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Clinical Pharmacokinetics of Antiplatelet Agents Used in the Secondary Prevention of Stroke

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Abstract

Stroke is one of the leading causes of death and debilitation. Several million stroke survivors are alive throughout the world today. Prevention of recurrent stroke is of major importance to stroke survivors. Several pharmacological agents are currently available for use in secondary stroke prevention.

Clopidogrel, the combination of immediate-release aspirin and extendedrelease dipyridamole and aspirin alone are the most widely recommended agents for use in the secondary prevention of strokes. Clopidogrel has shown superiority over aspirin in the combined endpoints of stroke, death and myocardial infarction. The immediate-release aspirin/extended-release dipyridamole combination has shown superiority to aspirin alone in the secondary prevention of stroke.

Dipyridamole has been studied as an antiplatelet agent for several decades. Early trials to prove its efficacy compared with aspirin were not favourable, and patients often experienced many adverse effects. Researchers began developing an extended-release formulation in an effort to maintain therapeutic blood concentrations with less frequent daily administration and better adverse effect profile. Pharmacokinetic analysis of this new product showed it to have a more consistent and reproducible absorption compared with immediate-release dipyridamole. The rate of absorption of extended-release dipyridamole is considerably slower than that of immediate-release dipyridamole, while similar plasma concentrations are maintained to optimise antiplatelet efficacy. This allows extended-release dipyridamole to be administered twice daily rather than four times daily.

A large-scale randomised trial was conducted with extended-release dipyridamole 200mg in combination with immediate-release aspirin 25mg given twice daily. The combination product showed a greater efficacy at preventing a recurring stroke then either agent administered alone. Indirect comparisons with clopidogrel show that the combination of immediate-release aspirin/extendedrelease dipyridamole may be more effective than clopidogrel at preventing a recurring stroke.

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  1. Use of tradenames is for product identification only and does not imply ndorsement.

References

  1. American Heart Association. 2002 Heart and stroke statistical update. Dallas: American Heart Association, 2002

    Google Scholar 

  2. World Health Organization. Statistical information system [online]. Available from URL: http://ww3.who.int/whosis/mort/table1_process.cfm [Accessed 2003 July 16]

  3. Heart and Stroke Foundation of Canada [online]. Available from URL: http://ww2.heartandstroke.ca [Accessed 2003 July 16]

  4. Weinberger J. Contemporary diagnosis and management of stroke. Newton (PA): Handbooks in Health Care, 1999

    Google Scholar 

  5. Fuster V. Epidemic of cardiovascular disease and stroke: the three main challenges. Circulation 1999; 99: 1132–7

    Article  PubMed  CAS  Google Scholar 

  6. Bamford J, Sandercock P, Dennis M. A prospective study of acute cerebrovascular disease in the community: The Oxford Community Stroke Project 1981–1986. J Neurol Neurosurg Psychiatry 1990; 53: 16–22

    Article  PubMed  CAS  Google Scholar 

  7. Weinberger J. Prevention and management of cerebrovascular events in primary care. Geriatrics 2002; 57(1): 38–43

    PubMed  Google Scholar 

  8. Lenz TL, Hilleman DE. Aggrenox: a fixed-dose combination of aspirin and dipyridamole. Ann Pharmacother 2000; 34: 1283–90

    Article  PubMed  CAS  Google Scholar 

  9. Wolf PA, Clagett GP, Easton JD, et al. Preventing ischemic stroke in patients with prior stroke and transient ischemic attack. Stroke 1999; 30: 1991–4

    Article  PubMed  CAS  Google Scholar 

  10. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001; 119: 300S–20S

    Article  PubMed  CAS  Google Scholar 

  11. Barnett HJ, Taylor DW, Eliesziw M, et al. Benefits of carotid endarterectomy in patients with symptomatic moderate to severe stenosis. N Engl J Med 1998; 339: 1415–25

