Antiplatelet therapy for secondary prevention of stroke
- Brett L Cucchiara, MD
Brett L Cucchiara, MD
- Associate Professor of Neurology
- University of Pennsylvania Medical Center
- Steven R Messé, MD
Steven R Messé, MD
- Associate Professor of Neurology
- Hospital of the University of Pennsylvania
Antiplatelet therapy is used for both the management of acute ischemic stroke and for the prevention of stroke. Antiplatelet therapy reduces the incidence of stroke in patients at high risk for atherosclerosis and in those with known symptomatic cerebrovascular disease.
Antiplatelet therapy for secondary stroke prevention will be reviewed here. Antiplatelet therapy for acute ischemic stroke and for primary stroke prevention is discussed separately. (See "Antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Overview of primary prevention of coronary heart disease and stroke".)
Prevention of recurrent stroke with antithrombotic therapy in patients with atrial fibrillation is reviewed elsewhere. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization".)
Aspirin, the most commonly used antiplatelet agent, inhibits the enzyme cyclooxygenase, reducing production of thromboxane A2, a stimulator of platelet aggregation. This interferes with the formation of thrombi, thereby reducing the risk of stroke. (See "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease".)
The effectiveness of aspirin for preventing ischemic stroke and cardiovascular events is supported by a meta-analysis from the Antithrombotic Trialists Collaboration (ATC) published in 2002 . The ATC analyzed 195 randomized controlled trials comparing antiplatelet therapy, primarily aspirin, with placebo in the prevention of stroke, myocardial infarction (MI), and vascular death among high-risk patients with some vascular disease or other condition implying an increased risk of occlusive vascular disease. Patients treated with an antiplatelet agent (primarily aspirin) had a 25 percent relative risk reduction in nonfatal stroke compared with placebo.
- 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.
- Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849.
- Sibon I, Orgogozo JM. Antiplatelet drug discontinuation is a risk factor for ischemic stroke. Neurology 2004; 62:1187.
- Maulaz AB, Bezerra DC, Michel P, Bogousslavsky J. Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol 2005; 62:1217.
- Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54:1044.
- Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143:1.
- United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. UK-TIA Study Group. Br Med J (Clin Res Ed) 1988; 296:316.
- Secondary prevention of vascular disease by prolonged antiplatelet treatment. Antiplatelet Trialists' Collaboration. Br Med J (Clin Res Ed) 1988; 296:320.
- The European Stroke Prevention Study (ESPS). Principal end-points. The ESPS Group. Lancet 1987; 2:1351.
- Johnson ES, Lanes SF, Wentworth CE 3rd, et al. A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med 1999; 159:1248.
- A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group. N Engl J Med 1991; 325:1261.
- Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353:2373.
- Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S.
- Hirsh J, Dalen JE, Fuster V, et al. Aspirin and other platelet-active drugs. The relationship among dose, effectiveness, and side effects. Chest 1995; 108:247S.
- Serebruany VL, Steinhubl SR, Berger PB, et al. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials. Am J Cardiol 2005; 95:1218.
- McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006; 119:624.
- CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348:1329.
- Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, Writing Committee Members, et al. ACCF/AHA Clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association. Circulation 2010; 122:537.
- Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:331.
- Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706.
- Usman MH, Notaro LA, Nagarakanti R, et al. Combination antiplatelet therapy for secondary stroke prevention: enhanced efficacy or double trouble? Am J Cardiol 2009; 103:1107.
- Lee M, Saver JL, Hong KS, et al. Risk-benefit profile of long-term dual- versus single-antiplatelet therapy among patients with ischemic stroke: a systematic review and meta-analysis. Ann Intern Med 2013; 159:463.
- Amarenco P, Donnan GA. Should the MATCH results be extrapolated to all stroke patients and affect ongoing trials evaluating clopidogrel plus aspirin? Stroke 2004; 35:2606.
- Liao JK. Secondary prevention of stroke and transient ischemic attack: is more platelet inhibition the answer? Circulation 2007; 115:1615.
- Clinical advisory: Secondary Prevention of Small Subcortical Strokes trial: NINDS stops treatment with combination antiplatelet therapy (clopidogrel plus aspirin) due to higher risk of major hemorrhage and death. www.nlm.nih.gov/databases/alerts/2011_ninds_stroke.html (Accessed on November 28, 2011).
- SPS3 Investigators, Benavente OR, Hart RG, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367:817.
- Markus HS, Droste DW, Kaps 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; 111:2233.
- Wong KS, Chen C, Fu J, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010; 9:489.
- Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:993.
- Amarenco P, Davis S, Jones EF, et al. Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques. Stroke 2014; 45:1248.
- Leonardi-Bee J, Bath PM, Bousser MG, et al. Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials. Stroke 2005; 36:162.
- ESPRIT Study Group, Halkes PH, van Gijn J, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367:1665.
- Lipton RB, Bigal ME, Kolodner KB, et al. Acetaminophen in the treatment of headaches associated with dipyridamole-aspirin combination. Neurology 2004; 63:1099.
- Diener HC, Darius H, Bertrand-Hardy JM, et al. Cardiac safety in the European Stroke Prevention Study 2 (ESPS2). Int J Clin Pract 2001; 55:162.
- Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004; 292:1867.
- Pfisterer M. Intravenous dipyridamole for stress thallium-201 perfusion scintigraphy. Cardiovasc Imag 1992; 4:31.
- Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 2003; 107:149.
- Verro P, Gorelick PB, Nguyen D. Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis. Stroke 2008; 39:1358.
- Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359:1238.
- Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1:1215.
- Hass WK, Easton JD, Adams HP Jr, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989; 321:501.
- Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003; 289:2947.
- Matsumoto M. Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study. Atheroscler Suppl 2005; 6:33.
- Huang Y, Cheng Y, Wu J, et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 2008; 7:494.
- Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010; 9:959.
- Matías-Guiu J, Ferro JM, Alvarez-Sabín J, et al. Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke 2003; 34:840.
- Culebras A, Rotta-Escalante R, Vila J, et al. Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology 2004; 62:1073.
- Costa J, Ferro JM, Matias-Guiu J, et al. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev 2005; :CD004296.
- Anderson DC, Goldstein LB. Aspirin: it's hard to beat. Neurology 2004; 62:1036.
- Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:2160.
- Dose of aspirin
- - Toxicity and risk of bleeding
- Side effects of clopidogrel
- Aspirin plus clopidogrel
- - Stroke subtypes
- Side effects of dipyridamole
- - Cardiac effects
- Aspirin plus dipyridamole
- Aspirin plus extended-release dipyridamole versus clopidogrel
- OTHER AGENTS
- - Side effects of ticlopidine
- CHOOSING THERAPY
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS