Pharmacology

Pharmacodynamics. Clopidogrel bisulfate is an inhibitor of adenosine diphosphate-induced platelet aggregation. It directly inhibits adenosine diphosphate from binding to its receptor and the subsequent adenosine diphosphate-mediated activation of the glycoprotein GPIIb/IIIa complex. Clopidogrel acts by irreversibly modifying the platelet adenosine diphosphate receptor. Therefore, platelets exposed to clopidogrel are affected for the remainder of their lifespan. Clopidogrel is a prodrug and requires metabolism via several CYP450 enzymes to exert its antiplatelet effects.

Inhibition of platelet aggregation occurs 2 hours after a single oral dose of clopidogrel. With repeated doses, it reaches a steady state within a few days, and the average inhibition level with a dose of 75 mg per day is between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued.

Approximately 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel's ability to prevent atherothrombotic events, is still lacking. Clopidogrel resistance varies greatly depending on the method of measuring platelet aggregation and the definition of resistance, but rates of 8% to 18% were reported in 1 study (07). Clopidogrel resistance, which increases risk of major vascular events, is likely to develop due to a decreased bioavailability of the active metabolite, genetic variation, or concomitant drug treatment (27). A study on patients hospitalized following a noncardioembolic ischemic stroke or transient ischemic attack who responded poorly to clopidogrel showed discordant results on laboratory tests -- light transmission aggregometry and flow cytometric assays, using vasodilator-stimulated phosphoprotein and CD62P (28). Usefulness of transmission electron microscopy has been suggested when platelet function assay results disagree.

Pharmacokinetics. Important pharmacokinetic features are as follows:

Clopidogrel is rapidly absorbed after oral administration with peak plasma levels of the main circulating metabolite occurring approximately 1 hour after dosing.

After oral dosing, clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, which represents approximately 85% of the circulating drug-related compounds in plasma and has no effect on platelet aggregation.

Approximately 50% of clopidogrel is excreted in the urine. The elimination half-life of the main circulating metabolite is 8 hours after single and repeated administration.

Clopidogrel resistance. This term is used for failure to achieve a drug response and may be due to a higher activation of platelets during clopidogrel therapy. Several contributing factors to clopidogrel resistance have been identified including genetic polymorphisms, concomitant use of other drugs, and vascular risk factors. Platelet function testing is recommended for patients with clopidogrel resistance, in whom an improvement in the efficacy of antiplatelet therapy is essential (29).

Pharmacogenetics/pharmacogenomics. P-glycoprotein encoded by ABCB1, a transmembrane calcium-dependent efflux pump for clopidogrel, is implicated in clopidogrel resistance. One study found that determination of ABCB1 genotype in addition to CYP2C19 enables better prediction of clopidogrel nonresponsiveness (19). Hypomethylation of ABCB1 promoter is associated with a decreased response to clopidogrel in Chinese patients with ischemic stroke via increased ABCB1 mRNA expression (31). The FDA has changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics, and clinical response. A systematic review and meta-analysis of published studies show that among patients with ischemic stroke or transient ischemic attacks treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers (21). There is still some controversy about the usefulness of CYP2C19 genotype testing in clinical use of clopidogrel. An ongoing meta-analysis of studies on the association of CYP2C19 genotype and clinical efficacy for stroke or transient ischemic attacks is expected to provide vigorous evidence on this issue to guide clinical decision-making as well as future research (32).

Genetic profiling is not recommended for routine use at present because CYP2C19 polymorphisms account for only approximately 12% of variability in clopidogrel platelet response, and it is unknown whether a specific genetic polymorphism is capable of influencing outcome for the individual patient (33). A polymorphism in the gene encoding PON1, a rate-limiting enzyme for clopidogrel bioactivation, also affects the response to clopidogrel (20). Because factors other than CYP2C19 genetic polymorphisms may contribute to the variability in antiplatelet effect seen with clopidogrel, adjustment of dosage is difficult. Ongoing trials dealing with adjusting antiplatelet therapy based on genetic testing will hopefully provide more useful information on how to integrate pharmacogenomics in the care of patients with atherothrombotic disease (08).

Clinical trials

In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study, clopidogrel demonstrated an overall 8.7% risk reduction in the combined end points of stroke, myocardial infarction, and vascular death compared with aspirin (325 mg/d) in patients with atherosclerosis documented by recent myocardial infarction, recent ischemic stroke, or established peripheral arterial disease (04).

Combined data from randomized trials of clopidogrel in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events including stroke when compared with placebo or control and a 10% reduction in vascular events when compared with aspirin (17).

Results of the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) clinical trial showed that aspirin plus extended-release clopidogrel versus dipyridamole used for treatment of patients with acute, mild ischemic stroke did not differ in terms of effects on functional outcome, recurrence, death, bleeding, or serious adverse events (02).

A pilot study, LOAD, has shown that loading with 375 mg of clopidogrel and 325 mg of aspirin appears to be safe when administered up to 36 hours after stroke and transient ischemic attack onset. It might decrease neurologic deterioration and requires further evaluation (18). In a randomized trial on patients with minor ischemic stroke or high-risk transient ischemic attacks, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 3 months than those who received aspirin alone (12).

A systematic review and metaanalysis of randomized clinical trials has shown that in patients who present with ischemic stroke/transient ischemic attack, short-course clopidogrel plus aspirin immediately following the index event appears to be more effective than and as safe as monotherapy for secondary stroke prevention (14). Another systematic review of randomized clinical trials showed that dual antiplatelet therapy with clopidogrel and aspirin given within 24 hours after high risk transient ischemic attack or minor ischemic stroke reduces subsequent stroke by about 20 in 1000 population, with a possible increase in moderate to severe bleeding of 2 per 1000 population (09).

