies have demonstrated varied efficacies of treatments based on the underlying risk factor of ischemic stroke.
Understanding the optimal therapies for secondary stroke prevention can enhance care of stroke patients and lower the incidence of recurrent cerebrovascular ischemia.
KeywordsIschemic stroke Aspirin Clopidogrel Anticoagulation Warfarin Direct oral anticoagulants
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
- 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.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.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
- 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
- 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
- 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.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
- 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
- 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
- 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.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
- 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
- 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
- 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.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.••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.•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
- 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