ATC Class:B01AC04

AHFS Class:

• Platelet-aggregation Inhibitors 20:12.18

Generic Name(s):

• Clopidogrel Bisulfate

Chemical Name:

• Methyl (+)-(S)-a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, sulfate

Molecular Formula:

• C₁₆H₁₆ClNO₂S • H₂SO₄

Clopidogrel bisulfate, a thienopyridine P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist, is a platelet-aggregation inhibitor.1

Acute Coronary Syndrome

Clopidogrel is used in combination with aspirin to reduce the risk of myocardial infarction (MI) and stroke in patients with acute coronary syndrome (ACS), including those with non-ST-segment-elevation ACS (NSTE-ACS) being managed medically or with revascularization strategies (e.g., percutaneous coronary intervention [PCI] with coronary stent implantation, coronary artery bypass grafting [CABG]) and those with acute ST-segment-elevation MI (STEMI) managed medically.1,5,18,31,35,36,991,992,994,1005,1010

The American College of Cardiology (ACC)/American Heart Association (AHA) has issued guidelines for treatment options and duration of dual antiplatelet therapy in patients with ACS.991,992,994,1005 Recommendations are similar for patients with NSTE-ACS and those with STEMI since both are part of the spectrum of ACS.1005 Decisions about the duration of dual antiplatelet therapy should be individualized based on the risks of bleeding versus benefits of ischemic reduction, clinical judgment, and patient preference.1005 Aspirin should almost always be continued indefinitely; therefore, recommendations are given for the duration of P2Y12 inhibitor therapy in patients treated with dual antiplatelet therapy.1005 While the addition of a P2Y12 inhibitor to aspirin therapy reduces ischemic complications, this occurs at the expense of increased bleeding; a similar risk-benefit trade-off should be considered when determining whether to use a prolonged versus shorter duration of dual antiplatelet therapy.1005,1006 ACC/AHA generally recommends considering shorter duration dual antiplatelet therapy for patients at reduced ischemic, but high bleeding, risk and longer duration dual antiplatelet therapy for patients at high ischemic, but reduced bleeding, risk.1005

The AHA/ACC guideline recommends that in patients with ACS who are managed medically (without revascularization or reperfusion therapy) or with PCI and stent implantation (bare-metal or drug-eluting), P2Y12 inhibitor therapy should be given for at least 12 months; in such patients who have tolerated dual antiplatelet therapy without bleeding complications and who do not have a high risk of bleeding, continuation of dual antiplatelet therapy for longer than 12 months may be reasonable.1005 With regard to the specific P2Y12 inhibitor, evidence supports the use of clopidogrel or ticagrelor in medically-managed ACS patients; clopidogrel, prasugrel, or ticagrelor may be used in ACS patients treated with PCI.1005 Use of more potent P2Y12 inhibitors such as ticagrelor or prasugrel over clopidogrel results in a greater reduction in ischemic events and stent thrombosis, but increases the risk of bleeding.991,1005 In some clinical guidelines, ticagrelor or prasugrel is preferred or suggested for maintenance P2Y12 inhibitor therapy in ACS patients while clopidogrel is considered an alternative when the more potent P2Y12 inhibitors cannot be used.33,1005

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 compared with administration of the drug in the catheterization laboratory.994 The potential benefit of pretreatment with clopidogrel should be balanced against the increased risk of bleeding should emergency CABG be needed.35,994 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 the procedure; if the need for CABG is urgent, clopidogrel should be discontinued for at least 24 hours.1,35,40,991 In patients undergoing CABG, P2Y12 inhibitor therapy (clopidogrel, prasugrel, or ticagrelor) should be resumed after surgery to complete 12 months of dual antiplatelet therapy after ACS.1005

Non-ST-Segment-Elevation Acute Coronary Syndrome

Efficacy of clopidogrel for the long-term reduction of cardiovascular events in patients with NSTE-ACS 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.1,18 In the CURE study, the combined incidence of cardiovascular death, nonfatal MI, or stroke, and the combined incidence of these events plus refractory ischemia in the clopidogrel group were reduced compared with these outcomes in the placebo group.1,18 Clopidogrel therapy also was associated with reductions in the incidences of refractory or severe ischemia, heart failure, and revascularization procedures (during the initial period of hospitalization).18 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.18 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%).1,18

