, Volume 65, Issue 4, pp 461–471

Adverse Effects and Drug Interactions of Antithrombotic Agents Used in Prevention of Ischaemic Stroke

Review Article


Stroke is the third most common cause of death in the US. Primary prevention of stroke can be achieved by control of risk factors including hypertension, diabetes mellitus, elevated cholesterol levels and smoking. Approximately one-third of all ischaemic strokes occur in patients with a history of stroke or transient ischaemic attack (TLA). The mainstay of secondary prevention of ischaemic stroke is the addition of medical therapy with antithrombotic agents to control the risk factors for stroke. Antithrombotic therapy is associated with significant medical complications, particularly bleeding.

Low-dose aspirin (acetylsalicylic acid) has been shown to be as effective as high-dose aspirin in the prevention of stroke, with fewer adverse bleeding events. Aspirin has been shown to be as effective as warfarin in the prevention of noncardioembolic ischaemic stroke, with significantly fewer bleeding complications. Ticlopidine may be more effective in preventing stroke than aspirin, but is associated with unacceptable haematological complications. Clopidogrel may have some benefit over aspirin in preventing myocardial infarction, but has not been shown to be superior to aspirin in the prevention of stroke. The combination of clopidogrel and aspirin may be more effective than aspirin alone in acute coronary syndromes, but the incidence of adverse bleeding is significantly higher. Furthermore, the combination of aspirin with clopidogrel has not been shown to be more effective for prevention of recurrent stroke than clopidogrel alone, while the rate of bleeding complications was significantly higher with combination therapy. The combination of aspirin and extended-release dipyridamole has been demonstrated to be more effective than aspirin alone, with the same rate of adverse bleeding complications as low-dose aspirin. When selecting the appropriate antithrombotic agent for secondary prevention of stroke, the adverse event profile of the drug must be taken into account when assessing the overall efficacy of the treatment plan.


