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MACLEODS PHARMA
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33342006015

clopidogrel 75 mg tablet (generic plavix)

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Uses

Reduction of Cardiovascular and Cerebrovascular Events

Clopidogrel bisulfate is used to reduce the risk of cardiovascular or cerebrovascular events (myocardial infarction [MI], stroke, and vascular death) in patients with atherosclerosis documented by recent ischemic stroke, recent MI, or established peripheral arterial disease (secondary prevention). Results of a large, randomized study (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [CAPRIE] study) suggest that clopidogrel is more effective than aspirin in reducing the risk of such cardiovascular or cerebrovascular events and has a similar overall safety profile. However, because of cost considerations, many clinicians state that aspirin should remain the drug of choice for most patients requiring long-term antiplatelet therapy for coronary artery disease, and recommend clopidogrel as an alternative in those who are unable to take aspirin because of intolerance or contraindications (e.g., allergy).

The American College of Chest Physicians (ACCP) recommends long-term antiplatelet therapy with either aspirin (75-100 mg daily) or clopidogrel (75 mg daily) in patients with established coronary artery disease (i.e., patients more than 1 year after an acute coronary syndrome, with prior revascularization, coronary stenosis greater than 50% by coronary angiogram, and/or evidence of cardiac ischemia on diagnostic testing). Long-term antiplatelet therapy also is recommended for the secondary prevention of stroke in patients with a history of noncardioembolic stroke or transient ischemic attacks (TIAs). In such patients, ACCP states that clopidogrel, aspirin, aspirin in combination with extended-release dipyridamole, or cilostazol are all acceptable options for long-term antithrombotic therapy. Based on a somewhat greater risk reduction for stroke, ACCP states that clopidogrel or the combination of aspirin with dipyridamole may be preferred over the other options for secondary prevention of noncardioembolic stroke; however, ACCP judges the evidence supporting this recommendation to be moderate in quality. Oral anticoagulation (e.g., warfarin, dabigatran) rather than antiplatelet therapy is recommended for the secondary prevention of cardioembolic stroke in patients with a history of ischemic stroke or TIA and concurrent atrial fibrillation; however, in patients who cannot or choose not to take oral anticoagulants (e.g., those with difficulty maintaining stable international normalized ratios [INRs], compliance issues, dietary restrictions, cost limitations), dual antiplatelet therapy with clopidogrel and aspirin is recommended.

ACCP and other experts also recommend antiplatelet therapy for the prevention of cardiovascular events and mortality in patients with peripheral arterial disease. Aspirin generally is suggested as the antiplatelet drug of choice for primary prophylaxis in patients with asymptomatic peripheral arterial disease. For the secondary prevention of cardiovascular events in patients with symptomatic peripheral arterial disease, including those with intermittent claudication, critical limb ischemia, or prior lower extremity procedures (e.g., peripheral artery percutaneous transluminal angioplasty, peripheral artery bypass graft surgery, amputation), long-term treatment with clopidogrel 75 mg daily or aspirin 75-100 mg daily is recommended; the addition of cilostazol may be considered in patients with refractory intermittent claudication. Dual antiplatelet therapy with clopidogrel and aspirin generally is not suggested in any of these patients with the exception of those receiving below-the-knee prosthetic bypass grafts. Clopidogrel also is recommended as an option for long-term antiplatelet therapy in patients with symptomatic carotid stenosis, including in patients who are intolerant of aspirin and those who have undergone recent carotid endarterectomy.

Efficacy of clopidogrel for reduction of the risk of atherosclerotic events has been established in a multicenter, randomized, controlled study (the CAPRIE trial) in patients with atherosclerotic disease (recent [within 6 months] ischemic stroke, recent [within 35 days] MI, or symptomatic peripheral arterial disease) who received clopidogrel 75 mg once daily or aspirin 325 mg daily for an average of 1.6 years (maximum 3 years). The primary analysis of efficacy was based on the first occurrence of a new cardiovascular event (i.e., fatal or nonfatal ischemic stroke or MI, other vascular death) in all patients receiving clopidogrel or aspirin. The annual cardiovascular event rate in patients receiving clopidogrel was 5.32% compared with 5.83% in those receiving aspirin, representing an 8.7% decrease in the annual risk of a new cardiovascular event for clopidogrel-treated patients. The difference in overall risk of cardiovascular events was apparent early in the study and was maintained throughout the 3-year follow-up period. While the study was not designed to evaluate relative benefit of clopidogrel versus aspirin among patients in specific disease subgroups, most of the risk reduction associated with clopidogrel therapy occurred in patients with peripheral arterial disease, who experienced a statistically significant 23.8% decrease in risk compared with those in the same subgroup who received aspirin. Patients in the stroke subgroup who received clopidogrel experienced a relative risk reduction of 7.3%, while those in the MI subgroup experienced a relative risk reduction of -3.7% (increased relative risk compared with aspirin); neither of these relative-risk reductions was statistically significant.

Therapy with clopidogrel plus aspirin for prevention of ischemic events in a broad population of patients with established cardiovascular disease or multiple risk factors for atherosclerosis was evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial. In this large, randomized, double-blind, parallel-group study, therapy with clopidogrel (75 mg daily) and low-dose aspirin (75-162 mg daily) for approximately 2 years was not significantly more effective than low-dose aspirin alone in reducing the rate of the composite primary end point of MI, stroke, or death from cardiovascular causes. In addition, the combination of clopidogrel and aspirin was associated with an increased rate of moderate to severe bleeding.

Acute Coronary Syndrome

Clopidogrel is used in combination with aspirin for the reduction of cardiovascular and cerebrovascular events in patients with a non-ST-segment elevation acute coronary syndrome (ACS), including unstable angina and non-ST-segment-elevation MI (NSTEMI). The drug is used in patients who are to be managed medically and in those who are to be managed with coronary intervention (PCI with or without coronary artery stenting or CABG). In patients in whom elective CABG is planned, it is recommended that clopidogrel be withheld for at least 5 days (the duration of effect of clopidogrel) since the drug, when added to aspirin treatment, increases the risk of bleeding during major surgery.

Clopidogrel also is used in combination with aspirin to reduce the rate of ischemic cardiovascular events (e.g., death, reinfarction, stroke) in patients with ST-segment-elevation MI (STEMI).