ST-Segment-Elevation Myocardial Infarction

Results of randomized, controlled studies indicate that clopidogrel reduces 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.1,31,32,36,38

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%.1,31 Rates of major bleeding, including intracranial hemorrhage, were similar with or without adjunctive clopidogrel therapy.1,31 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%.32

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.1,36 In addition, death from any cause was reduced by 7%, and fatal or nonfatal reinfarction by 14%, in patients receiving adjunctive clopidogrel.1,36 Clopidogrel treatment was associated with a small increase in minor bleeding but no excess in major (i.e., transfused, cerebral, or fatal) bleeding complications.1,36

Peripheral Arterial Disease or History of MI or Stroke

Clopidogrel is used to reduce the risk of MI and stroke in patients with established peripheral arterial disease (PAD) or a history of recent MI or recent stroke.1,2,6,8,132,1009,1010,1102,1103

Both aspirin and clopidogrel have been used for secondary prevention in patients with stable ischemic heart disease (SIHD).1010,1101 Results of a large, randomized study (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [CAPRIE] study) showed that clopidogrel was more effective than aspirin in reducing the risk of cardiovascular events in a population of patients with symptomatic atherosclerotic vascular disease and had a similar overall safety profile.1,5,8,20 However, because of cost considerations, many clinicians recommend aspirin as the antiplatelet drug of choice for most patients requiring long-term antiplatelet therapy for SIHD, and consider clopidogrel an alternative when aspirin is contraindicated.5,8,20,1010,1101

Antiplatelet therapy also is recommended for secondary prevention of stroke in patients with a history of noncardioembolic ischemic stroke or transient ischemic attack (TIA).1009,1103 In such patients, experts recommend aspirin, clopidogrel, or aspirin in combination with extended-release dipyridamole for antiplatelet therapy.1009,1103 The American Heart Association (AHA) and American Stroke Association (ASA) guidelines recommend that in patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70-99%) of a major intracranial artery, the addition of clopidogrel to aspirin for 90 days may be reasonable.1103 Oral anticoagulation (e.g., warfarin, direct oral anticoagulants [DOACs]) 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.1007,1009,1014 (See Embolism Associated with Atrial Fibrillation under Uses.)

Recommendations on antiplatelet therapy in patients with lower extremity PAD are provided in guidelines from AHA/ACC.1102,1107 Antiplatelet therapy with either aspirin or clopidogrel is recommended to reduce the risk of cardiovascular events in patients with symptomatic PAD.1102 AHA/ACC states that the effectiveness of dual antiplatelet therapy to reduce the risk of ischemic events in patients with symptomatic PAD is uncertain, but may be reasonable in certain situations.1102

Efficacy of clopidogrel in patients with recent MI, recent stroke, or established PAD 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); in this study, patients received clopidogrel 75 mg once daily or aspirin 325 mg daily for an average of 1.6 years (maximum 3 years).1,2,3,5,6,8,11 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.1,2,3,6,8,11 The annual cardiovascular event rate in patients receiving clopidogrel was 5.32% compared with 5.83% in those receiving aspirin,2,3,6,8,11 representing an 8.7% decrease in the annual risk of a new cardiovascular event for clopidogrel-treated patients.1,2,3,6,11,20 The difference in overall risk of cardiovascular events was apparent early in the study and was maintained throughout the 3-year follow-up period.1,3 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 PAD, who experienced a statistically significant 23.8% decrease in risk compared with those in the same subgroup who received aspirin.1,3,11 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.3,11

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.1,126,132 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.1,126,132 In addition, the combination of clopidogrel and aspirin was associated with an increased rate of moderate to severe bleeding.1,126,132

Prevention of Stent Thrombosis

Clopidogrel has been used in combination with aspirin (dual antiplatelet therapy) to prevent stent thrombosis following implantation of coronary artery stents†.43,44,45,46,50,51,52,54,992,994,1005,1010

Compared with bare-metal stents (BMS), implantation of drug-eluting stents (DES) 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.43,44,53,55,57,58,994 Various drug-eluting stents are available; however, newer-generation (e.g., everolimus- or zotarolimus-eluting) stents have demonstrated lower risk of stent thrombosis and MI compared with first-generation (e.g., sirolimus- and paclitaxel-eluting) stents, which are rarely, if ever, used in current practice.1005,1105,1106 Therefore, current recommendations for duration of dual antiplatelet therapy apply principally to the use of newer-generation stents.1005