  1. 1.
    American Heart Association. Heart disease and stroke statistics: 2003 update. Dallas (TX): American Heart Association, 2002Google Scholar
  2. 2.
    Broderick J, Brott T, Kothari R, et al. The Greater Cincinnati/Northern Kentucky Study: preliminary first-ever and total incidence rates of strokes among blacks. Stroke 1998; 29: 415–21PubMedCrossRefGoogle Scholar
  3. 3.
    Wolf P, Glagett G, Easton J, et al. Preventing ischemic stroke in patients with prior stroke and transient ischemic attack: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke 1999; 30: 1991–4PubMedCrossRefGoogle Scholar
  4. 4.
    Petty G, Brown Jr R, Whisnant J, et al. Survival and recurrence after first cerebral infarction: a population-based study in Rochester, Minnesota, 1975 through 1989. Neurology 1998; 50: 208–16PubMedCrossRefGoogle Scholar
  5. 5.
    Sacco R, Wolf P, Kannel W, et al. Survival and recurrence following stroke: the Framingham Study. Stroke 1982; 13: 290–5PubMedCrossRefGoogle Scholar
  6. 6.
    Taylor T, Davis P, Torner J, et al. Lifetime cost of stroke in the United States. Stroke 1996; 27: 1459–66PubMedCrossRefGoogle Scholar
  7. 7.
    Wilterdink J, Easton J. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurol 1992; 49: 857–63PubMedCrossRefGoogle Scholar
  8. 8.
    Easton JD, Sherman DG. Management of cerebral embolism of cardiac origin. Stroke 1980; 11: 433–42PubMedCrossRefGoogle Scholar
  9. 9.
    Stroke Prevention in Atrial Fibrillation II Study. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation. Lancet 1994; 343: 687–91Google Scholar
  10. 10.
    Olsson SB, Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362: 1691–8PubMedCrossRefGoogle Scholar
  11. 11.
    Halperin JL. Antithrombotic therapy in atrial fibrillation: ximelagatran, an oral direct thrombin inhibitor. Expert Rev Cardiovasc Ther 2004; 2(2): 163–74PubMedCrossRefGoogle Scholar
  12. 12.
    North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325: 445–53CrossRefGoogle Scholar
  13. 13.
    Wennberg DE, Lucas FL, Birkmeyer JD, et al. Variation in carotid endarterectomy mortality in the Medicare population: trial hospitals, volume, and patient characteristics. JAMA 1998; 279: 1278–81PubMedCrossRefGoogle Scholar
  14. 14.
    Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273: 1421–8CrossRefGoogle Scholar
  15. 15.
    MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial. Lancet 2004; 363: 1491–02CrossRefGoogle Scholar
  16. 16.
    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: 81–106Google Scholar
  17. 17.
    Suttie JW. Warfarin and vitamin K. Clin Cardiol 1990; 13 Suppl. 6: VII6–8Google Scholar
  18. 18.
    Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. I: acetylation of a particulate fraction protein. J Clin Invest 1975; 56: 624–32Google Scholar
  19. 19.
    Moncada S, Korbut R. Dipyridamole and other phosphodiesterase inhibitors act as antithrombotic agents by potentiating endogenous prostacyclin. Lancet 1978; I: 1286–9CrossRefGoogle Scholar
  20. 20.
    Serebruany VL, Malinin AI, Sane DC, et al. Magnitude and time course of platelet inhibition with Aggrenox and aspirin in patients after ischemic stroke: the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Eur J Pharmacol 2004; 499: 315–24PubMedCrossRefGoogle Scholar
  21. 21.
    Hardisty RM, Powling MJ, Nokes TJ. The action of ticlopidine on human platelets: studies on aggregation, secretion, calcium mobilization and membrane glycoproteins. Thromb Haemost 1990; 64: 150–5PubMedGoogle Scholar
  22. 22.
    Herbert JM, Tissinier A, Defreyn G. Inhibitory effect of clopidogrel on platelet adhesion and intimai proliferation after arterial injury in rabbits. Arterioscler Thromb 1993; 13: 1171–9PubMedCrossRefGoogle Scholar
  23. 23.
    Herbert JM, Frehel D, Vallee E, et al. Clopidogrel, a novel antiplatelet and antithrombotic agent. Cardiovasc Drug Rev 1993; 11: 180–98CrossRefGoogle Scholar
  24. 24.
    Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30mg vs 283mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325: 1261–6CrossRefGoogle Scholar
  25. 25.
    Farrell B, Godwin J, Richards S, et al. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991; 54: 1044–54PubMedCrossRefGoogle Scholar
  26. 26.
    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: 1–13PubMedCrossRefGoogle Scholar
  27. 27.
    Gent M, Blakely J, Easton J, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; I: 1215–20CrossRefGoogle Scholar
  28. 28.
    Hass W, Easton J, Adams Jr H, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501–7PubMedCrossRefGoogle Scholar
  29. 29.
    CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–39CrossRefGoogle Scholar
  30. 30.
    Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342: 1773–7PubMedCrossRefGoogle Scholar
  31. 31.
    Fischer T, Worm M, Groneberg D. Clopidogrel-associated angioedema. Am J Med 2003; 114: 77–8PubMedCrossRefGoogle Scholar
  32. 32.
    Yusuf S, Zhao F, Mehta S, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation: the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. N Engl J Med 2001; 345: 494–502PubMedCrossRefGoogle Scholar
  33. 33.
    ESPS Group. European Stroke Prevention Study. Stroke 1990; 21: 1122–30CrossRefGoogle Scholar
  34. 34.
    Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice. JAMA 2003; 290: 2685–92PubMedCrossRefGoogle Scholar
  35. 35.