Dual-drug antiplatelet therapy with a P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin is part of the current standard of care in patients with ACS. The American Heart Association (AHA), the American College of Cardiology Foundation (ACCF), the Society for Cardiovascular Angiography and Interventions (SCAI), and ACCP recommend antiplatelet therapy with a P2Y12-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in conjunction with aspirin for treatment and secondary prevention in patients with ACS. These experts generally recommend ticagrelor or clopidogrel as the P2Y12-receptor antagonist in patients with ACS who are treated medically without stent placement; because prasugrel has been studied principally in patients undergoing planned percutaneous coronary intervention (PCI), recommendations for the use of this drug are restricted to that population. In patients being managed medically, therapy with a P2Y12-receptor antagonist should be continued for up to 12 months, while aspirin should be continued indefinitely. In patients undergoing PCI with stent placement (bare-metal or drug-eluting), a loading dose of ticagrelor, clopidogrel, or prasugrel is recommended, followed by maintenance therapy with one of these agents for at least 12 months (unless the risk of bleeding outweighs the anticipated net benefit of therapy); aspirin should be continued indefinitely in such patients. While current ACCF/AHA guidelines make no recommendations regarding the P2Y12-receptor antagonist of choice in patients with ACS, ACCP suggests the use of ticagrelor over clopidogrel, regardless of whether PCI is performed. When selecting an appropriate antiplatelet regimen for patients with ACS, clinicians should consider individual risks of ischemia and bleeding as well as the specific characteristics (e.g., adverse effects, drug interaction potential) of the drugs.

The efficacy of pretreatment with clopidogrel prior to diagnostic cardiac catheterization is controversial; while some studies have suggested a benefit in terms of decreased platelet aggregation and lower rates of periprocedural MI with clopidogrel pretreatment, other studies have found no such benefit. The potential benefit of pretreatment with clopidogrel should be balanced against the increased risk of bleeding should emergency coronary artery bypass grafting (CABG) be needed. If clopidogrel is given at hospital admission or diagnosis of ACS and the patient is subsequently scheduled for CABG, the drug should be temporarily discontinued for at least 5 days prior to CABG.

In patients with ACS who have indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical heart valves), the addition of warfarin (INR 2-3) to antiplatelet therapy is recommended; in some cases, triple antithrombotic therapy (warfarin, low-dose aspirin, and clopidogrel) is suggested. However, such triple-drug antithrombotic regimens are associated with an increased risk of bleeding, and patients should be monitored closely. Triple antithrombotic therapy with clopidogrel, aspirin, and warfarin is suggested by ACCP in patients with anterior MI and left ventricular thrombus (or at high risk for such thrombi) undergoing stent implantation; the recommended duration of such triple therapy is dependent on whether the patient has a bare-metal or drug-eluting stent.

Unstable Angina/NSTEMI

Efficacy of clopidogrel for the long-term reduction of cardiovascular events in patients with unstable angina/NSTEMI has been established in a randomized, controlled study (the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events [CURE] trial) in patients who received clopidogrel (75 mg once daily) or placebo in addition to aspirin (75-325 mg daily) and other standard therapy (e.g., heparin) for 3-12 months. Some evidence suggests that aspirin and clopidogrel may have synergistic antithrombotic effects related to their different mechanisms of action. In the CURE study, the combined incidence of cardiovascular death, nonfatal MI, or stroke, and the combined incidence of these 3 types of events plus refractory ischemia in the clopidogrel group were reduced compared with these outcomes in the placebo group. Clopidogrel therapy also was associated with reductions in the incidences of refractory or severe ischemia, heart failure, and (during the initial period of hospitalization) revascularization procedures. In this study, aspirin and clopidogrel or placebo were administered to patients within 24 hours of symptom onset and for 3-12 months (mean: 9 months) thereafter. Although no substantial increase in life-threatening bleeding episodes occurred with clopidogrel and aspirin therapy, major bleeding (principally GI hemorrhage and bleeding at recent arterial puncture sites) was more common in patients receiving clopidogrel and aspirin (3.7%) than in patients receiving aspirin and placebo (2.7%). While clopidogrel has been administered concomitantly with aspirin for up to 1 year in clinical studies, the manufacturer states that nonsteroidal anti-inflammatory agents (NSAIAs) should be used with caution in patients receiving clopidogrel.(See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

ST-Segment-Elevation Myocardial Infarction

Results of randomized, controlled studies indicate that clopidogrel produces reductions in mortality and vascular events beyond those of low-dose aspirin and other standard therapy (e.g., thrombolytic agents, heparin) in patients with acute STEMI, including those undergoing subsequent PCI. In patients with suspected STEMI, experts recommend clopidogrel in addition to aspirin with or without reperfusion therapy (i.e., thrombolytic therapy, primary PCI) for 14-28 days. In patients taking clopidogrel in whom CABG is planned, ACCP suggests that the drug be withheld for at least 5 days prior to surgery.(See Managing Antiplatelet Therapy in Patients Requiring Invasive Procedures under Dosage and Administration: Dosage.)

In a randomized, controlled study in approximately 3500 patients with STEMI who were scheduled to receive therapy with a thrombolytic agent, unfractionated heparin or a low molecular weight heparin when appropriate, and aspirin (Clopidogrel as Adjunctive Reperfusion Therapy [CLARITY] study), addition of clopidogrel (300-mg loading dose followed by 75 mg once daily) was associated with a 36% reduction in the risk of the primary composite end point (occluded infarct-related artery at angiography 2-8 days later or death or recurrent MI prior to angiography); at 30 days, clopidogrel therapy had reduced the composite end point of cardiovascular death, recurrent MI, or recurrent ischemia requiring urgent revascularization by 20%. Rates of major bleeding, including intracranial hemorrhage, were similar with or without adjunctive clopidogrel therapy. In a prospective analysis of a subset of patients from the CLARITY study who underwent PCI after angiography (PCI-Clopidogrel as Adjunctive Reperfusion Therapy [CLARITY] study), pretreatment before PCI with clopidogrel (300-mg loading dose followed by 75 mg once daily) in addition to initial standard therapy (e.g., thrombolytic agents, aspirin) during hospitalization for acute STEMI was associated with a reduction of 38% in recurrent MI and stroke compared with standard therapy; considering cardiovascular events before and after PCI through 30 days after randomization in patients undergoing coronary artery stenting, adjunctive clopidogrel therapy reduced cardiovascular death, MI, and stroke by 41%.

In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) in approximately 45,000 patients with acute STEMI, treatment with clopidogrel (75 mg once daily without a loading dose) in addition to aspirin (162 mg daily) beginning at hospital admission and continuing during hospitalization for up to 4 weeks (mean treatment duration: 14.9 days) was associated with a 9% reduction in death, reinfarction, or stroke (the primary composite end point) compared with aspirin therapy. In addition, death from any cause was reduced by 7%, and fatal or nonfatal reinfarction by 14%, in patients receiving adjunctive clopidogrel. Clopidogrel treatment was associated with a small increase in minor bleeding but no excess in major (i.e., transfused, cerebral, or fatal) bleeding complications.

