Dosage

Following hospital discharge, clopidogrel should be administered at a dose of 75 mg OD. Following ACS a loading dose of 300–600 mg of clopidogrel should be administered. There is evidence that double dose clopidogrel (150 mg OD) may be beneficial for the first 7 days in ACS patients undergoing PCI. Absorption is not effected by food and no dosing adjustment is required in patients with chronic renal disease.

Mechanism of Action

Clopidogrel, a thienopyridine, exerts its antithrombotic effect by the binding of its active metabolite, in a competitive and irreversible manor, to the adenosine diphosphate (ADP) P2Y12 receptor. Natural binding of the receptor by ADP results in inhibition of cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (VASP-P), which is known to be closely related to the inhibition of glyprotein IIb/IIIa receptor activation.

The formation of the active metabolite of clopidogrel requires a 2 step process mediated largely through the action of CYP2C19. Due to the existence of at least 2 known loss of function alleles of CYP2C19, designated *2 and *3, it is estimated that approximately 24% of the population may have reduced ability to metabolize clopidogrel to its active form. Further, CYP2C19 activity is known to be inhibited by the proton pump inhibitors omeprazole and esomeprazole as well as other less well defined drug interactions. It is well established that reduced CYP2C19 activity is associated with reduced clopidogrel induced platelet inhibition, however, the effect on vascular ischemic events remains controversial.

Recommendations in Vascular Prevention

Secondary CAD Prevention

Data from randomized clinical trials demonstrate that compared with acetylsalicylic acid (ASA) alone, combination therapy with oral P2Y12 receptor antagonists, including clopidogrel, improves clinical outcomes in patients with acute coronary syndrome (ACS) although combination therapy does increase the risk of bleeding. This benefit was demonstrated in patients with STEMI or NSTEACS managed medically or with PCI, as well as those undergoing elective PCI. Although the studies with clopidogrel in patients with STEMI were of short duration the common underlying pathophysiology of all types of ACS is the basis for continuing therapy in patients with STEMI after hospital discharge.

Recommendations

For patients allergic to or intolerant of ASA, indefinite therapy with clopidogrel 75 mg daily is recommended (Class IIa, Level B).

For patients presenting with STEMI who are medically managed, clopidogrel 75 mg daily is recommended in addition to ASA 75 to -162 mg daily for at least 14 days (Class I, Level B) and up to 12 months in the absence of an excessive risk of bleeding (Class IIb, Level C).

For patients presenting with STEMI who are managed by PCI, clopidogrel 75 mg daily is recommended in addition to ASA 75 to 162 mg daily for 12 months (Class I, Level B). Continuation of combined therapy beyond 12 months may be considered in patients with a high risk of thrombosis and a low risk of bleeding (Class IIb, Level C).

For patients presenting with NSTEACS who are medically managed, clopidogrel 75 mg daily is recommended in addition to ASA 75 to 162 mg daily for at least 1 month (Class I, Level A) and up to 12 months in the absence of an excessive risk of bleeding (Class I, Level B).

For patients presenting with NSTEACS who are managed by PCI, clopidogrel 75 mg daily is recommended in addition to ASA 75 to 162 mg daily for 12 months (Class I, Level A). Continuation of combined therapy beyond 12 months may be considered in patients with a high risk of thrombosis and a low risk of bleeding (Class IIb, Level C).

For patients presenting with NSTEACS who are managed by coronary artery bypass grafting (CABG), clopidogrel 75 mg daily is recommended in addition to ASA 75 to 162 mg daily for a minimum of 1month and up to 12 months (Class I, Level B).

All patients who have undergone PCI with bare-metal stent (BMS) implantation should be given clopidogrel 75 mg daily in addition to ASA 75 to 162 mg daily for at least 1 month (Class I, Level B) and up to 12 months in the absence of an excessive risk of bleeding (Class I, Level B) after stent implantation.

For patients with recent bleeding or at increased risk for bleeding, a BMS should be implanted, and clopidogrel 75 mg daily should be added to ASA 75 to 162 mg daily for a minimum of 2 weeks (Class I, Level B).

All patients who have undergone PCI with DES implantation should be given clopidogrel 75 mg daily in addition to ASA 75 to 162 mg daily for 12 months (Class I, Level A).

Continuation of dual antiplatelet therapy with ASA 75 to 162 mg daily and clopidogrel 75 mg daily beyond 1 year may be considered in patients with an increased risk of stent thrombosis as long as the perceived risk of bleeding is deemed acceptable (Class IIb, Level C).

Secondary Prevention of Cerebrovascular Disease

For secondary prevention in patients with TIA or ischemic stroke, antiplatelet therapy regimens with proven efficacy include clopidogrel monotherapy. However, combined ASA-clopidogrel therapy should not be used for long-term secondary prevention following stroke or TIA because it does not significantly improve ischemic event prevention but significantly increases the risk of bleeding. Some evidence suggests that combination therapy may provide benefit in the period immediately following stroke or TIA.

Recommendations

Patients who sustain a TIA or ischemic stroke of noncardiac origin should be treated with an antiplatelet agent (Class I, Level A). Initial therapy should be ASA 75-162 mg once daily, clopidogrel 75 mg once daily, or ER dipyridamole 200 mg twice daily plus ASA 25 mg twice daily (Class I, Level A). The choice of antiplatelet therapy regimen is determined by consideration of cost, tolerance, and other associated vascular conditions.

The combination of ASA 75 to 162 mg daily plus clopidogrel 75 mg daily in the first month after TIA or minor ischemic stroke may be superior to ASA alone in patients not at a high risk of bleeding (Class IIb, Level C).

The combination of ASA 75 to 162 mg daily plus clopidogrel 75 mg daily should not be used for secondary stroke prevention beyond 1month unless otherwise indicated and the risk of bleeding is low. (Class III, Level B).

Vascular Prevention in Patients With PAD

Data suggest a benefit for ASA monotherapy and clopidogrel monotherapy in patients with symptomatic PAD (ie, patients with claudication, rest pain, or ischemic lesions). The combination of ASA and clopidogrel does not appear to provide significant clinical benefit.

Recommendations

For patients with symptomatic PAD without overt CAD or cerebrovascular disease, low-dose ASA (75-162 mg daily) or clopidogrel 75 mg daily is recommended, providing the risk for bleeding is low (Class IIb, Level B). The choice of drug may depend on patient preference and cost considerations.

For patients with intermittent claudication, using clopidogrel 75 mg daily in addition to ASA 75 to 162 mg daily is not recommended unless the patient is judged to be at high vascular risk along with a low risk of bleeding (Class IIb, Level B).

Warnings & Special Considerations

Because clopidogrel requires conversion to its active metabolite by CYP2C19 concomitant administration of drugs inhibiting this enzyme, including omeprazole and esomeprazole, should be avoided.

Statistically higher rates of skin rash have been noted in studies of clopidogrel vs comparators. For example in the CAPRIE study the incidence of skin and appendage disorders in patients receiving clopidogrel was 15.8% (0.7% serious); the corresponding rate in ASA patients was 13.1% (0.5% serious).