The current ACC/AHA guideline states that patients with ACS who receive a BMS or DES should be treated with dual antiplatelet therapy for at least 12 months.1005 Continuation of dual antiplatelet therapy beyond 12 months may be reasonable in patients who have tolerated such therapy without a bleeding complication and who are not at high bleeding risk.1005 (See Acute Coronary Syndrome under Uses.) A shorter duration of dual antiplatelet therapy may be reasonable in patients with a newer-generation DES.1005 If patients with a DES develop a high risk of bleeding or have a high risk of severe bleeding, discontinuation of a P2Y12 inhibitor after 3 months may be reasonable.1005

Recommendations are also provided by ACC/AHA for patients with stable ischemic heart disease (SIHD) who undergo stent implantation.1005 Dual antiplatelet therapy with aspirin and clopidogrel should be given for a minimum of 1 month to patients with SIHD who receive a BMS, and for a minimum of 6 months to patients who receive a DES.1005 Continuation of dual antiplatelet therapy beyond these periods may be reasonable in patients who have tolerated dual antiplatelet therapy without a bleeding complication and who are not at high bleeding risk.1005 If patients treated with DES develop a high risk of bleeding or have a high risk of severe bleeding, discontinuation of a P2Y12 inhibitor after 3 months may be reasonable.1005 In patients with SIHD who undergo CABG, treatment with dual antiplatelet therapy for 12 months may be reasonable to improve vein graft patency.1005 In patients treated for an MI that occurred 1 to 3 years earlier who have tolerated dual antiplatelet therapy and are not at high bleeding risk, continuation of dual antiplatelet therapy may be reasonable.1005

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 DES 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.1006 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);1006 however, these adverse mortality findings were not observed during FDA's final review of the DAPT study and other randomized, controlled clinical studies.806 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.806 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.806 Additionally, there was no apparent increase in the risk of cancer-related deaths or cancer-related adverse effects with such long-term treatment.806

Embolism Associated with Atrial Fibrillation

Clopidogrel has been used in combination with aspirin for the prevention of stroke and systemic embolism in patients with atrial fibrillation†.1007,1014 Because of the superiority of warfarin over antiplatelet therapy in reducing the risk of stroke in patients with atrial fibrillation, clopidogrel and aspirin have been used generally as an alternative to warfarin anticoagulation.1007 Dual antiplatelet therapy with clopidogrel and aspirin was evaluated as a potential alternative to warfarin in a randomized controlled study (ACTIVE-W) in patients with atrial fibrillation at high risk of stroke.995 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.995 Results of another study (ACTIVE-A) 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.997 These studies were conducted prior to contemporary use of oral anticoagulation in patients with atrial fibrillation.1007 With the availability of direct oral anticoagulants (DOACs) and evidence demonstrating that these drugs are at least as safe and effective as warfarin for preventing stroke and systemic embolism in patients with atrial fibrillation, DOACs are generally recommended over warfarin in patients with atrial fibrillation.1007 Based on the current evidence, oral anticoagulants are currently recommended for antithrombotic therapy in patients with atrial fibrillation; antiplatelet therapy should not be used alone for stroke prevention, but may be added if the patient has other indications for use (e.g., ACS, PCI with stenting).1007,1014

Clopidogrel has been used in patients with atrial fibrillation and ACS.993,1014,1015 These patients have an indication for treatment with both antiplatelet and anticoagulant agents.1014,1015 Selecting the optimal antithrombotic regimen in such patients can be challenging.1014,1015 Current guidelines from AHA/ACC/Heart Rhythm Society and other experts provide recommendations regarding the use of P2Y12 inhibitors in patients with atrial fibrillation who present with ACS and/or undergo PCI.1014,1015 Because of the high risk of bleeding associated with triple antithrombotic therapy (aspirin, a P2Y12 inhibitor, and an oral anticoagulant), experts generally recommend against this approach for most patients.33,1014,1015 Studies have shown similar or lower rates of bleeding and similar rates of thrombotic events with dual antithrombotic therapy compared with triple therapy.993,1014,1015,1018,1019,1020,1021 Therefore, the preferred strategy in patients with atrial fibrillation who have undergone recent PCI is to use dual antithrombotic therapy (an oral anticoagulant and a P2Y12 inhibitor); if triple therapy is considered in patients with high thrombotic risk and low bleeding risk, such therapy should be given over the shortest possible duration.33,993,1014,1015 Clopidogrel is generally recommended over the more potent P2Y12 inhibitors (prasugrel, ticagrelor) when combination antithrombotic therapy is needed because of a lower risk of bleeding.1014,1015,1017 Clopidogrel has also been used in combination with low-dose rivaroxaban (15 mg daily) instead of triple therapy to reduce the risk of bleeding in patients with atrial fibrillation who have undergone PCI with stenting.1014

