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Clopidogrel

A Review of its Use in the Prevention of Atherothrombosis

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Summary

Abstract

Clopidogrel is an ADP receptor antagonist that is indicated for the reduction of atherosclerotic events including myocardial infarction, ischaemic stroke and vascular death in patients with atherosclerosis manifested by recent stroke, myocardial infarction or established peripheral vascular disease.

In the 19185 patients enrolled in the multicentre, randomised double-blind CAPRIE study, the annual risk of the combined end-point of ischaemic stroke, myocardial infarction and death from vascular disease (vascular death) was significantly lower during treatment with clopidogrel 75 mg/day than aspirin 325 mg/day [5.3 vs 5.8%/year, respectively; relative risk reduction (RRR) 8.7%, p = 0.043] after a mean follow-up of 1.9 years. Clopidogrel provided even greater reductions in the risk of recurrent ischaemic events than aspirin in patients with a history of coronary artery bypass surgery, diabetes mellitus and in those receiving concomitant lipid-lowering therapy. Moreover there was a significant reduction in the incidence of hospitalisation in patients treated with clopidogrel.

In a patient population (Saskatchewan, Canada) with a greater risk of ischaemic events than the CAPRIE study population, the number of patients needed to be treated with clopidogrel to prevent 1 ischaemic event was estimated to be 70 (vs 200 in the CAPRIE study).

In randomised trials and registry surveys, clopidogrel 75 mg/day plus aspirin had similar efficacy (as measured by adverse cardiac outcomes) to ticlopidine 250mg twice daily plus aspirin during the 30 days after placement of intracoronary stents. Tolerability of clopidogrel was significantly better than ticlopidine in the randomised, double-blind CLASSICS study.

Among patients treated with clopidogrel or aspirin in the CAPRIE study, the overall gastrointestinal tolerability of clopidogrel was generally better than that of aspirin; the frequency of gastrointestinal haemorrhage was significantly lower among patients treated with clopidogrel than aspirin. Diarrhoea, rash and pruritis were significantly more common with clopidogrel than aspirin.

Conclusion: Clopidogrel was significantly more effective than aspirin in the prevention of vascular events (ischaemic stroke, myocardial infarction or vascular death) in patients with atherothrombotic disease manifested by recent myocardial infarction, recent ischaemic stroke or symptomatic peripheral arterial occlusive disease in the CAPRIE study. The overall tolerability profile of the drug was similar to that of aspirin, although gastrointestinal haemorrhage occurred significantly less often in clopidogrel recipients. The drug is widely used in combination with aspirin for the prevention of atherothrombosis after placement of intravascular stents, and available data suggest that this combination is as effective as ticlopidine plus aspirin for this indication.

Pharmacodynamic Properties

After activation by cytochrome P450 (CYP)-mediated hepatic metabolism, clopidogrel is a selective and irreversible inhibitor of ADP-induced platelet aggregation. The putative clopidogrel-sensitive purinoceptor (P2YAC) is thought to be linked to adenylyl cyclase through an inhibitory G-protein.

At a clinically relevant dosage (75 mg/day), clopidogrel prevented ADP-induced inhibition of adenylate cyclase and binding of fibrinogen without modifying the glycoprotein (GP) IIb/IIIa complex in platelets obtained from healthy volunteers. The drug also abolished cyclic AMP-dependent phosphorylation of vasodilator-stimulated phosphoprotein, an event associated with activation of the GP IIb/IIIa complex. Pretreatment with clopidogrel 75 mg/day enhanced the anti-aggregatory response to GP IIb/IIIa receptor antagonists. Four days of treatment with clopidogrel 75 mg/day also inhibited thrombin receptor agonist peptide (TRAP)-induced fibrinogen binding and expression of P-selectin in healthy volunteers. The combination of clopidogrel plus aspirin 75 mg/day further reduced TRAP-induced expression of P-selectin, but not fibrinogen binding, in these volunteers.

In patients who survived a myocardial infarction, clopidogrel inhibited expression of P-selectin, although the addition of aspirin did not enhance this effect.

Platelet aggregation induced by ADP was significantly attenuated by clopidogrel in a dose-dependent manner in healthy volunteers. Clinically relevant dosages of clopidogrel (≥75 mg/day for 4 days) produced selective and irreversible inhibition of ADP-induced platelet aggregation, but did not interfere with ADP-induced changes in platelet shape.

Clopidogrel 75 mg/day for ≥4 days had no effect on collagen-induced platelet aggregation in healthy volunteers or patients. Although aspirin does not alter ADP-induced platelet aggregation and does not augment that attributable to clopidogrel, clopidogrel 75 mg/day plus aspirin 100 or 300 mg/day for 7 days provided significantly greater inhibition of collagen-induced platelet aggregation than either agent alone. This suggests that combination therapy may be beneficial (see Therapeutic Use summary).

