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Clopidogrel
Mario de Lemos, Pharm.D. student, Rubina Sunderji, Pharm.D

May 1999 Drug & Therapeutics Newsletter
(C) 1999, CSU-Pharmaceutical Sciences
Vancouver Hospital & Health Sciences Centre

Clopidogrel is a new antiplatelet agent with a similar chemical structure and mode of action to ticlopidine.1,2 Clopidogrel inhibits platelet aggregation by irreversibly inhibiting the adenosine diphosphate (ADP) pathway for platelet activation, thus suppressing the activation of the glycoprotein IIb/IIIa receptor. Unlike aspirin (ASA), clopidogrel does not affect the cyclo-oxygenase pathway and thromboxane-A2.

Role of Antiplatelet Agents

Low dose ASA is indicated for secondary prevention of mycocardial infarction (MI), stroke and other vascular events in patients with symptomatic atherosclerotic disease.3,4 Ticlopidine represents a formulary alternative to ASA in patients who cannot tolerate or have failed ASA.4 It is also used in combination with ASA for the prevention of stent thrombosis. However, hematological adverse effects of ticlopidine (e.g. neutropenia, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP)) necessitate close CBC monitoring. Clopidogrel does not appear to cause these hematological effects and thus offers a safer, but more expensive alternative to ticlopidine.

Clinical efficacy: Prevention of Vascular Events

ASA prevents approximately 15 secondary ischemic events annually per 1000 patients with atherosclerotic disease.5 A comparative study of ASA 650mg bid and ticlopidine 250mg bid in 3069 patients within 3 months of transient ischemic attack (TIA) or minor thrombotic stroke showed a significant benefit of ticlopidine over ASA.6 The 3 year event rate for fatal or non-fatal stroke was 10% for ticlopidine and 13% for ASA (p=0.024, number needed to treat, NNT = 33).

Recently, a large randomized, controlled trial (CAPRIE) in 19,185 patients with previous stroke, MI or peripheral vascular disease ccompared clopidogrel 75mg/day to ASA 325mg/day.7 The annual combined risk of MI, ischemic

7 and less than that reported with ticlopidine (0.8%).4,6 Unlike ticlopidine, clopidogrel has not been reported to cause TTP.16 Consequently, clopidogrel does not require the hematological monitoring (every 2 weeks for 3 months) as is necessary with ticlopidine.

Table 1. Comparison of Antiplatelet Agents

Antiplatelet Agent

Dosing Regimen

Daily Cost†

Pharmacare Coverage

Clopidogrel

75mg daily

$2.44

No

Ticlopidine

250mg bid

$1.48

Yes

Enteric Coated ASA

81mg daily
325mg daily

$0.09
$0.01

Yes

† based on VHHSC acquisition costs

Formulary Status

Both clopidogrel and ticlopidine are restricted to the divisions of neurology, vascular surgery, cardiology, and cardiovascular surgery.

References

  1. Coukell AJ et al. Clopidogrel. Drugs 1997;54:745-50.

  2. Sharis PJ et al. The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 1998;129:394-405.

  3. Hennekens CH et al Aspirin as a therapeutic agent in cardiovascular disease. Circulation 1997;96:2751-3.

  4. Anon. Clopidogrel for reduction of atherosclerotic events. Med Lett Drugs Ther 1998;40:59-60.

  5. 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;308:81-106.

  6. Hass WK 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.

  7. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.

  8. Popma JJ et al. Antithrombotic therapy in patients undergoing coronary angioplasty. Chest 1995;108(Suppl 4):S486-S501.

  9. Rupprecht HJ et al. Comparison of antiplatelet effects of aspirin, ticlopidine, or their combination after stent implantation. Circulation 1998;97:1046-52.

  10. Schomig A et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084-9.

  11. Leon MB et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998;339:1665-71.

  12. Makkar R et al. Clopidogrel, a novel platelet ADP-receptor antagonist inhibits aspirin and ticlopidine-resistant stent thrombosis. J Am Coll Cardiol 1997;29(Suppl A):353A.

  13. Makkar RR et al. Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J 1998;10:1538-46.

  14. Berger PB. Advances in antiplatelet therapy during stent placement. Educational symposium supported by Sanofi and Bristol-Myers Squibb, Dallas, Texas, 7 November 1998.
  15. Bachmann F et al. Rapid onset of inhibition of ADP-induced platelet aggregation by a loading dose of clopidogrel. Eur Heart J 1996;17(Suppl S):263A.

  16. Bennett CL et al. Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases. Ann Intern Med 1998;128:541-4.