Clopidogrel is administered orally.1,6,8 Food does not affect systemic exposure to the active metabolite of clopidogrel; therefore, the drug may be administered without regard to meals.1

Dosage

Dosage of clopidogrel bisulfate is expressed in terms of clopidogrel.1

Acute Coronary Syndrome

In patients with acute coronary syndrome (ACS) who need an antiplatelet effect within hours, an initial clopidogrel loading dose of 300 mg is recommended by the manufacturer, followed by 75 mg once daily given concomitantly with aspirin (75-325 mg once daily).1

The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend a clopidogrel loading dose of 300 or 600 mg followed by a dosage of 75 mg daily in patients with non-ST-segment-elevation ACS (NSTE-ACS) who are treated with an early invasive or ischemia-guided strategy.991

In patients with ST-segment-elevation MI (STEMI) who are receiving thrombolytic therapy (e.g., alteplase), experts recommend a clopidogrel loading dose of 300 mg in patients 75 years of age or younger; a loading dose is not recommended in patients older than 75 years of age.992 Clopidogrel therapy should be initiated prior to or with the thrombolytic agent and continued for at least 14 days and up to 1 year at a maintenance dosage of 75 mg daily.992

In patients undergoing percutaneous coronary intervention (PCI), ACC/AHA recommends a loading dose of 600 mg, administered before the procedure; clopidogrel should then be continued at a maintenance dosage of 75 mg once daily for at least 12 months in those who receive a coronary stent.146,991,992,994

In patients who are scheduled to undergo CABG, clopidogrel should be temporarily discontinued at least 5 days prior to surgery and resumed as soon as possible after the procedure.1

Recommendations for duration of dual antiplatelet therapy can be found in the ACC/AHA guideline.1005 (See Acute Coronary Syndrome under Uses.)

Peripheral Arterial Disease or History of MI or Stroke

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.1,2,3,5,6,8

Special Populations

No dosage adjustments are necessary in geriatric patients or in those with hepatic impairment.1

Contraindications

• Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).1,6
• Known hypersensitivity to clopidogrel or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Reduced Efficacy in Poor CYP2C19 Metabolizers

The prescribing information for clopidogrel has a boxed warning regarding diminished antiplatelet effects in patients with 2 loss-of-function alleles of CYP2C19.1 Clopidogrel is a prodrug that requires conversion by the cytochrome P-450 (CYP) enzyme system, principally by CYP2C19, to its pharmacologically active metabolite.1,2,6,8,11,121,1000 (See Description.) Production of the active metabolite and response to clopidogrel may be reduced in patients who are poor metabolizers of CYP2C19.1,72,78,79,80,81,82,83,84,86,100,101,121,350,351,356,1000 Genetic tests are available to identify a patient's CYP2C19 genotype and can be used to help individualize and optimize clopidogrel therapy.1,20,79,121,122,131,143,145,1000 Use of an alternative P2Y12 inhibitor (e.g., prasugrel, ticagrelor) should be considered in patients who are identified as poor metabolizers of CYP2C19.1,121,123,140,143,1000

