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Clopidogrel

A Review of its Use in the Prevention of Thrombosis

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Summary

Abstract

Clopidogrel (Plavix®, Iscover®) selectively and irreversibly inhibits adenosine diphosphate (ADP)-induced platelet aggregation. Long-term administration of clopidogrel was associated with a modest but statistically significant advantage over aspirin in reducing adverse cardiovascular outcomes in patients with established cardiovascular disease in the CAPRIE trial. In other large well designed multicentre trials, such as CURE, COMMIT and CLARITY-TIMI 28, the addition of clopidogrel to aspirin therapy improved outcomes in patients with acute coronary syndromes. However, some issues regarding the use of clopidogrel remain unresolved, such as the optimal loading dose in patients undergoing percutaneous coronary interventions (PCI) and the optimal treatment duration following drug-eluting intracoronary stent placement.

Results of several large randomised trials, therefore, have established clopidogrel as an effective and well tolerated antiplatelet agent for the secondary prevention of ischaemic events in patients with various cardiovascular conditions, including those with ischaemic stroke or acute coronary syndromes. In addition, treatment guidelines from the US and Europe acknowledge the importance of clopidogrel in contemporary cardiovascular medicine.

Pharmacological Properties

Clopidogrel is a thienopyridine antiplatelet agent that acts by selectively and irreversibly inhibiting ADP-induced platelet aggregation mediated by the P2Y12 purinoceptor on the platelet surface. Inhibition of platelet aggregation occurs within 2 hours of administration of clopidogrel. The time to achieve maximal inhibition of platelet aggregation is significantly reduced by the use of a loading dose of clopidogrel. Platelet aggregation and bleeding times gradually return to baseline values ≈5 days after discontinuation of the drug. However, as demonstrated in ex vivo platelet aggregation studies, there can be substantial inter-individual variability in the onset and offset of the antiplatelet effect of clopidogrel.

Clopidogrel is a prodrug that must undergo biotransformation via cytochrome P450 (CYP)-mediated hepatic metabolism to an active metabolite. The active moiety is highly unstable and its pharmacokinetic properties have not been determined. Plasma concentrations of the parent compound are usually undetectable ≈2 hours after administration of clopidogrel because it is rapidly converted to the main circulating metabolite, an inactive carboxylic acid derivative, which represents ≈85% of circulating drug-related compounds in plasma. A peak plasma concentration of ≈3 mg/L for the main metabolite occurs ≈1 hour after repeated doses of clopidogrel 75 mg/day. Food does not affect bioavailability. The elimination half-life of the carboxylic acid metabolite is ≈7–8 hours.

Activation of clopidogrel occurs via CYP3A4 in humans, and ex vivo studies indicate that atorvastatin inhibits its activation; however, the clinical benefit of clopidogrel has not been shown to be reduced by concomitant administration of atorvastatin and further study appears to be warranted.

Therapeutic Efficacy

Clopidogrel has been evaluated in several large, randomised, double-blind, placebo-controlled, multicentre clinical trials. Treatment with clopidogrel for 1–3 years in the CAPRIE study was associated with a modest but statistically significant advantage over aspirin in reducing adverse cardiovascular outcomes in patients with recent myocardial infarction (MI), recent stroke or established peripheral arterial disease. In the CURE trial, the early and long-term use of clopidogrel plus aspirin for up to 1 year was associated with a significant reduction in adverse cardiovascular outcomes (e.g. composite of death from cardiovascular causes, nonfatal MI or stroke) compared with that of aspirin alone in patients with acute coronary syndromes without ST-segment elevation. In COMMIT, patients presenting within 24 hours of onset of ST-segment elevation MI (STEMI) who were randomised to receive a short course (e.g. 4 weeks) of clopidogrel plus aspirin had significantly lower rates of death and the composite of death, MI or stroke than those who were randomised to aspirin alone. The CLARITY-TIMI 28 trial, which was conducted in patients who presented within 12 hours after the onset of STEMI and were deemed candidates for coronary angiography, showed a marked reduction in the rate of an occluded infarct-related artery (as reflected byThrombolysis in MI [TIMI] flow grade 0 or 1), recurrent MI or death among patients who were randomised to receive a short course of clopidogrel (e.g. ≤8 days, including a loading dose) in addition to standard therapy (including aspirin, a thrombolytic and, if necessary, heparin) compared with those who received standard therapy only. Essentially all patients (99.7%) in CLARITY-TIMI 28 received thrombolytic therapy, whereas thrombolytics were not mandated in COMMIT and only about half of patients received such therapy.

Prospectively planned analyses of patients who underwent PCI in CURE and CLARITY-TIMI 28 were also conducted. Results of PCI-CURE in patients with non-ST-segment elevation acute coronary syndromes showed that the use of clopidogrel plus aspirin was associated with a reduced incidence of events in the primary outcome cluster of cardiovascular death, MI or urgent target vessel revascularisation within 30 days of PCI compared with aspirin alone; longer-term cardiovascular events (mean follow-up period 8 months) were also significantly reduced with dual antiplatelet therapy. Results of PCI-CLARITY in patients with STEMI showed that randomisation to clopidogrel (in addition to standard therapy) was associated with a significant reduction in the incidence of the primary composite endpoint of cardiovascular death, recurrent MI or stroke from the time of PCI to 30 days after randomisation.