    Article  PubMed  CAS  Google Scholar 

  12. Albers GW, Hart RG, Lutsep HL, et al. Supplement to the guidelines for management of transient ischemic attacks. Stroke 1999; 30: 2502–11

    Article  PubMed  CAS  Google Scholar 

  13. Hass WK, Easton JD, Adams HP, 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: 501–7

    Article  PubMed  CAS  Google Scholar 

  14. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348: 1329–39

    Article  Google Scholar 

  15. 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: 1–13

    Article  PubMed  CAS  Google Scholar 

  16. Sanofi-Synthelabo. Plavix® (clopidogrel bisulfate): package insert. New York (NY): Sanofi-Synthelabo, 2001 Mar

  17. Thebault JJ, Kieffer G, Cariou R. Single-dose pharmacodynamics of clopidogrel. Semin Thromb Hemost 1999; 25 Suppl. 2: 3–8

    PubMed  CAS  Google Scholar 

  18. Savcic M, Hauert J, Bachmann F, et al. Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost 1994; 25 Suppl. 2: 15–9

    Google Scholar 

  19. Verstraete M. New developments in antiplatelet and antithrombotic therapy. Eur Heart J 1995; 16 Suppl. L: 16–23

    Article  PubMed  CAS  Google Scholar 

  20. Caplian H, Ds’Honneur G, Cariou R, et al. Clopidogrel for prevention of major cardiac events after coronary stent implantation: 30-day and 6-month results in patients with smaller stents. Am Heart J 2000; 140: 483–91

    Article  Google Scholar 

  21. Verstraete M, Zolkhelyi P. Novel antithrombotic drugs in development. Drugs 1995; 49: 856–84

    Article  PubMed  CAS  Google Scholar 

  22. McEwen J, Strauch G, Perles P, et al. Clopidogrel bioavailability in unaffected by food or antacids [abstract]. J Clin Pharmacol 1996; 36: 856

    Google Scholar 

  23. ©1974–2003 Thomson MICROMEDEX. All rights reserved. MICROMEDEX® Health Care Series. Vol. 117, expires 9/2003. USPDI/Advice for the patient are registered USP trademarks used herein under license.

  24. Savi P, Herbert JM, Pflieger AM, et al. Importance of hepatic metabolism in the antiaggregating activity of thienopyridine clopidogrel. Biochem Pharmacol 1992; 44: 527–32

    Article  PubMed  CAS  Google Scholar 

  25. Savi P, Combalbert J, Gaich C, et al. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost 1994; 72: 313–7

    PubMed  CAS  Google Scholar 

  26. Schror K. Antiplatelet drugs: a comparative review. Drugs 1995; 50: 7–28

    Article  PubMed  CAS  Google Scholar 

  27. Lins R, Broekhuysen J, Necciari J, et al. Pharmacokinetic profile of 14C-labeled clopidogrel. Semin Thromb Hemost 1999; 25 Suppl. 2: 29–33

    PubMed  CAS  Google Scholar 

  28. Roche Pharmaceuticals. Ticlid® (ticlopidine hydrochloride): package insert. Nutley (NJ): Roche Pharmaceuticals, 2001

    Google Scholar 

  29. Boehringer Ingelheim Pharmaceuticals. Aggrenox® (aspirin/dipyridamole): package insert. Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals Inc, 2001

    Google Scholar 

  30. Saltiel E, Ward A. Ticlopidine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states. Drugs 1987; 34: 222–62

    Article  PubMed  CAS  Google Scholar 

  31. Panak E, Maffrand JP, Picard-Fraire C, et al. Ticlopidine: a promise for the prevention and treatment of thrombosis and its complications. Haemostasis 1983; 13: 1–52

    PubMed  Google Scholar 

  32. Roe RL, Bruno JJ, Ellis DE. Ticlopidine hydrochloride: a new anti-thrombotic drug. Clin Res 1981; 29: 346A

    Google Scholar 

  33. Knudsen JB, Gormsen J. The effect of ticlopidine on platelet function in normal volunteers and in patients with platelet hyperaggregability in vitro. Thromb Res 1979; 16: 663–71