The use of loading doses of clopidogrel significantly reduces the time required to achieve maximal inhibition of platelet aggregation in healthy volunteers and hastens platelet inhibition after coronary stent implantation. A 300mg dose of clopidogrel provided significantly greater inhibition of ADP-induced platelet aggregation on the first day of treatment than either ticlopidine 500 mg/day or clopidogrel 75 mg/day.

Clopidogrel inhibits thrombus formation. At a dosage of 75 mg/day the drug prevented platelet degranulation and inhibited platelet-platelet binding independent of blood flow conditions in healthy volunteers. The proportion of loosely aggregated unactivated platelets increased significantly in concert with the inhibition of ADP-induced platelet aggregation.

The antithrombotic effect of clopidogrel 75 mg/day plus aspirin 325 mg/day was greater than that of aspirin alone in healthy volunteers; a 300mg loading dose on day 1 hastened the antithrombotic effect of clopidogrel.

Clopidogrel prolongs bleeding time. In patients with symptomatic atherosclerotic disease increases in bleeding time were similar with 28 days’ treatment with clopidogrel 50 to 100 mg/day and ticlopidine 250mg twice daily.

Pharmacokinetic Properties

Clopidogrel is rapidly converted to an inactive carboxylic acid metabolite (SR 26334) after absorption from the gastrointestinal tract. CYP-mediated hepatic metabolism is required to produce the active antiaggregating moiety. As the identity of the active metabolite was unknown until recently, the disposition of clopidogrel has been characterised by investigating the pharmacokinetics of SR 26334.

Plasma concentrations of unchanged clopidogrel were below the limit of quantification (0.00025 mg/L) beyond 2 hours after administration. Based on urinary excretion of clopidogrel-related metabolites, approximately 50% of a dose is absorbed from the gastrointestinal tract. Administration of clopidogrel with food or antacids does not significantly alter the bioavailability.

SR 26334 is detected in the plasma of healthy volunteers within an hour after oral administration of clopidogrel. Plasma concentrations of SR 26334 increase linearly in proportion to the dose after single dose administration of 50 to 150mg clopidogrel. SR 26334 comprises approximately 85% of circulating drug-related compounds in plasma after multiple dose administration.

Clopidogrel and SR 26334 are reversibly and avidly (98 and 94%, respectively) bound in a nonsaturable manner to human plasma proteins in vitro. Clopidogrel and its metabolites do not distribute into red blood cells to a substantial extent.

The elimination half-life of SR 26334 is about 7 to 8 hours after both single and multiple dose administration. Approximately 50 and 46% of [14C]-labelled clopidogrel is eliminated in the urine and faeces, respectively, within 5 days of oral administration. Approximately 2% of the radiolabel is covalently bound to platelets.

Plasma concentrations of SR 26334 were greater in elderly than in young persons and exposure to SR 26334 was lower in patients with severe versus moderate renal dysfunction. Bleeding times are unaffected by age or renal dysfunction so these changes do not appear to be of clinical relevance. Mild to moderate hepatic impairment slows the metabolic transformation of clopidogrel but does not alter the disposition of SR 26334.

Clopidogrel has a low propensity for drug-drug interactions according to studies in humans. Antacids do not significantly alter absorption of clopidogrel. Steady-state pharmacokinetic profiles of digoxin, theophylline and antipyrine were unaffected by coadministration of clopidogrel 75 mg/day. The anticoagulant properties of heparin were unaffected by concurrent administration of clinically relevant dosages of clopidogrel, and aspirin, theophylline and antipyrine did not modify the antiaggregating effects of clopidogrel. There is no evidence of pharmacodynamic interactions between clopidogrel and commonly prescribed cardiovascular medications in patients with symptomatic atherothrombotic disease. oncomitant administration of clopidogrel and naproxen resulted in an increase of occult gastrointestinal blood loss in healthy volunteers.

Therapeutic Use

In Patients at High Risk of Ischaemic Events: the CAPRIE Trial In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study the risk of ischaemic stroke, myocardial infarction and death from vascular disease (vascular death) during treatment with clopidogrel 75 mg/day or aspirin 325 mg/day was examined in 19 185 patients with recent ischaemic stroke, recent myocardial infarction or peripheral arterial disease. Clopidogrel recipients had an annual risk of primary ischaemic events of 5.3% compared with 5.8% in patients who received aspirin. This significant relative risk reduction (RRR) of 8.7% (p = 0.043) in favour of clopidogrel translates into 26% more major clinical events prevented per year per 1000 patients compared with aspirin in a population similar to that in CAPRIE (24 vs 19 events per 1000 atients per year).

A beneficial trend, which was consistent with the primary outcome analysis, was apparent in clopidogrel recipients for 4 prespecified secondary outcome clusters that included predominantly vascular events.