In patients with STEMI who have undergone diagnostic cardiac catheterization and in whom PCI is planned, experts recommend a loading dose of a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) before or at the time of PCI in conjunction with aspirin therapy. Therapy with a P2Y12-receptor antagonist should be continued for at least 12 months after stent (bare-metal or drug-eluting) placement, unless the risk of bleeding outweighs the anticipated net benefit of therapy; aspirin should be continued indefinitely in such patients.

The American Diabetes Association (ADA) suggests that clopidogrel may be used for prevention of a first MI (primary prevention) as an alternative to aspirin in aspirin-allergic patients with type 1 or type 2 diabetes mellitus who are at high risk for cardiovascular events (i.e., family history of CHD, smoking, hypertension, obesity, albuminuria, elevated blood cholesterol or triglyceride concentrations).

Prevention of Stent Thrombosis

Clopidogrel has been used in combination with aspirin (dual-drug therapy) to prevent stent thrombosis following implantation of coronary artery stents.

Compared with bare-metal stents, implantation of drug-eluting stents has been associated with a reduction in the frequency of restenosis and repeat revascularization without evidence of excess MI or death in randomized controlled trials evaluated for US Food and Drug Administration (FDA) approval of these stents (in clinically stable patients without other serious medical conditions who had newly diagnosed coronary lesions less than 28-30 mm in length). Previous recommendations based on clinical trials in such patients advised dual-drug therapy with aspirin and a thienopyridine derivative (i.e., clopidogrel, ticlopidine) for at least 3 or 6 months following implantation of a sirolimus- or paclitaxel-eluting stent, respectively. However, with expanded use of drug-eluting stents to include patients with high-risk coronary lesions and coexisting medical conditions (e.g., diabetes, renal dysfunction), an increase in the incidence of late (e.g., 1-12 months or more post-implantation) stent thrombosis has been noted in patients with drug-eluting stents compared with bare-metal stents, often coincident with discontinuance of clopidogrel after initially recommended durations of dual-drug antiplatelet therapy.

Conflicting data have been reported regarding the risks of cardiovascular events in patients receiving drug-eluting stents, which may be related to variable definitions of stent thrombosis and differences in patient characteristics and coronary lesions in the populations studied. Some observational studies have indicated an increased risk of late cardiovascular events (e.g., death or death and MI) in patients with drug-eluting stents following discontinuance of dual-drug antiplatelet therapy with aspirin and clopidogrel, or just the clopidogrel component of such therapy. In a study in patients who had stopped taking clopidogrel (75 mg once daily) after 6 months but continued low-dose aspirin therapy (100 mg daily) and were without major adverse events 6 months after stent placement, the incidence of late cardiac events (defined as cardiac death or documented nonfatal MI in months 7-18 of follow-up) was higher in patients with drug-eluting stents versus bare-metal stents (4.9 versus 1.3% of patients, respectively). Thrombosis-related events, including late stent thrombosis and death related to stent thrombosis or target-vessel MI, were twice as frequent in patients with drug-eluting stents versus bare-metal stents (2.6 versus 1.3%, respectively). Overall rates of cardiac death and nonfatal MI during the entire 18-month follow-up period (6 months of clopidogrel therapy and 1 year of subsequent aspirin therapy) were not different in patients with either type of stent. Target vessel revascularizations related to restenosis were less frequent in patients with drug-eluting stents. In another observational study, patients with drug-eluting stents who were event-free (no death, MI, or revascularization) and who reported continued clopidogrel use at 6 or 12 months after stent implantation had lower rates of death, nonfatal MI, or the combined end point of death or MI at 24 months' follow-up than patients with drug-eluting stents who did not report continued use of clopidogrel. In contrast, rates of these cardiac events at 24 months in patients with bare-metal stents were similar regardless of reported clopidogrel use. A subgroup analysis by reported aspirin use did not alter the effect of clopidogrel on cumulative rates of death or combined death or MI in patients with drug-eluting stents except that event rates were lower.

A pooled analysis of data from a large patient records database in Sweden covering 3 years of follow-up revealed an increased rate of death beginning 6 months after stent implantation in patients with drug-eluting stents compared with bare-metal stents. An increase of 18% in the relative long-term risk of death was found in patients with drug-eluting stents at 3 years, corresponding to an absolute increase in the risk of death of 0.5% per year after the initial 6 months. However, results of 2 pooled analyses of data from randomized controlled trials that served as the basis for approval of drug-eluting stents in the US indicate a similar incidence of death or MI over long-term follow-up (4 years) in patients with sirolimus- or paclitaxel-eluting stents compared with bare-metal stents. Another pooled analysis of data from 14 randomized trials that included patients with high-risk features (e.g., diabetes, prior MI, long or complex coronary lesions) who received sirolimus-eluting or bare-metal stents also found similar outcomes with respect to the risk of death or the combined risk of death or MI. While the overall incidence of stent thrombosis was not increased with sirolimus-eluting versus bare-metal stents over the entire period of follow-up (approximately 1-5 years) in this analysis, the risk of stent thrombosis was greater with the drug-eluting stents after the first year following stent implantation (0.6 or 0.05% with the sirolimus-eluting or bare-metal stent, respectively), which coincided with the protocol-specified discontinuance of dual-drug antiplatelet therapy in these trials.

Because of evidence suggesting an increased incidence of late stent thrombosis and cardiovascular events (e.g., cardiac death, nonfatal MI) in patients with drug-eluting stents following discontinuance of dual-drug antiplatelet therapy with aspirin and clopidogrel, or just the clopidogrel component of such therapy(see Unstable Angina/NSTEMI under Uses: Acute Coronary Syndrome), a broad range of experts recommend that patients who have undergone placement of a drug-eluting stent and who are not at high risk for bleeding receive clopidogrel for at least 12 months in conjunction with low-dose aspirin therapy. Current expert guidelines recommend a treatment duration of at least 12 months for patients with any type of coronary artery stent (bare-metal or drug-eluting). While a minimum duration of therapy of 1 month may be acceptable in patients receiving a bare-metal stent for a non-ACS indication, clopidogrel should ideally be given up to 12 months for these patients as well unless the patient is at increased risk of bleeding; in such a case, clopidogrel should be administered for a minimum of 2 weeks. There is some evidence suggesting that an even longer duration of dual antiplatelet therapy (for more than 12 months) may be beneficial in some patients with drug-eluting stents to reduce the risk of late stent thrombosis and other cardiovascular events, but such prolonged therapy may be associated with an increased risk of bleeding.