    Mohr J, Thompson J, Lazar R, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke: the Warfarin and Aspirin Recurrent Stroke Study Group. N Engl J Med 2001; 345: 1444–51PubMedCrossRefGoogle Scholar
  36. 36.
    Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed atrial origin. Ann Neurol 1997; 42: 857–65CrossRefGoogle Scholar
  37. 37.
    Chimowitz MI, Kokkinos J, Strong J, et al. The warfarin-aspirin symptomatic intracranial disease study. Neurology 1995; 45: 1488–93PubMedCrossRefGoogle Scholar
  38. 38.
    Caplan LR. Advances in stroke research: Basic science, treatment, and clinical trial outcomes. Highlights of the 29th International Stroke Conference. Rev Neurol Dis 2004; 1(2): 91–4Google Scholar
  39. 39.
    Vane J, Flower R, Botting R. History of aspirin and its mechanism of action. Stroke 1990; 21 (12 Suppl.): IV12–23PubMedGoogle Scholar
  40. 40.
    Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 1978; 299: 53–9CrossRefGoogle Scholar
  41. 41.
    Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, et al. Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases. Ann Intern Med 1998; 128: 541–4PubMedGoogle Scholar
  42. 42.
    Steinhubl SR, Tan WA, Foody JM, et al. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. JAMA 1999; 281: 806–10PubMedCrossRefGoogle Scholar
  43. 43.
    Bennett CL, Kiss JE, Weinberg PD, et al. Thrombotic thrombocytopenic purpura after stenting and ticlopidine. Lancet 1998; 352: 1036–7PubMedCrossRefGoogle Scholar
  44. 44.
    Bennett CL, Davidson CJ, Raisch DW, et al. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med 1999; 159: 2524–8PubMedCrossRefGoogle Scholar
  45. 45.
    Bhatt DL, Hirsch AT, Ringleb PA. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. Am Heart J 2000; 140: 67–73PubMedCrossRefGoogle Scholar
  46. 46.
    Bhatt DL, Chew DP, Hirsch AT, et al. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001; 103: 363–8PubMedCrossRefGoogle Scholar
  47. 47.
    Zakarija A, Bandarenko N, Pandey DK, et al. Clopidogrel-associated TTP: an update of pharmacovigilance efforts conducted by independent researchers, pharmaceutical suppliers, and the Food and Drug Administration. Stroke 2004; 35: 533–7PubMedCrossRefGoogle Scholar
  48. 48.
    Plavix [package insert]. New York: Bristol-Myers Squibb Co. and Sanofi-Synthelabo, 2002 MayGoogle Scholar
  49. 49.
    Jonas S, Grieco G. An approach to the estimation of the risk of TTP during clopidogrel therapy. Stroke 2004; 35: 537–8PubMedGoogle Scholar
  50. 50.
    Lau W, Waskell L, Watkins P, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003; 107: 32–7PubMedCrossRefGoogle Scholar
  51. 51.
    Grotta JC, Norris JW, Kamm B. Prevention of stroke with ticlopidine: who benefits most? TASS baseline and angiographic data subgroup. Neurology 1992; 42: 111–5PubMedCrossRefGoogle Scholar
  52. 52.
    Gorelick PB, Richardson DJ, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003; 289: 2947–57PubMedCrossRefGoogle Scholar
  53. 53.
    Acarin L, Gonzalez B, Castellano B. Decrease of proinflammatory molecules correlates with neuroprotective effect of the fluorinated salicylate triflusal after postnatal excitotoxic damage. Stroke 2002; 33: 2499–505PubMedCrossRefGoogle Scholar
  54. 54.
    Acarin L, Gonzalez B, Castellano B. Triflusal posttreatment inhibits glial nuclear factor-kB, downregulates the glial response, and is neuroprotective in an excitotoxic injury model in postnatal brain. Stroke 2001; 32: 2394–402PubMedCrossRefGoogle Scholar
  55. 55.
    Matias-Guiu J, Ferro JM, Alvarez-Sabin 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: 840–8Google Scholar
  56. 56.
    Nappi J, Talbert R. Dual antiplatelet therapy for prevention of recurrent ischemic events. Am J Health Syst Pharm 2002; 59: 1723–35PubMedGoogle Scholar
  57. 57.
    Peters RJG, Mehta SR, Fox KAA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108: 1682–7PubMedCrossRefGoogle Scholar
  58. 58.
    Vickrey B, Rector T, Wickstrom S, et al. Occurrence of secondary ischemic events among persons with atherosclerotic vascular disease. Stroke 2002; 33: 901–6PubMedCrossRefGoogle Scholar
  59. 59.
    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. The MATCH investigators. Lancet 2004; 364: 331–7CrossRefGoogle Scholar
  60. 60.
    Albers GW, Amarenco P. Combination therapy with clopidogrel and aspirin: can the CURE results be extrapolated to cerebrovascular patients? Stroke 2001; 32: 2948–9PubMedCrossRefGoogle Scholar
  61. 61.
    American Canadian Co-Operative Study Group. Persantine Aspirin Trial in cerebral ischemia. Part II: endpoint results. Stroke 1985; 40: 406–5Google Scholar
  62. 62.
    Lipton RB, Bigal ME, Kolodner KB, et al. Acetaminophen in the treatment of headache associated with dipyridamole-aspirin combination. Neurology 2004; 63: 1099–101PubMedCrossRefGoogle Scholar
  63. 63.
    PRoFESS [online]. Available from URL: http://www.professstudy.com/com/homepage.jsp [Accessed 2003 May 1]
  64. 64.
    Serebruany V, Steinhubl S, Hennekens C. Are antiplatelet effects of clopidogrel inhibited by atorvastatin? A research question formulated but not yet adequately tested. Circulation 2003; 107: 1568–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Neurovascular Laboratory, Department of NeurologyThe Mount Sinai School of MedicineNew YorkUSA
  2. 2.Division of NeurologyNorth General HospitalNew YorkUSA
  3. 3.Department of NeurologyThe Mount Sinai School of MedicineNew YorkUSA

Personalised recommendations