Clopidogrel in cardiovascular disorders.
Department of Pharmacology & Therapeutics, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai - 400 012, India., India
R A Kulkarni
Department of Pharmacology & Therapeutics, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai - 400 012, India.
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Kulkarni R A. Clopidogrel in cardiovascular disorders. J Postgrad Med 2000;46:312-3
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Kulkarni R A. Clopidogrel in cardiovascular disorders. J Postgrad Med [serial online] 2000 [cited 2022 May 23 ];46:312-3
Available from: https://www.jpgmonline.com/text.asp?2000/46/4/312/249
Clopidogrel, a thienopyridine compound, is a novel antiplatelet agent that has been evaluated in a large, multicentric CAPRIE (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.
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., 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.
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. Its absorption is unaffected by the presence of food or antacids. 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.
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.
The major clinical evidence for the efficacy of Clopidogrel is derived from the CAPRIE trial. 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 trialís 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.
Clopidogrel is free from clinically significant interactions with a wide range of drugs, including phenobarbital, cimetidine, estrogen, digoxin, theophylline, atenolol, nifedipine, or nifedipine-atenolol combination. However, due to pharmacologic considerations or limited clinical data in some instances, caution should be used when clopidogrel is co-administered with heparin, warfarin, or non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin.
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.,
The recommended dose is 75 mg once daily with or without food., No dosage adjustment is for age, body weight, gender, race, renal impairment, or mild or moderate hepatic impairment.
In the CAPRIE trial, clopidogrel was shown to have a favourable safety profile, with an overall tolerability that was similar to that of aspirin. 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.
Clopidogrel is contraindicated if there is hypersensitivity to the drug or any component of the product and active pathological bleeding.
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.
Symptoms of toxicity were observed only at very high doses in animals. However, no adverse events have been reported after single oral administration of 600 mg of clopidogrel in healthy volunteers. 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.
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.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339. |
|2||Herbert JM, Frehel D, Vallee E, et al. Clopidogrel, a novel anti-platelet and anti-thrombotic agent. Cardiovasc Drug Rev 1993;11:180-198.|
|3||Mills DCB, Puri R, Hu CJ, Minniti C, Grana G, Freedman MD, et al. Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase. Arterioscler Thromb 1992;12:430-436.|
|4||Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP, Berger Y, et al. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost 1994 72; 313-317.|
|5||Guillin MC, Bonnet G, Sissmann J, Necciari J, Dickinson JP. Pharmacodynamics and pharmacokinetics of the novel antiplatelet agent, clopidogrel, in the young and the elderly with and without symptomatic atherosclerosis. Eur Heart J 1996; 17(Suppl): 161.|
|6||McEwen J, Strauch G, Perles P, et al. Clopidogrel bioavailability is unaffected by food or antacids. J Clin Pharmacol 1996; 36:856. |
|7||Caplain H, Kieffer G. Thiercelin JF et al. Tolerance and clinical pharmacology of repeated administration of clopidogrel (SR 25990) a new antiplatelet agent, at three dose levels in normal healthy volunteers. Thromb Haemost 1989; 62: 410.|
|8||Morais J (on behalf of the CAPRIE Investigators). Use of concomitant medications in the CAPRIE trial: clopidogrel is un-likely to be associated with clinically significant drug interactions. Eur Heart J 1998;19 (Suppl):5. |
|9||Peeters PAM, Crijns WJ, Tammings WJ, et al. Absence of pharmacokinetic interaction between the novel antiplatelet agent, clopidogrel, and digoxin. Eur Heart J 1996;17(Suppl): 160.|
|10||Caplain H, Thebault JJ, Necciari J. Clopidogrel does not affect the pharmacokinetics of theophylline. Semin Thromb Hemost 1999;25 (Suppl2):65-68. |
|11||Forbes CD, Belch JJF, Bridges AB, et al. Pharmacodynamic compatibility of clopidogrel with atenolol and nifedipine co-med-ication in patients with atherosclerotic disease. Eur Heart J 1996;17 (Suppl):160. |
|12||D’Honneur G, Caplain H, Cariou R, et al. Interaction study between clopidogrel and prolonged intravenous heparin administration in young healthy volunteers. Haemostasis 1996;26 (Suppl 3):554. |
|13||Caplain H, D’Honneur GD, Cariou R. Lack of interaction of aspirin (1000 mg) with chronic clopidogrel in volunteers. Haemostasis 1996; 26(Suppl 3):557.|
|14||Easton JD. Clinical aspects of the use of Clopidogrel, a new antiplatelet agent. Semin Thromb Haemost 1999; 25 (Suppl 2): 69-75. |
|15||Denninger M-H, Necciari J, Serre-Lacroix E, Sissmann J. Clopidogrel antiplatelet activity is independent of age and presence of atherosclerosis. Semin Thromb Hemost 1999;25 (Suppl 2):41-46 |
|16||Deray G, Brouard R, Bagnis C, et al. Safety and activity of clopidogrel, an antiplatelet agent, in chronic renal failure patients. J Am Soc Nephrol 1995;6 (Suppl 1):384. |
|17||Slugg PH, Much DR, Smith WB, et al. Cirrhosis does not affect the pharmacokinetics and pharmacodynamics of Clopidogrel. J clin Pharmacol 2000; 40: 396-401.|
|18||Thebault JJ, Kieffer G, Cariou R. Single Ėdose pharmacodynamics of Clopidorel. Semin Thromb Hemost 1999;25 (Suppl 2):3-8.