Indications

Clopidogrel is indicated for the reduction of thrombosis in recent myocardial infarction, recent stroke, or established peripheral arterial disease. FDA-approved indications for clopidogrel include the following:

Contraindications

Clopidogrel is contraindicated in patients with active pathologic bleed. Clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or coadministration with nonsteroidal antiinflammatory drugs or warfarin.

Goals and duration of treatment

For patients with a history of recent myocardial infarction, recent stroke, or established peripheral arterial disease, clopidogrel has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), and other vascular death. The role of clopidogrel in secondary prevention of stroke is well defined, but there are insufficient data at present to recommend its use in acute ischemic stroke (10). Clopidogrel as well as a combination of aspirin plus extended-release dipyridamole are both slightly more effective than aspirin, but the combination of aspirin and clopidogrel does not reduce the risk of new vascular events and increases life-threatening bleedings (16). However, analysis of data derived from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial shows that clopidogrel-aspirin combination treatment may have a benefit in reducing stroke risk, which outweighs the potential risk of increased bleeding, especially within the first 2 weeks compared with aspirin alone in patients with minor stroke or transient ischemic attacks (22).

Clopidogrel can be considered as first-line secondary therapy to prevent recurrent cerebral ischemic events because it is superior to aspirin monotherapy and has fewer side effects compared with extended-release dipyridamole (01). However, besides an increased risk of hemorrhage, drawbacks of clopidogrel include slow onset of effect that is irreversible, genetically determined variability in clinical potency, and interactions with other commonly used drugs (05).

Use of a Markov model for prognosis has shown that therapy with clopidogrel plus aspirin should be preferred to aspirin alone to prevent recurrent stroke in patients with intracranial artery stenosis, especially in those patients with a history of transient ischemic attacks or coronary artery disease (30). A metaanalysis of randomized controlled trials shows that dual antiplatelet therapy with clopidogrel and aspirin, whether short-term or long-term, is associated with a lower risk of stroke but higher risk of bleeding complications (26). Currently available evidence, however, does not substantiate the widespread use of long-term aspirin with clopidogrel as dual antiplatelet therapy for the secondary prevention of ischemic stroke or transient ischemic attacks (06). In view of the controversy about the use of dual antiplatelet therapy, a personalized approach should carefully balance the risks of hemorrhage and benefits of stroke prevention in individual patients.

According to an evidence-based medicine analysis, dual antiplatelet therapy with clopidogrel and aspirin is beneficial for patients with high-risk transient ischemic attacks, severe intracranial artery stenosis, intracranial and extracranial artery stenosis causing artery-to-artery embolism, ischemic stroke due to aortic arch plaques, atrial fibrillation not suitable for oral anticoagulants, intracranial and extracranial stent implantation, and ischemic stroke concomitant with acute coronary syndrome (25).

Dosing

The recommended daily dose of clopidogrel is 75 mg once daily orally.

Special considerations

Pediatric. A prospective consecutive cohort study of children with arterial ischemic stroke found clopidogrel to be tolerated relatively well, but intracranial bleeding may be seen in combination with aspirin and in the presence of other risk factors (24).

Geriatric. No dosage adjustment is needed for the elderly even though plasma levels are higher than in younger adults.

Pregnancy and lactation. Toxicity studies in rats and rabbits have not revealed any evidence of impaired fertility or fetotoxicity due to clopidogrel. According to a review of the limited data available in the literature, clopidogrel use in pregnancy has not shown significant toxicity to either the mother or the newborn (23). There are, however, no adequate and well-controlled studies in pregnant women. Clopidogrel should be used during pregnancy only if clearly needed.

Studies in rats have shown that clopidogrel and its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the nursing woman.

Anesthesia. No relevant information is available.

Interactions

In healthy volunteers receiving naproxen, concomitant administration of clopidogrel was associated with increased occult gastrointestinal blood loss. There are several interactions between clopidogrel and drugs that are widely used in clinical practice, particularly with drugs shown to interfere with the pharmacodynamic and pharmacokinetic effects of clopidogrel. These drugs include proton pump inhibitors of gastric secretions, statins, calcium channel blockers, antidiabetic agents, and antimicrobial agents (15).

Aspirin and heparin do not modify the clopidogrel-mediated inhibition of platelet aggregation and can be administered concomitantly.

The antiplatelet potency of clopidogrel may be attenuated by short-term co-administration of lipophilic statins metabolized through the cytochrome P-450, but atorvastatin does not affect the antiplatelet efficacy of clopidogrel.

Adverse effects

Details of adverse events observed in clinical trials of clopidogrel are listed in the Physicians’ Desk Reference. Bleeding is the most common side effect and can occur at varying degrees of severity and at any site. Risk factors for bleeding include age older than 75 years, recent bleeding event, low body weight, or use of medications such as nonsteroid antiinflammatory agents or warfarin that can increase the risk of bleeding (03). In worldwide postmarketing surveillance with clopidogrel, suspected cases of thrombotic thrombocytopenic purpura were reported at a rate of about 4 cases per million patients exposed. If bleeding should occur, a decision regarding the risks and benefits of continuing therapy should be made by the primary prescriber of clopidogrel. There is no available agent for reversal of clopidogrel effect. Although, exogenous platelet administration could restore hemostasis, it should be reserved for severe, life-threatening bleeding (11). In clinical trials, the most common clinically important side effects were pruritus, purpura, diarrhea, and rash; infrequent events included intracranial hemorrhage (0.4%) and severe neutropenia (0.05%). Patients receiving antiplatelet medications are at an increased risk for traumatic intracranial hemorrhage after blunt head trauma and should have a routine repeat head CT scan (13).