In addition to these analyses in patients undergoing PCI, the CREDO trial compared the early and long-term use of clopidogrel plus aspirin for 1 year with a shorter course of dual antiplatelet therapy (28 days starting after PCI) followed by aspirin only to the end of the study. Patients in the former group had a significantly lower incidence of events in the 1-year primary composite endpoint of death, MI or stroke than those in the latter group. There was also a numerical advantage in the 28-day composite endpoint, although this did not achieve statistical significance. CREDO is the only large prospective trial involving clopidogrel in the setting of elective PCI.

Results have been less favourable in the MATCH study in high-risk patients with recent ischaemic stroke or transient ischaemic attack and the CHARISMA trial in patients with clinically evident cardiovascular disease or multiple risk factors. In MATCH, the combined use of clopidogrel and aspirin for 18 months was associated with a nonsignificant reduction in the composite primary endpoint of ischaemic stroke, MI, vascular death or rehospitalisation for acute ischaemia compared with clopidogrel alone, but the dual antiplatelet regimen was also associated with an increased risk of life-threatening or major bleeding. After a median follow-up period of 28 months in CHARISMA, patients randomised to receive clopidogrel plus aspirin had a nonsignificant reduction in the primary composite endpoint of MI, stroke or cardiovascular death compared with those receiving aspirin only. However, there was also a nonsignificant increase in the risk of primary events and a significant increase in mortality with dual antiplatelet therapy in the subgroup of patients without documented cardiovascular disease, suggesting that clopidogrel plus aspirin should not be used for primary prevention of cardiovascular disease.

Additional data in patients undergoing PCI suggest that a loading dose of clopidogrel 600mg is required to ensure adequate antiplatelet activity if the drug is administered 2–6 hours before the procedure; a standard loading dose of 300mg is recommended when pretreatment can be administered at least 6 hours before PCI. Also, in patients receiving drug-eluting intracoronary stents, treatment with clopidogrel beyond the recommended 3- or 6-month period (for sirolimus- and paclitaxel-coated stents, respectively) appears to be warranted to reduce adverse long-term clinical outcomes, although the optimal duration of treatment is not established.

Results of a two-part phase III trial in Japanese patients with cerebral infarction (excluding cardiogenic cerebral embolism) verified the noninferiority of the efficacy of clopidogrel to that of ticlopidine in terms of preventing the primary composite endpoint of vascular events (cerebral infarction, MI and other vascular death). These results contributed to the approval of clopidogrel in Japan for use in patients with ischaemic stroke.

Tolerability

In general, the overall tolerability profile of clopidogrel, including bleeding complications, is similar to that of aspirin. In the CAPRIE trial, which directly compared clopidogrel and aspirin, significantly more patients receiving long-term clopidogrel therapy experienced rash or diarrhoea, whereas significantly more patients treated with aspirin reported gastrointestinal symptoms (indigestion, nausea or vomiting), experienced gastrointestinal haemorrhage or had abnormal liver function tests. In addition, clopidogrel was associated with a significantly higher rate of discontinuation because of diarrhoea, whereas aspirin was associated with a significantly higher rate of discontinuation because of indigestion, nausea or vomiting.

Although the risk of bleeding is generally increased when clopidogrel and aspirin are used concurrently, the benefits of dual antiplatelet therapy outweigh the risks in the management of acute coronary syndromes, particularly in patients undergoing PCI with or without intracoronary stent placement. In addition, results of CLARITY-TIMI 28 in patients with STEMI showed that clopidogrel could be administered safely in patients receiving aspirin, a thrombolytic and heparin.

Clopidogrel was shown to have a more favourable tolerability profile than ticlopidine in CLASSICS, which compared the tolerability of clopidogrel plus aspirin with that of ticlopidine plus aspirin for 28 days after intracoronary stent placement. The incidence of the combined primary outcome events (major bleeding, neutropenia, thrombocytopenia or early discontinuation) was significantly lower in the clopidogrel arm. Clopidogrel was also associated with significantly fewer adverse events (including laboratory abnormalities) than ticlopidine in the two-part phase III Japanese trial. In many countries, the use of clopidogrel has generally supplanted that of ticlopidine because of the better tolerability profile of clopidogrel (e.g. the use of ticlopidine is limited by life-threatening neutropenia).

Treatment guidelines suggest that clopidogrel be withheld for at least 5 days before coronary artery bypass grafting (CABG), as it can lead to an excess in bleeding complications if administered close to the time of CABG surgery.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Correspondence to Greg L. Plosker.

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Various sections of the manuscript reviewed by: D.L. Bhatt, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA; C.L. Campbell, University of Kentucky, Lexington, Kentucky, USA; J. Carlsson, Department of Internal Medicine II, Klinikum Lippe-Detmold, Detmold, Germany; C. Doecke, Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia; S. Dunn, University of Kentucky, Lexington, Kentucky, USA; J. Latour-Pérez, Hospital General Universitario de Elche and University de Alicante, Alicante, Spain; U. Zeymer, Herzzentrum Ludwigshafen, Ludwigshafen, Germany.

Data Selection

Sources: Medical literature published in any language since 1980 on clopidogrel, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search term was ‘clopidogrel’. Searches were last updated 15 February 2007.

Selection: Studies in patients with or at risk of cardiovascular disorders who received clopidogrel. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Clopidogrel, antiplatelet, acute coronary syndromes, atherothrombosis, percutaneous coronary intervention, myocardial infarction, stroke, pharmacodynamics, pharmacokinetics, therapeutic use.

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Plosker, G.L., Lyseng-Williamson, K.A. Clopidogrel. Drugs 67, 613–646 (2007). https://doi.org/10.2165/00003495-200767040-00013

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