Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 46, Num. 4, 2000, pp. 312-313

Journal of Postgraduate Medicine, Vol. 46, No. 4, October-December, 2000, pp. 312-313

Drug Review

Clopidogrel in Cardiovascular Disorders

RA Kulkarni

Department of Pharmacology & Therapeutics, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai - 400 012, India

Code Number: jp00102

Clopidogrel, a thienopyridine compound, is a novel antiplatelet agent that has been evaluated in a large, multicentric CAPRIE¹ (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events) study for the secondary prevention of atherothrombotic events in patients with a recent ischaemic stroke or myocardial infarction or with objectively established peripheral arterial disease.

Pharmacodynamics

Clopidogrel is an irreversible inhibitor of platelet aggregation. It acts by irreversibly modifying the platelet ADP receptor, thus selectively inhibiting the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent activation of the glycoprotein GPIIb/ IIIa complex, thereby inhibiting platelet aggregation.^2,3 Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan. Biotransformation of clopidogrel to its active metabolite is necessary to produce inhibition of platelet aggregation.⁴

Pharmacokinetics

Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg with peak plasma levels (~3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing.⁵ Its absorption is unaffected by the presence of food or antacids.⁶ Plasma concentrations of the clopidogrel are, however, very low beyond 2 hours of dosing even after repeated oral doses as it is extensively metabolised by the liver to its active metabolite which has not yet been isolated. The main circulating metabolite is its carboxylic acid derivative, which however has no effect on platelet aggregation. Clopidogrel and its metabolite bind reversibly to human plasma proteins (»94-98%) and are excreted in both urine (50%) and faeces (46%) with an elimination half- life of eight hours.⁵

Dose dependent inhibition of platelet aggregation can be seen 2 hours after a single oral dose of 75 mg of clopidogrel. This inhibition reaches a steady state between day 3 and day 7 with repeated doses. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.⁶

Clinical Studies

The major clinical evidence for the efficacy of Clopidogrel is derived from the CAPRIE trial.¹ This was a multicentre randomised, double-blind, parallel-group study comparing clopidogrel (75 mg daily) to aspirin (325 mg daily) in 19,185 patients with established cardiovascular disease. The trial's primary outcome was the time to first occurrence of new ischaemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. The results showed that clopidogrel was associated with a lower incidence of outcome events of every kind i.e. overall risk reduction, a decrease in all-cause mortality and all-cause strokes. It was also shown to be more effective than aspirin, in reducing the combined risk of ischaemic stroke, myocardial infarction or vascular death in a broad spectrum of patients with symptomatic atherosclerosis. In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was again lower in the clopidogrel group. The benefits of clopidogrel appeared to be strongest in patients with peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients.

Drug Interactions

Clopidogrel is free from clinically significant interactions with a wide range of drugs,⁸ including phenobarbital, cimetidine, estrogen, digoxin,⁹ theophylline,¹⁰ atenolol, nifedipine, or nifedipine-atenolol combination.¹¹ However, due to pharmacologic considerations or limited clinical data in some instances, caution should be used when clopidogrel is co-administered with heparin,¹² warfarin, or non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin.¹³

Indications

Clopidogrel is indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.^1,14

Dosage and Administration

The recommended dose is 75 mg once daily with or without food.^1,14 No dosage adjustment is for age,¹⁵ body weight, gender, race, renal impairment,¹⁶ or mild or moderate hepatic impairment.¹⁷

Adverse Reactions

In the CAPRIE trial, clopidogrel was shown to have a favourable safety profile, with an overall tolerability that was similar to that of aspirin.¹ The clinically important adverse events observed were gastrointestinal haemorrhage, neutropaenia/agranulocytosis, gastrointestinal events (abdominal pain, dyspepsia, gastritis, diarrhoea and/or constipation) and rash and other skin disorders.

Contraindications

Clopidogrel is contraindicated if there is hypersensitivity to the drug or any component of the product and active pathological bleeding.

Precautions^1,14

Clopidogrel should be used with caution in patients at risk of increased bleeding from trauma, surgery, or other pathological conditions. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, it should be discontinued 7 days prior to surgery.

Clopidogrel prolongs the bleeding time, hence should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients taking clopidogrel.

Experience with clopidogrel is limited in patients with severe hepatic disease, pregnant women and children; hence it should be used with caution in these populations.

Animal studies have shown that clopidogrel and/or its metabolites are excreted in the milk. Although it is not known whether this drug is excreted in human milk, there is a potential for adverse reactions in nursing infants, hence a decision whether to discontinue nursing or to discontinue the drug, should be made taking into account the importance of the drug to the nursing woman.

Overdosage

Symptoms of toxicity were observed only at very high doses in animals.² However, no adverse events have been reported after single oral administration of 600 mg of clopidogrel in healthy volunteers.¹⁸ Bleeding time was prolonged by a factor of 1.7, which is similar to that observed with the therapeutic dose. Platelet transfusion may be used to reverse the pharmacological effects of clopidogrel if quick reversal is required.

Summary

Clopidogrel is conveniently dosed at 75 mg once daily, with no dose adjustments required in certain special patient populations. This dose is to be used whether the primary manifestation of atherosclerosis is ischaemic stroke, myocardial infarction or symptomatic peripheral arterial disease. Clinically significant interactions between clopidogrel and concomitant medications are unlikely; however, the use of caution is prudent when clopidogrel is prescribed in those at risk of increased bleeding, due to any cause.

RA Kulkarni

Department of Pharmacology & Therapeutics

Seth G. S. Medical College and K. E. M. Hospital,

Parel, Mumbai - 400 012, India

References

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