When the results of the CAPRIE study were prospectively analysed by qualifying cardiovascular condition the benefits appeared to differ significantly across the 3 main subgroups. However, retrospective analyses suggest that the apparent heterogeneity across the 3 qualifying conditions was due to chance. Thus, in patients with a history of any previous myocardial infarction, cardiovascular disease or history of cerebrovascular disease, the RRR ranged from 7.4 to 8.3% and corresponds closely with the overall RRR obtained with clopidogrel (8.7%). The benefit of clopidogrel treatment was consistent regardless of the extent of atherosclerotic burden. In patients with a history of atherosclerotic events in 2 or more vascular beds, the RRR was 15.4% in favour of clopidogrel.

Compared with aspirin, RRR of approximately 7 to 11% were obtained with clopidogrel for a variety of combined vascular events. A significant reduction in the relative risk of the combined end-point of stroke (including haemorrhagic) or vascular/haemorrhagic death reflects the trend toward fewer intracranial haemorrhages or haemorrhagic deaths in clopidogrel recipients.

Clopidogrel consistently reduced the risk of a composite end-point (vascular death, myocardial infarction, stroke or hospitalisation for ischaemia or bleeding) to a significantly greater extent than aspirin in patients with a history of coronary artery bypass surgery or diabetes mellitus and in those receiving concomitant lipid-lowering therapy according to retrospective analyses. Moreover there was a significant reduction in the incidence of hospitalisation in patients treated with clopidogrel.

In a data linkage study, adverse outcome rates (hospitalisation for myocardial infarction or stroke including intracranial haemorrhage, or death) were estimated for 12 931 residents of Saskatchewan, Canada who were prescribed aspirin after an ischaemic event. The RRR observed in CAPRIE (8.7%) was multiplied by the reference risk (per year) estimated from patients treated with aspirin in the Saskatchewan population (15.9 ischaemic events per 100 patient-years), which was higher than the rate in CAPRIE (6.9 per 100 patient-years). The greater reference risk of adverse outcomes in the Saskatchewan cohort translates into a reduction in the number of patients that need to be treated with clopidogrel to prevent 1 ischaemic event from 200 to 70.

Prevention of Thrombosis after Percutaneous Placement of Inlra vascular StentsClopidogrel 75 mg/day plus aspirin had similar efficacy (as measured by adverse cardiac outcomes) to ticlopidine 250mg twice daily plus aspirin after 30 days of follow-up in 3 randomised trials and in a number of registry surveys of patients after coronary stent implantation. Cardiovascular outcomes 6 months after stent implantation were not statistically different in patients treated with clopidogrel or ticlopidine in 1 survey of 1378 patients.

In patients fitted with carotid artery stents, preliminary evidence indicates that clopidogrel plus aspirin is associated with a very low risk of procedural stroke or stent thrombosis and does not increase the risk of intracranial haemorrhage.

Tolerability

Among patients treated with clopidogrel or aspirin in the CAPRIE study, the overall frequency of adverse events and the percentage of patients withdrawing because of an adverse event were similar between treatment groups. Clopidogrel recipients reported significantly lower overall rates of gastrointestinal and central nervous system adverse events, and significantly higher rates of skin-related events, than aspirin-treated patients.

Although the overall frequency of bleeding disorders was similar between the 2 groups, the gastrointestinal tolerability of clopidogrel, including haemorrhage was generally better than that of aspirin. Abdominal pain, dyspepsia, constipation, gastritis and ulcer were reported by significantly fewer clopidogrel-than aspirin-treated patients, but diarrhoea occurred in significantly more clopidogrel recipients. The frequency of gastrointestinal haemorrhage was significantly lower, and the proportion of patients requiring hospitalisation for gastrointestinal haemorrhage tended to be lower, among patients treated with clopidogrel than aspirin. There was no significant difference in the frequency of low platelet or neutrophil counts among those treated with clopidogrel or aspirin.

Clopidogrel was better tolerated than ticlopidine in patients after intracoronary stent placement in the CLASSICS study. Discontinuations because of noncardiac adverse events, gastrointestinal disturbance, rash and allergic adverse events were all less frequent in clopidogrel than ticlopidine recipients in the CLASSICS study. Discontinuation rates because of medication intolerance were also significantly lower in stent recipients during 4 weeks of treatment with aspirin 100mg plus clopidogrel 75mg once daily than aspirin 100 mg/day plus ticlopidine 250mg twice daily in another randomised study.

Dosage and Administration

Clopidogrel is indicated for the reduction of atherosclerotic events including myocardial infarction, stroke and vascular death in patients with atherosclerosis manifested by recent ischaemic stroke, recent myocardial infarction or established peripheral vascular disease. The recommended dosage of clopidogrel is 75mg once daily and the drug may be given with or without meals. The dosage does not need to be modified in elderly patients or in those with renal or mild hepatic impairment. Use of clopidogrel is contraindicated in patients with active bleeding (e.g. peptic ulcer or intracranial haemorrhage) and the drug should be used with caution in patients at increased risk of bleeding complications (e.g. trauma, surgery) and in those with severe hepatic dysfunction.

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Jarvis, B., Simpson, K. Clopidogrel. Drugs 60, 347–377 (2000). https://doi.org/10.2165/00003495-200060020-00012

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