    Article  PubMed  CAS  Google Scholar 

  34. David JL, Monfort F, Herion F, et al. Compared effects of three dose-levels of ticlopidine on platelet function in normal subjects. Thromb Res 1979; 14: 35–49

    Article  PubMed  CAS  Google Scholar 

  35. Os’Brien JR, Etherington MD, Shuttleworth RD. Ticlopidine: an antiplatelet drug: effects in human volunteers. Thromb Res 1978; 13: 245–54

    Article  Google Scholar 

  36. Thebault JJ, Blatrix CE, Blanchard JF, et al. Effects of ticlopidine, a new platelet aggregation inhibitor in man. Clin Pharmacol Ther 1975; 18: 485–90

    PubMed  CAS  Google Scholar 

  37. Aubert D, Bernat A, Ferrand JC, et al. Pharmacological profile of PCR 3787: a metabolite of ticlopidine [abstract]. 7th Int Congr Thrombosis. Valencia. Haemostasis 1982; 12: 137

    Google Scholar 

  38. Shah J, Teitelbaum P, Molony B, et al. Single and multiple dose pharmacokinetics of ticlopidine in young and elderly subjects. Br J Clin Pharmacol 1991; 32: 761–4

    PubMed  CAS  Google Scholar 

  39. Frias-Iniesta J, Soto-Matos A, Guerra P, et al. Average bioequivalence of two oral formulations of ticlopidine in healthy volunteers. Curr Ther Res 2000; 61(8): 523–33

    Article  Google Scholar 

  40. The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75mg aspirin as secondary prophylaxis after cerebrovascular ischemia events. Lancet 1991; 338: 1345–9

    Article  Google Scholar 

  41. Alga A, van Gijn J. Aspirin at any dose above 30mg offers only modest protection after cerebral ischemia. J Neurol Neurosurg Psychiatry 1996; 60: 197–9

    Article  Google Scholar 

  42. The 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: 1261–6

    Article  Google Scholar 

  43. Muller TH, Binder K, Guth BD. Pharmacology of current and future antithrombotic therapies. Cardiol Clin 1994; 12: 411–42

    PubMed  CAS  Google Scholar 

  44. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets: acetylation of a particulate fraction protein. J Clin Invest 1975; 56: 624–32

    Article  PubMed  CAS  Google Scholar 

  45. Tisdale JE. Antiplatelet therapy in coronary artery disease: review and update of efficacy studies. Am J Health Syst Pharm 1998; 55 Suppl. 1: S8–16

    PubMed  CAS  Google Scholar 

  46. Boeymaems JM, Van Coevarden A, Demolle D. Dipyridamole and vascular prostacyclin production. Biochem Pharmacol 1986; 35: 2897–902

    Article  Google Scholar 

  47. Moncada S, Korbut R. Dipyridamole and other phosphodiesterase inhibitors act as anti-thrombotic agents by potentiating endogenous prostacyclin. Lancet 1978; I: 1286–9

    Article  Google Scholar 

  48. Mojaverian P, Rocci ML, Conner DP, et al. The effect of food on absorption of enteric-coated aspirin: correlation with gastric residence time. Clin Pharmacol Ther 1987; 41: 11–7

    Article  PubMed  CAS  Google Scholar 

  49. Anon. Drug facts and comparisons. St Louis: Wolters Kluwer, 1994 Nov

  50. Stringer KA, Branconi JM, Abadier R, et al. Disposition of oral dipyridamole in patients undergoing thallium 201 myocardial imaging. Pharmacotherapy 1992; 12: 83–7

