Clopidogrel Bisulfate Tablets
March 30, 1998
Pharmacology Update
Clopidogrel Bisulfate Tablets
By William T. Elliott, MD, and James Chan, PharmD, PhD
The fda has approved clopidogrel (plavix, bristol-Myers Squibb), a new thienopyridine antiplatelet drug that is chemically similar to ticlopidine. These drugs inhibit adenosine diphosphosphate (ADP)-induced platelet aggregation by their action on the ADP receptor. ADP appears to play an important role in platelet activation in the formation of arterial thrombi. They do not act directly on the glycoprotein IIb/IIIa receptor but appear to indirectly affect fibrinogen binding to this receptor by inhibiting the activation of the glycoprotein IIb/IIIa complex, which is the primary receptor for fibrinogen.1-3 Clopidogrel requires activation by hepatic biotransformation for activity that has an onset of about two hours after the first dose, and the effect of the drug on platelets persists for about five days after discontinuation of treatment.2
Clopidogrel will be copromoted by Bristol-Myers Squibb Co. and Sanofi Plarmaceutical, Inc., and will compete in the marketplace with ticlopidine and aspirin.
Indications
Clopidogrel is indicated for the reduction of atherosclerosis events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established arterial disease.2
Potential Advantages
Clopidogrel appears to be much less likely to cause severe neutropenia compared to ticlopidine, and the incidences of low neutrophil counts were not significantly different than those with aspirin.4 Because of this, unlike ticlopidine, monitoring of CBC and white blood cell differentials is not recommended for clopidogrel.
Potential Disadvantages
Clopidogrel has similar side effects as aspirin. Common side effects compared to aspirin are indigestion/nausea/vomiting (15% vs 17.6%), any bleeding disorder (9.3% vs 9.3%), rash (6% vs 4.6%), and diarrhea (4.5% vs 3.4%).
Compared to aspirin, clopidogrel appears to have a slightly higher risk for gastrointestinal hemorrhage (2% vs 2.7%), intracranial hemorrhage (0.35% vs 0.5%), and abnormal liver function (3% vs 3.15%). Coadministration with NSAIDs has been associated with increased occult GI blood loss. The safety of chronic concomitant use with warfarin and aspirin has not be established.2
Dosing Information
Clopidogrel is supplied as 75 mg tablets. The daily dose is one tablet daily without regard to meals.
Comments
Clopidogrel is the second thienopyridine derivative to be approved by the FDA. At a dose of 75 mg daily, its inhibition of ADP-induced platelet aggregation was similar to that produced by ticlopidine (250 mg bid).6 Clopidogrel has been reported in a large trial (CAPRIE) to be as effective as aspirin (325 mg) in reducing stroke, myocardial infarction, and other vascular death in patients with ischemic stroke (including retinal and lacunar infarction), myocardial infarction, and atherosclerotic peripheral arterial disease.4 In this trial, clopidogrel showed an 8.7% overall risk reduction advantage over aspirin. In a post-hoc analysis, the data suggest that clopidogrel may be more effective than aspirin in reducing stroke, myocardial infarction, or other vascular death among patients with peripheral artery disease. The relative risk reduction was 23.8% compared to aspirin (95% CI 8.9%-36.2%).4 Peripheral arterial disease included patients with intermittent claudication (WHO criteria) or history of intermittent claudication with previous leg amputation, reconstructive surgery, or angioplasty with no persisting complication from intervention. Since the CAPRIE study was not powered to allow subgroup analysis, the FDA allowed the language of "marginal" benefit over aspirin but not a superiority claim. The same subgroup analysis indicated no difference between aspirin and clopidogrel in patients with ischemic stroke or myocardial infarctions.
Clinical Implications
The leading cause of death in the United States is thromboembolic events such as myocardial infarction and stroke. Antiplatelet therapy with aspirin and ticlopidine has been effective in preventing thromboembolic events in cardiovascular disease. Studies have indicated a reduction in the risk of nonfatal myocardial infarction and stroke by 25-30% and the rate of vascular death by 15%.5 The use of ticlopidine is limited by its potential to cause severe neutropenia, which necessitates monitoring of blood count. Aspirin is the mainstay due to its effectiveness and low cost. Whether clopidogrel is more effective than aspirin needs to be established. Clopidogrel is priced similar to ticlopidine, with a wholesale cost of about $2.30 per day.
References
1. Coukell AJ, et al. Drugs 1997;54(5):745-750.
2. Plavix Product Information. Bristol-Myers Squibb. November 1997.
3. Schror K. Drugs 1995;50(1):7-28.
4. CAPRIE Steering Committee. Lancet 1996;348: 1329-1339.
5. Antiplatelet Trialists Collaboration. BMJ 1994;308: 81-106.
6. Herbert JM, et al. Cardiovasc Drug Rev 1993;11: 180-198.
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