In a randomized, placebo-controlled, double-blind study (Dual Antiplatelet Therapy [DAPT] study), patients who received 30 months of dual antiplatelet therapy (aspirin plus clopidogrel or prasugrel) following placement of a drug-eluting stent had substantially reduced rates of stent thrombosis and major adverse cardiovascular and cerebrovascular events compared with those who received 12 months of dual antiplatelet therapy. Preliminary data from the study indicated that a longer duration of therapy was associated with a higher incidence of moderate to severe bleeding and also an unexpected finding of an increased rate of noncardiovascular mortality (principally related to trauma or cancer); however, these adverse mortality findings were not observed during FDA's final review of the DAPT study and other randomized, controlled clinical studies. FDA review of the DAPT study and additional long-term studies of clopidogrel, including meta-analyses conducted by FDA, concluded that there is no evidence of either a harmful or beneficial effect of clopidogrel on all-cause mortality or cancer-related deaths in a population with, or at risk for, coronary artery disease. The results of the FDA-conducted meta-analyses indicated that long-term (12 months or longer) dual antiplatelet therapy with clopidogrel and aspirin does not appear to change the overall risk of death when compared to short-term (6 months or less) clopidogrel and aspirin therapy, or aspirin alone. Additionally, there was no apparent increase in the risks of cancer-related deaths or cancer-related adverse effects with such long-term treatment.

Because of the potentially life-threatening consequences of premature discontinuance of dual-drug antiplatelet therapy in patients with drug-eluting stents, AHA/ACC/SCAI, the American College of Surgeons, and the American Dental Association currently state that implantation of a drug-eluting stent should be performed only in patients who can tolerate and are highly likely to comply with such prolonged combination therapy. For management of patients with coronary stents who require additional invasive procedures, see Managing Antiplatelet Therapy in Patients Requiring Invasive Procedures, under Dosage and Administration: Dosage.

Chronic Stable Angina

Clopidogrel may be used as an alternative to aspirin in patients with symptomatic chronic stable angina who cannot tolerate aspirin.

Embolism Associated with Atrial Fibrillation and/or Valvular Heart Disease

Clopidogrel has been used in combination with aspirin as an alternative to warfarin anticoagulation for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Dual antiplatelet therapy with clopidogrel and aspirin was evaluated as a potential alternative to warfarin in a randomized controlled study in patients with atrial fibrillation at high risk of stroke. The study was terminated early because of clear evidence of superiority of warfarin over antiplatelet therapy for the primary outcome of stroke, systemic embolism, MI, or vascular death. Results of another study comparing dual antiplatelet therapy (clopidogrel and aspirin) with aspirin monotherapy in patients with atrial fibrillation who had an increased risk of stroke but were unable to take warfarin showed that the combination of clopidogrel and aspirin was more effective than aspirin in reducing the risk of stroke; however, dual antiplatelet therapy was also associated with an increased risk of bleeding. Based on these findings, ACCP and other experts recommend the use of clopidogrel and aspirin rather than aspirin alone as an alternative to oral anticoagulation in patients with atrial fibrillation at increased risk of stroke who cannot or choose not to take oral anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations). Because the risk of bleeding with combination aspirin and clopidogrel therapy is similar to the risk of bleeding with warfarin, such combination therapy is not recommended in patients with a hemorrhagic contraindication to warfarin.

In patients with atrial fibrillation and mitral stenosis who cannot or choose not to take warfarin therapy (for reasons other than concerns about major bleeding), ACCP recommends combination therapy with aspirin and clopidogrel rather than aspirin alone.

While the risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation, the risk has been estimated to be less than that for atrial fibrillation but greater than that for sinus rhythm. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.

Dosage and Administration

Administration

Clopidogrel bisulfate is administered orally. Food does not affect systemic exposure to the active metabolite of clopidogrel, and the drug may be administered without regard to meals. Dosage of clopidogrel bisulfate is expressed in terms of clopidogrel.

Dosage

Pharmacogenomic factors can influence response to clopidogrel; the manufacturer states that an appropriate dosage of clopidogrel has not been determined in patients who are poor metabolizers based on their cytochrome P-450 (CYP) 2C19 genotype and who may have a diminished response to the drug because of reduced formation of the active metabolite.(See Reduced Efficacy Associated with Impaired CYP2C19 Function under Warnings/Precautions: Warnings, in Cautions.)

Reduction of Cardiovascular and Cerebrovascular Events

In patients with established peripheral arterial disease or a history of recent myocardial infarction (MI) or stroke, the recommended dosage of clopidogrel for reducing the risk of fatal or nonfatal MI, stroke, or vascular death in adults is 75 mg once daily.

Acute Coronary Syndrome

Unstable Angina/Non-ST-Segment-Elevation Myocardial Infarction

In patients with unstable angina/non-ST-segment-elevation MI (NSTEMI) (i.e., non-ST-segment-elevation acute coronary syndrome [NSTE ACS]), an initial loading dose of 300 mg of clopidogrel is recommended by the manufacturer, followed by 75 mg once daily given concomitantly with aspirin.

Although the optimal loading dose of clopidogrel in patients with NSTE ACS undergoing percutaneous coronary intervention (PCI) is uncertain, some experts suggest a loading dose of 600 mg, administered as early as possible prior to or at the time of the procedure in conjunction with aspirin; clopidogrel should then be continued at a maintenance dosage of 75 mg once daily for at least 12 months. There appears to be no benefit in increasing the clopidogrel loading dose to 900 mg in patients undergoing PCI. The manufacturer states that the optimal duration of clopidogrel therapy in patients with ACS is unknown; experts recommend that clopidogrel be administered for up to 12 months in patients with unstable angina/NSTEMI being managed medically, and for at least 12 months in those undergoing PCI with coronary artery stent placement; aspirin should be continued indefinitely.

In patients who have indications for anticoagulation (e.g., atrial fibrillation, anterior MI and left ventricular thrombus or at high risk for left ventricular thrombosis), the addition of warfarin (international normalized ratio [INR] 2-3) to antiplatelet therapy is recommended by some experts during the period of greatest risk.