    PubMed  CAS  Google Scholar 

  51. Mahony C, Wolfrom KM, Cocchetto DM, et al. Dipyridamole kinetics. Clin Pharm Ther 1982; 31: 330–8

    Article  CAS  Google Scholar 

  52. Nielson-Kudsk F, Pedersen AK. Pharmacokinetics of dipyridamole. Acta Pharmacol Toxicol 1979; 44: 391–9

    Article  Google Scholar 

  53. Markiewicz A, Semenowicz K, Korczynska J, et al. Chronopharmacokinetics of dipyridamole. Int J Clin Pharmacol Biopharm 1979; 17: 222–4

    PubMed  CAS  Google Scholar 

  54. Bjornsson TD, Mahoney C. Clinical pharmacokinetics of dipyridamole. Thromb Res 1983; 29 Suppl. 4: 94–104

    Google Scholar 

  55. Emmons PR, Harrison MJG, Honour A, et al. Effect of pyrimidopyrimidine derivative on thrombus formation of a rabbit. Nature 1965; 208: 255–7

    Article  PubMed  CAS  Google Scholar 

  56. Gent AE, Brook CGD, Foley TH, et al. Dipyridamole: a controlled trial of its effect on acute myocardial infarction. BMJ 1968; 4: 366–8

    Article  PubMed  CAS  Google Scholar 

  57. Acheson J, Danta G, Hutchinson EC. Controlled trial of dipyridamole in cerebral vascular disease. BMJ 1969; 1: 614–5

    Article  PubMed  CAS  Google Scholar 

  58. Boehringer Ingelheim Pharmaceuticals. Data on file. Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals Inc, 2002

    Google Scholar 

  59. Dresse A, Chevolet C, Delapierre D, et al. Pharmacokinetics of oral dipyridamole (Persantine) and its effect on platelet adenosine uptake in man. Eur J Clin Pharmacol 1982; 23: 229–34

    Article  PubMed  CAS  Google Scholar 

  60. Krasinski SD, Russell RM, Samloff IM, et al. Fundic atrophic gastritis in an elderly population: effect on hemoglobin and several serum nutritional indicators. J Am Geriatrics Soc 1986; 34: 800–6

    CAS  Google Scholar 

  61. Hurwitz A, Brady DA, Schaal SE, et al. Gastric acidity in older adults. JAMA 1997; 278: 659–62

    Article  PubMed  CAS  Google Scholar 

  62. Bousser MG, Eschwege E, Haguenau M, et al. AICLA controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. Stroke 1983; 14: 5–14

    Article  PubMed  CAS  Google Scholar 

  63. The American-Canadian Co-Operative Study Group. Persantine aspirin trial in cerebral ischemia: Part II: endpoint results. Stroke 1985; 16: 406–15

    Article  Google Scholar 

  64. ESPS Group. European Stroke Prevention Study. Stroke 1990; 21: 1122–30

    Article  Google Scholar 

  65. Antithrombotic Trialistss’ Collaboration. Collaborative metaanalysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86

    Article  Google Scholar 

  66. Wilterdink JL, Easton JD. Dipyridamole plus aspirin in cerebrovascular disease. Arch Neurol 1999; 56: 1087–92

    Article  PubMed  CAS  Google Scholar 

  67. De Schryver EL. Design of ESPRIT: an international randomized trial for secondary prevention after non-disabling cerebral ischemia of arterial origin. uropean/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) Group. Cerebrovasc Dis 2000; 10: 147–50

    Article  PubMed  Google Scholar 

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  1. School of Pharmacy and Allied Health Professions, Department of Pharmacy Practice, Creighton University, 2500 California Plaza, Omaha, Nebraska, 68178, USA

    Thomas L. Lenz & Amy F. Wilson

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Lenz, T.L., Wilson, A.F. Clinical Pharmacokinetics of Antiplatelet Agents Used in the Secondary Prevention of Stroke. Clin Pharmacokinet 42, 909–920 (2003). https://doi.org/10.2165/00003088-200342100-00003

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