Specific variant alleles of CYP2C19 (e.g., CYP2C19*2, CYP2C19*3) have been associated with reduced metabolism of and diminished antiplatelet response to clopidogrel; higher rates of major adverse cardiovascular events (e.g., death, MI, 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.1,78,79,80,82,83,88,89,90,92,117,118,121,1000 (See Pharmacogenomics under Description.) The impact of CYP2C19 metabolizer status on the pharmacokinetic and antiplatelet response to clopidogrel was evaluated in a study in healthy individuals.1 Results showed that exposure to the active metabolite of clopidogrel was decreased and inhibition of platelet response was diminished in poor metabolizers compared with other CYP2C19 metabolizer groups (intermediate, extensive, ultrarapid).1,121 The relationship between CYP2C19 genotype and clopidogrel response is particularly evident in ACS patients undergoing PCI.1000 An increased risk of major cardiovascular events and stent thrombosis has been observed in such patients who are CYP2C19*2 heterozygotes or homozygotes.1000 The Clinical Pharmacogenetics Implementation Consortium (CPIC) has issued guidelines for CYP2C19 genotype and clopidogrel therapy.1000 When considering the use of clopidogrel in patients with ACS being managed with PCI, these experts strongly recommend the use of an alternative antiplatelet agent (e.g., prasugrel, ticagrelor) in those who are poor metabolizers of CYP2C19.1000 CPIC gives a moderate recommendation for alternative anticoagulation therapy in patients with an intermediate CYP2C19 phenotype.1000

Reduced Efficacy with Concomitant Use of Omeprazole or Esomeprazole

Concurrent use of clopidogrel and omeprazole, a potent inhibitor of CYP2C19, can reduce the antiplatelet effects of clopidogrel and should be avoided.1,72,79,84,88,89,98,100,101,102,103,109 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.1,73,74,81,89,91,92,98,102,103,115 A similar reduction in antiplatelet activity has been observed when esomeprazole was used concurrently with clopidogrel.1,350 The manufacturer states that concomitant use of clopidogrel and omeprazole or esomeprazole should be avoided.1 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Drug Interactions.)

Other Warnings and Precautions

Bleeding

Clopidogrel increases the risk of bleeding.1 In patients undergoing surgical procedures with a low or high risk of bleeding, the American College of Surgeons recommends that clopidogrel be held for 5-7 days and resumed when bleeding risk has diminished.1104 The drug should be discontinued at least 5 days prior to elective coronary artery bypass grafting (CABG) and at least 24 hours prior to urgent CABG to reduce the risk of bleeding.1,35,43,991 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.1 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.1

In patients with transient ischemic attack (TIA) 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.1

Thienopyridines do not appear to cause GI ulcers or erosions,136,137 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.136,138 Current American College of Cardiology Foundation (ACCF)/American College of Gastroenterology (ACG)/American Heart Association (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.81,87,89,136 However, the possibility of reduced antiplatelet effects should be considered when clopidogrel is used concomitantly with a proton-pump inhibitor (e.g., omeprazole, esomeprazole).1,76,100,101,350 (See Proton-Pump Inhibitors under Drug Interaction.)

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.1,45 If clopidogrel must be temporarily discontinued (e.g., prior to surgery), therapy should be reinitated as soon as possible.1,45 Patients should be advised to not discontinue clopidogrel therapy without first consulting the prescribing clinician.1,45 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.1,45

Premature discontinuance of dual antiplatelet therapy (a P2Y12 inhibitor and aspirin) in patients with coronary artery stents has been associated with stent thrombosis, often leading to myocardial infarction (MI) and/or death.43,44,45,46,47,48,49,54 Before implantation of a drug-eluting stent, patients should be carefully assessed regarding the likelihood of compliance with dual antiplatelet therapy; some experts recommend that PCI with coronary stenting should not be performed in patients not likely to tolerate or comply with dual antiplatelet therapy for the appropriate duration of treatment based on the type of stent implanted.994 Superficial or “nuisance” bleeding is common in patients receiving dual antiplatelet therapy after drug-eluting stent implantation and may be a reason for premature discontinuation of clopidogrel.133 In a single-center observational study in 2360 patients who underwent drug-eluting stent implantation, 11.1% of patients who were receiving dual antiplatelet therapy discontinued clopidogrel prematurely as a result of superficial bleeding.133 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.136,139 (See Proton-Pump Inhibitors under Drug Interactions.)