For information on the dosage of aspirin used as adjunctive antithrombotic therapy in the management of NSTE ACS,

ST-Segment-Elevation Myocardial Infarction

In patients with acute ST-segment-elevation MI (STEMI), the manufacturer recommends a clopidogrel dosage of 75 mg once daily in conjunction with aspirin. The manufacturer states that clopidogrel may be initiated with or without a loading dose in patients with STEMI.

In patients with STEMI who will undergo PCI, a clopidogrel loading dose of 600 mg, administered as soon as possible before or at the time of PCI, is recommended. A higher loading dose of 900 mg does not appear to provide additional benefit in patients undergoing PCI.

The manufacturer states that the optimal duration of clopidogrel therapy in patients with ACS is unknown. In general, dual antiplatelet therapy (e.g., clopidogrel and aspirin) should be continued for up to 12 months in patients who have experienced an acute coronary syndrome, and possibly longer in those undergoing PCI with stent placement.

In patients who have indications for anticoagulation (e.g., atrial fibrillation, anterior MI and left ventricular thrombus or at high risk for left ventricular thrombosis), the addition of warfarin (INR 2-3) is recommended by some experts during the period of greatest risk.

For information on the dosage of aspirin used as adjunctive antithrombotic therapy in the management of STEMI,

Managing Antiplatelet Therapy in Patients Requiring Invasive Procedures

The American College of Chest Physicians (ACCP) states that the decision to interrupt antiplatelet therapy prior to surgery or other invasive procedures should be individualized based on assessment of the patient's risks of thromboembolism and perioperative bleeding. The possible increased risk of stent thrombosis also should be considered when making decisions regarding the perioperative management of patients with coronary artery stents.(See Risks of Discontinuance of Therapy under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Antiplatelet agents generally should be discontinued prior to surgery or other invasive procedures to minimize the risk of perioperative bleeding. The manufacturer states that in patients requiring an invasive procedure in whom an antiplatelet effect is not desired, clopidogrel should be temporarily discontinued 5 days prior to the procedure and resumed as soon as possible.

In patients receiving dual antiplatelet therapy (e.g., aspirin and clopidogrel) who require coronary artery bypass grafting (CABG), interruption of clopidogrel therapy is recommended at least 5 days prior to surgery. However, aspirin generally should be continued around the time of surgery in such patients.

In patients receiving dual antiplatelet therapy (e.g., aspirin and clopidogrel) who require surgery within 6 weeks of bare-metal stent implantation or within 6 months of drug-eluting stent implantation, ACCP suggests continuation of dual antiplatelet therapy in the periprocedural period. If therapy with clopidogrel is interrupted prior to nonelective major surgery to reduce the risk of excessive bleeding, the American College of Cardiology (ACC)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) recommends that aspirin be continued if at all possible and clopidogrel be restarted as soon as possible after the procedure because of concerns about late stent thrombosis.

Special Populations

No dosage adjustments are necessary in geriatric patients or in those with hepatic impairment.

Cautions

Contraindications

Known hypersensitivity to clopidogrel or any ingredient in the formulation. Presence of active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).

Warnings/Precautions

Warnings

Reduced Efficacy Associated with Impaired CYP2C19 Function

Clopidogrel is a prodrug that requires activation by the cytochrome P-450 (CYP) enzyme system to produce its pharmacologically active metabolite.(See Description.) Production of the active metabolite and response to clopidogrel may be reduced by genetic polymorphism of CYP2C19, one of the key enzymes involved in the metabolic activation of clopidogrel, or concurrent use of drugs (e.g., omeprazole, esomeprazole) that inhibit CYP2C19. Use of alternative clopidogrel dosing strategies or other antiplatelet therapy options (e.g., prasugrel, ticagrelor) should be considered in patients who are identified as potential poor metabolizers of CYP2C19.

Specific variant alleles of CYP2C19 (e.g., CYP2C19*2, CYP2C19*3) have been associated with reduced metabolism of and diminished antiplatelet response to clopidogrel; while data on clinical outcomes are conflicting, higher rates of major adverse cardiovascular events (e.g., death, myocardial infarction, stroke, stent thrombosis) have been reported in patients receiving recommended dosages of clopidogrel who possess such variant alleles compared with those who have normal CYP2C19 activity.(See Description.) The impact of CYP2C19 metabolizer status on the pharmacokinetic and antiplatelet response to clopidogrel was evaluated in a randomized, crossover study in healthy individuals. Individuals were classified into one of 4 groups according to their CYP2C19 metabolizer phenotype (ultrarapid, extensive, intermediate, or poor metabolizer). Individuals in each group received either a 300-mg loading dose of clopidogrel followed by 75 mg daily or a 600-mg loading dose followed by 150 mg daily, with crossover to the alternate clopidogrel regimen after 5 days. Exposure to the active metabolite of clopidogrel was decreased and inhibition of platelet response was diminished in poor metabolizers compared with the other CYP2C19 metabolizer groups. When poor metabolizers received the higher-dose regimen of clopidogrel (600 mg loading dose followed by 150 mg daily), active metabolite exposure and antiplatelet response increased relative to that with the lower-dose regimen. Retrospective analyses of clopidogrel-treated patients from 2 large randomized, controlled studies (The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA] trial and Trial to Assess Improvement with Prasugrel-Thrombolysis in Myocardial Infarction [TRITON-TIMI 38]) and several published cohort studies have shown higher rates of adverse cardiovascular events (death, myocardial infarction, stroke) or stent thrombosis in patients with impaired CYP2C19 metabolizer status (intermediate or poor) compared with that in extensive metabolizers.

Genetic tests are available to identify a patient's CYP2C19 genotype and can be used to help individualize and optimize clopidogrel therapy. While such tests are considered appropriate for patients currently receiving or considering treatment with clopidogrel, ACCF/AHA states that the predictive value of pharmacogenomic testing is very limited at this time and the need for pharmacogenetic testing should be determined on an individual basis. Management options in patients who are identified as poor metabolizers of CYP2C19 include the use of higher dosages of clopidogrel or the use of alternative P2Y12 receptor antagonists (e.g., prasugrel, ticagrelor) that have not been shown to be affected by CYP2C19 genetic polymorphism; however, ACCF/AHA states that the relative efficacy and safety of these alternative treatment strategies remains to be determined. Although preliminary data indicate that higher initial and maintenance clopidogrel dosages (e.g., 600-mg loading dose followed by 150 mg daily) or administration of additional loading doses may improve the antiplatelet response in poor metabolizers, the manufacturer states that the appropriate dosage of clopidogrel in such patients has not been established in clinical outcome trials. When considering the use of alternative antiplatelet agents, clinicians should balance the anticipated greater benefits of these agents against the possible increased risk of bleeding, and also consider the patient populations in whom the drugs have been used.

Concurrent use of clopidogrel and omeprazole, a potent inhibitor of CYP2C19, also has been shown to reduce the antiplatelet effects of clopidogrel. Although the clinical importance of this interaction has not been fully elucidated, some evidence suggests that concurrent use of clopidogrel and omeprazole may result in reduced efficacy of clopidogrel in preventing cardiovascular events. A similar reduction in antiplatelet activity has been observed when esomeprazole was used concurrently with clopidogrel. Concomitant use of other drugs that inhibit CYP2C19 also may decrease the response to clopidogrel.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Other genetic variants of CYP isoenzymes (e.g., CYP2C19*17, CYP2B6) also may affect response to clopidogrel.

Other Warnings and Precautions

Bleeding

Clopidogrel increases the risk of bleeding. The drug should be discontinued 5-10 days prior to surgery or coronary artery bypass grafting (CABG), if antiplatelet effect is undesirable.(See Managing Antiplatelet Therapy in Patients Requiring Invasive Procedures under Dosage and Administration: Dosage.) If bleeding occurs, hemostasis may be restored with exogenous administration of platelets; however, platelet transfusions within 4 hours of a loading dose of clopidogrel or within 2 hours of a maintenance dose may have reduced effectiveness. Withholding a dose is unlikely to resolve a bleeding episode or prevent bleeding associated with an invasive procedure because of clopidogrel's prolonged effects on platelet inhibition.

In patients with transient ischemic attacks (TIAs) or stroke who are at high risk for recurrent ischemic events, the combination of clopidogrel and aspirin has not been shown to be more effective than clopidogrel alone but has been associated with an increase in major bleeding.

Thienopyridines do not appear to cause GI ulcers or erosions, but their antiplatelet effects may promote bleeding at the site of preexisting lesions associated with use of aspirin or nonsteroidal anti-inflammatory agents or H. pylori infection. Current ACCF/ACG/AHA guidelines recommend prophylactic use of a proton-pump inhibitor to reduce the risk of ulcer complications and GI bleeding in patients receiving clopidogrel and aspirin therapy who have additional GI risk factors. However, the possibility of reduced antiplatelet effects should be considered when clopidogrel is used concomitantly with a proton-pump inhibitor (e.g., omeprazole, esomeprazole).(See Drug Interactions: Proton-Pump Inhibitors.)

Risks of Premature Discontinuance of Therapy

In general, treatment with a thienopyridine derivative should not be discontinued prematurely because of the increased risk of cardiovascular events. If clopidogrel must be temporarily discontinued (e.g., prior to surgery), therapy should be reinitated as soon as possible. Patients should be advised to never stop clopidogrel therapy without first consulting the prescribing clinician. Prior to scheduling an invasive procedure, patients should inform their clinicians (including dentists) that they are currently taking clopidogrel, and clinicians performing the invasive procedure should consult with the prescribing clinician before advising patients to discontinue therapy.

Premature discontinuance of dual-drug antiplatelet therapy with a thienopyridine derivative (e.g., clopidogrel, prasugrel) and aspirin in patients with coronary artery stents, particularly discontinuance of clopidogrel therapy in patients with drug-eluting stents, has been associated with stent thrombosis, often leading to myocardial infarction (MI) and/or death.(See Uses: Prevention of Stent Thrombosis.) Before implantation of a drug-eluting stent, patients should be carefully assessed regarding the likelihood of compliance with prolonged (e.g., at least 12 months) dual-drug antiplatelet therapy (i.e., aspirin and a thienopyridine derivative); strong consideration should be given to avoiding use of a drug-eluting stent in patients who are not expected to comply. In addition, patients should be educated before discharge about the reasons they have been prescribed the drugs and the substantial risks associated with premature discontinuance of dual-drug antiplatelet therapy. Superficial or ''nuisance'' bleeding is common in patients receiving dual-drug antiplatelet therapy after drug-eluting stent implantation and may be a reason for premature discontinuation of clopidogrel. In a single-center observational study in 2360 patients who underwent drug-eluting stent implantation, 11.1% of patients who were receiving dual-drug antiplatelet therapy discontinued clopidogrel prematurely as a result of superficial bleeding. The American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) states that concomitant use of proton-pump inhibitors may reduce GI symptoms (e.g., dyspepsia) associated with antiplatelet agents and thereby prevent patients from discontinuing their antiplatelet treatment.(See Drug Interactions: Proton-Pump Inhibitors.) Patients should be advised to never stop taking dual-drug antiplatelet therapy without first consulting with their cardiologist, even if instructed to do so by another health-care professional (e.g., dentist). In patients who are likely to require invasive or surgical procedures within 12 months of drug-eluting stent implantation, implantation of a bare-metal stent or balloon angioplasty with provisional stent placement should be considered instead.

Health-care professionals who perform invasive or surgical procedures and are concerned about periprocedural or postprocedural bleeding must understand the potentially catastrophic consequences of premature discontinuance of thienopyridine derivative (i.e., clopidogrel, ticlopidine) therapy in patients with drug-eluting stents. If issues about a patient's antiplatelet therapy are unclear, such professionals should contact the patient's cardiologist to discuss optimal patient management. Elective procedures with substantial bleeding risk should be deferred until 12 months of dual-drug antiplatelet therapy has been completed. For non-elective procedures that mandate discontinuance of thienopyridine-derivative therapy, aspirin should be continued if at all possible and the thienopyridine derivative (i.e., clopidogrel, ticlopidine) restarted as soon as possible after the procedure because of concerns about late stent thrombosis.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) has been reported rarely with clopidogrel, sometimes after short exposure (less than 2 weeks) to the drug. TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes on peripheral blood smear), neurologic findings, renal dysfunction, and fever. TTP is a potentially fatal condition that requires urgent referral to a hematologist for prompt treatment (e.g., plasmapheresis).

Specific Populations

Pregnancy

Category B.

Lactation

Clopidogrel is distributed into milk in rats; not known whether the drug is distributed into milk in humans. Discontinue nursing or the drug because of potential for severe adverse effects in infants.

Pediatric Use

Safety and efficacy of clopidogrel have not been established in patients younger than 21 years of age. However, the drug has been used for thromboprophylaxis in children; regular monitoring of liver and renal function is recommended. In neonates and infants up to 24 months of age with systemic to pulmonary artery shunts or other cardiac conditions predisposing to thrombosis, clopidogrel 0.2 mg/kg daily for 1-4 weeks achieved similar inhibition of platelet aggregation as a 75-mg daily dosage in adults; no serious hemorrhagic events were reported.

Geriatric Use

No difference in platelet aggregation has been observed in patients 75 years of age or older compared with younger healthy individuals. In the CURE trial, geriatric patients (65 years of age or older) were at greater risk for thrombotic events and major bleeding compared with younger patients. However, in the COMMIT study evaluating patients with ST-segment-elevation MI (STEMI), the efficacy and safety of clopidogrel in preventing ischemic events was independent of age. Dosage adjustment based solely on age does not appear to be necessary in geriatric patients.

Hepatic Impairment

Inhibition of ADP-induced platelet aggregation in patients with severe hepatic impairment appears to be similar to that observed in healthy individuals.

Renal Impairment

Experience is limited in patients with moderate (creatinine clearance of 30-60 mL/minute) or severe (creatinine clearance of 5-15 mL/minute) renal impairment. Inhibition of ADP-induced platelet aggregation may be decreased by 25% in such patients.

Common Adverse Effects

Adverse effects occurring in at least 2.5% of patients with recent MI, stroke, or established peripheral arterial occlusive disease receiving clopidogrel in the CAPRIE study included chest pain, accidental injury, influenza-like symptoms, pain, fatigue, edema, hypertension, headache, dizziness, abdominal pain, dyspepsia, diarrhea, nausea, hypercholesterolemia, arthralgia, back pain, purpura (bruising), epistaxis, depression, upper respiratory tract infection, dyspnea, rhinitis, bronchitis, coughing, rash, pruritus, and urinary tract infection. In this study, rash and diarrhea were reported more frequently with clopidogrel therapy while patients receiving aspirin experienced indigestion/nausea/vomiting, GI hemorrhage, or abnormal liver function more frequently. Rash classified as severe was more common with clopidogrel therapy, while GI hemorrhage classified as severe was more common in patients receiving aspirin.

Adverse effects occurring in at least 2% of patients with non-ST-segment-elevation acute coronary syndrome (NSTE ACS) receiving clopidogrel and aspirin in the CURE study included chest pain, headache, dizziness, abdominal pain, dyspepsia, or diarrhea. In this study, the incidence of major bleeding (principally GI hemorrhage and bleeding at puncture sites), including life-threatening bleeding, was substantially greater in patients receiving clopidogrel and aspirin than in those receiving placebo and aspirin (3.7 and 2.7%, respectively); the incidence of life-threatening bleeding (2.2 and 1.8%, respectively) was similar.

In the COMMIT study in patients with STEMI, the incidence of major bleeding (intracranial hemorrhage or bleeding associated with a decrease in hemoglobin concentrations exceeding 5 mg/dL) was similar in patients receiving clopidogrel and aspirin and in those receiving placebo and aspirin (1.3 and 1.1%, respectively); the incidence of fatal bleeding (0.8 and 0.6%, respectively) also was similar. Only limited safety data were collected in the COMMIT study.

The incidence of severe neutropenia (neutrophil count less than 450/mm) was similar in patients receiving clopidogrel or aspirin (0.05 or 0.04%, respectively) in the CAPRIE study and much lower than that reported with ticlopidine therapy (0.8%). In the CURE study, the incidence of neutropenia was similar in patients receiving clopidogrel and aspirin or placebo and aspirin (0.08 or 0.1%, respectively).

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (clopidogrel-induced inhibition of the cytochrome P-450 [CYP] 2C9 isoenzyme [CYP2C9] at high drug concentrations in vitro).

Drugs that inhibit CYP2C19 decrease plasma concentrations of the active metabolite of clopidogrel and reduce its antiplatelet effects.(See Drug Interactions: Proton-Pump Inhibitors.) Concomitant use of drugs that are known to be potent inhibitors of CYP2C19 activity (e.g., omeprazole, esomeprazole) should be avoided in patients receiving clopidogrel.

Cilostazol

Potential additive inhibition of platelet aggregation. Caution is advised; bleeding times should be monitored during concurrent administration.

Pharmacokinetic interaction unlikely.

Nonsteroidal Anti-inflammatory Agents

Potential pharmacodynamic interaction (increased risk of bleeding).

Warfarin

Potential pharmacodynamic interaction (increased risk of bleeding). Caution is advised.

Proton-Pump Inhibitors

Potential pharmacokinetic interaction (decreased plasma concentrations of the active metabolite of clopidogrel) and pharmacodynamic interaction (reduced antiplatelet effects) with certain proton-pump inhibitors. Because the antiplatelet activity of clopidogrel (a prodrug) is dependent on biotransformation, principally by CYP2C19, of the prodrug to an active metabolite, concurrent use of drugs such as omeprazole or esomeprazole that inhibit CYP2C19 reduces plasma concentrations of the active metabolite and potentially could reduce clinical efficacy.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes and also see Reduced Efficacy Associated with Impaired CYP2C19 Function under Warnings/Precautions: Warnings, in Cautions.) Some experts, including the American College of Cardiology (ACC) and the American Heart Association (AHA), state that additional data from large, prospective trials are needed to fully elucidate the clinical consequences, if any, of the observed interaction between clopidogrel and certain proton-pump inhibitors. If concomitant proton-pump inhibitor therapy is considered necessary, use of an agent with little or no CYP2C19-inhibitory activity should be considered.

Proton-pump inhibitors vary in their potency for inhibiting CYP2C19. The change in inhibition of adenosine diphosphate (ADP)-induced platelet aggregation associated with concomitant use of proton-pump inhibitors is related to the change in exposure to the active metabolite of clopidogrel. In pharmacokinetic and pharmacodynamic studies in healthy individuals, dexlansoprazole, lansoprazole, or pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole. Pharmacokinetic and pharmacodynamic data from these interaction studies suggested that of these proton-pump inhibitors, dexlansoprazole had the least potential to interact with clopidogrel. In these studies, the observed effects of dexlansoprazole, lansoprazole, or pantoprazole on exposure to the active metabolite of clopidogrel and on clopidogrel-induced platelet inhibition were not considered clinically important, and the manufacturers of dexlansoprazole, lansoprazole, and pantoprazole state that no adjustment of clopidogrel dosage is required if clopidogrel is used concomitantly with FDA-labeled dosages of these proton-pump inhibitors. Omeprazole and esomeprazole substantially reduce the antiplatelet activity of clopidogrel; therefore, concomitant use of omeprazole or esomeprazole with clopidogrel should be avoided. (For additional information, see Drug Interactions: Clopidogrel in the individual monographs for proton-pump inhibitors in 56:28.36.)

The decision to use any proton-pump inhibitor concomitantly with clopidogrel should be based on the assessed risks and benefits in individual patients. The American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) states that use of a proton-pump inhibitor concomitantly with dual antiplatelet therapy may provide the optimal balance of risk and benefit in patients with acute coronary syndrome (ACS) who have a history of upper GI bleeding since such a history is the strongest and most consistent risk factor for GI bleeding in patients receiving antiplatelet therapy. Among stable patients with a history of GI bleeding who undergo coronary revascularization and receive a coronary stent, ACCF/ACG/AHA states that the risk/benefit tradeoff may favor concomitant use of dual antiplatelet therapy and a proton-pump inhibitor. ACCF/ACG/AHA also states that the risk reduction with proton-pump inhibitors is substantial in patients with risk factors for GI bleeding (e.g., advanced age; concomitant use of warfarin, corticosteroids, or nonsteroidal anti-inflammatory agents [NSAIAs]; H. pylori infection) and may outweigh any potential reduction in the cardiovascular efficacy of antiplatelet treatment associated with a drug-drug interaction. In contrast, patients without these risk factors for GI bleeding receive little if any absolute risk reduction from proton-pump inhibitor therapy, and the risk/benefit balance may favor use of antiplatelet therapy without a concomitant proton-pump inhibitor.

In a crossover clinical trial in healthy individuals who received clopidogrel (a 300-mg loading dose, followed by 75 mg daily) alone or with a high dosage of omeprazole (80 mg administered at the same time as the clopidogrel dose) for 5 days, exposure to the active metabolite of clopidogrel was decreased by 46 and 42% on days 1 and 5, respectively, when the drugs were administered simultaneously. In addition, mean inhibition of platelet aggregation was reduced by 47 and 30% at 24 hours and on day 5, respectively. When administration of the 2 drugs (at the same dosages) was separated by 12 hours in another study, results were similar in terms of reduced exposure to the active clopidogrel metabolite and reduced platelet inhibition. The effects of a lower dosage of omeprazole on inhibition of platelet aggregation have not been established. When a higher dosage of clopidogrel was administered concomitantly with omeprazole, an increase in antiplatelet response was observed; however, an appropriate dosage regimen has not been established. Concomitant use of clopidogrel and omeprazole also has been associated with substantially decreased antiplatelet effects as determined by vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The potential for such interactions must be considered for any drug that inhibits CYP2C19.

Results of several large observational studies suggest that concomitant therapy with clopidogrel and omeprazole (or potentially other proton-pump inhibitors) can reduce the effectiveness of clopidogrel in preventing cardiovascular events. However, conflicting data have been reported, including results of a prematurely discontinued randomized controlled trial suggesting no effect of concomitant clopidogrel-proton-pump inhibitor therapy on cardiovascular outcomes; given the limitations of observational studies (possibility of confounding factors such as comorbid conditions, unreported use of aspirin or OTC proton-pump inhibitors), the clinical importance of this interaction has been questioned. Pharmacokinetic/pharmacodynamic studies conducted by the manufacturer indicate that administration of the drugs at separate times (e.g., 12 hours apart) will not prevent the interaction.

Some clinicians suggest that an antacid or a histamine H2-receptor antagonist (ranitidine, famotidine, nizatidine) may be considered as an alternative to therapy with a proton-pump inhibitor, although such agents may not be as effective as a proton-pump inhibitor in providing gastric protection. However, cimetidine should not be used as alternative therapy since it is a potent CYP2C19 inhibitor. There currently is no evidence that histamine H2-receptor antagonists (other than cimetidine) or other drugs that reduce gastric acid (e.g., antacids) interfere with the antiplatelet effects of clopidogrel.

Several observational studies involving large numbers of patients suggest that proton-pump inhibitors reduce the effectiveness of clopidogrel in preventing cardiovascular events. In a case-control study in patients 66 years of age or older, concomitant use of clopidogrel and a proton-pump inhibitor that inhibits CYP2C19 (omeprazole, lansoprazole, rabeprazole) was associated with a 40% greater risk of recurrent myocardial infarction within 90 days of hospital discharge; this effect was not seen with pantoprazole, which does not inhibit CYP2C19. In 2 retrospective cohort studies involving more than 30,000 patients, the incidence of major adverse cardiovascular events (e.g., hospitalization for stroke, angina, myocardial infarction, coronary artery bypass grafting, urgent target vessel revascularization, death) in patients receiving clopidogrel for 12 months following stent placement was higher in those who were also prescribed a proton-pump inhibitor than in those who did not receive a proton-pump inhibitor. A subgroup analysis in one of these studies revealed that each proton-pump inhibitor (omeprazole, esomeprazole, pantoprazole, lansoprazole) was individually associated with an increased risk of cardiovascular events. In other retrospective cohort studies in patients with acute coronary syndrome (ACS), concomitant use of clopidogrel and a proton-pump inhibitor was associated with a significantly higher rate of adverse cardiovascular events (e.g., death or rehospitalization for ACS, coronary stent placement) versus administration of clopidogrel alone.

Data discounting the clinical importance of a clopidogrel-proton-pump inhibitor interaction also have been reported. In a study evaluating health insurance records of more than 18,500 patients 65 years of age or older who had received clopidogrel with or without proton-pump inhibitor therapy, a slightly increased risk of myocardial infarction or death was observed in patients receiving clopidogrel concurrently with a proton-pump inhibitor, but the finding was not statistically significant. In a post hoc analysis of a large randomized study evaluating a clopidogrel loading dose in patients prior to PCI (Clopidogrel for the Reduction of Events During Observation [CREDO]), use of a proton-pump inhibitor was independently associated with an increased risk of a cardiovascular event (e.g., death, myocardial infarction, stroke) regardless of whether patients received clopidogrel therapy. Post-hoc analysis of another large randomized controlled study (Trial to Assess Improvement with Prasugrel-Thrombolysis in Myocardial Infarction [TRITON-TIMI 38]) also found no clinically meaningful interaction between clopidogrel and a proton-pump inhibitor. In the only randomized, placebo-controlled trial (Clopidogrel Optimization of Gastrointestinal EveNTs [COGENT] trial) to date evaluating potential clinical outcomes of the clopidogrel-proton-pump inhibitor interaction, no effect of such concomitant therapy on the rate of cardiovascular events was found in patients receiving an investigational fixed-dose combination of clopidogrel and omeprazole or clopidogrel without a proton-pump inhibitor; however, interpretation of the data is limited due to premature termination of the study, insufficient statistical power, and incomplete follow-up.

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