AHA/ACC guidelines provide recommendations for timing of elective surgical procedures in patients with coronary stents.1005 For patients treated with dual antiplatelet therapy after coronary implantation who must undergo surgical procedures that mandate discontinuance of P2Y12 inhibitor therapy, aspirin should be continued if at all possible and the P2Y12 inhibitor restarted as soon as possible after the procedure because of concerns about late stent thrombosis.1005

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) has been reported rarely with clopidogrel, sometimes after short exposure (less than 2 weeks) to the drug.1,11,12 TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes on peripheral blood smear), neurologic findings, renal dysfunction, and fever.1 TTP is a potentially fatal condition that requires urgent referral to a hematologist for prompt treatment (e.g., plasmapheresis).1

Cross-Reactivity Among Thienopyridines

Patients with a history of hypersensitivity or hematologic reaction to other thienopyridines have experienced hypersensitivity, including rash, angioedema, or hematologic reaction, after receiving clopidogrel.1

Specific Populations

Pregnancy

Available data from case reports and postmarketing surveillance have not suggested any risks of major birth defects, miscarriage, or adverse fetal outcomes with clopidogrel use in pregnant women.1 In animal studies, no evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses up to 78 times to recommended daily human dose.1

MI and stroke present risks to both the pregnant woman and fetus.1 Use of clopidogrel during labor or delivery increases the risk of maternal bleeding and hemorrhage.1 Neuraxial blockade during clopidogrel use should be avoided because of the risk of spinal hematoma.1 When possible, clopidogrel should be discontinued 5-7 days prior to labor, delivery, or neuraxial blockade.1

Lactation

Clopidogrel is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.1 The benefits of breast-feeding should be considered along with the importance of the drug to the mother and any potential adverse effects on the infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of clopidogrel have not been established in pediatric patients.1 However, the drug has been used in neonates and infants† with certain cardiac conditions that predispose them to arterial thrombosis.97

Geriatric Use

No difference in platelet aggregation has been observed in patients 75 years of age or older compared with younger healthy individuals.1 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.1 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.1,36 Dosage adjustment based solely on age does not appear to be necessary in geriatric patients.1

Hepatic Impairment

Inhibition of ADP-induced platelet aggregation in patients with severe hepatic impairment appears to be similar to that observed in healthy individuals.1

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.1 Inhibition of ADP-induced platelet aggregation may be decreased by 25% in such patients.1

Common Adverse Effects

Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse effect of clopidogrel.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clopidogrel is converted to its active metabolite in part by cytochrome P-450 (CYP) isoenzyme 2C19.1

Drugs that induce CYP2C19 (e.g., rifampin) are expected to result in increased concentrations of the active metabolite of clopidogrel and increase its antiplatelet effects.1 Concomitant use should be avoided.1

Drugs that inhibit CYP2C19 are expected to decrease plasma concentrations of the active metabolite of clopidogrel and reduce its antiplatelet effects.1,72,76,81,88,89 (See Proton-Pump Inhibitors under Drug Interactions.) 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.1,20,101,356

Nonsteroidal Anti-inflammatory Agents

Potential pharmacodynamic interaction (increased risk of bleeding).1

Opiate Agonists

Concomitant use of opioids may delay and reduce absorption of and exposure to the active metabolites of clopidogrel because of slowed gastric emptying.1 The use of a parenteral antiplatelet should be considered in patients with ACS who require coadministration of opioid agonists.1

Proton-Pump Inhibitors

Decreased systemic exposure to clopidogrel's active metabolite and reduced antiplatelet effects may occur when clopidogrel is used concomitantly with certain proton-pump inhibitors.1,72,73,74,84,86,88,89,91,100,101,102,103,106,107,109 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.1,76,78,81,88,89,350,351 (See Reduced Efficacy with Concomitant Use of Omeprazole or Esomeprazole under Cautions.) Some experts 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.92,102,103,106,107,109,112,113,114,115,119,125,126,136 The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) state that although proton-pump inhibitors (e.g., omeprazole) can affect clopidogrel metabolism and result in diminished antiplatelet activity in vitro, these pharmacokinetic effects do not appear to be associated with worse clinical outcomes.992 If concomitant proton-pump inhibitor therapy is considered necessary, use of an agent with little or no CYP2C19-inhibitory activity should be considered.81,89,92,102,103,109,111,112,114,350

Proton-pump inhibitors vary in their potency for inhibiting CYP2C19.100,106,114 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.350,351 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,350,351,353,354,355 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.353,354,355 Omeprazole and esomeprazole substantially reduce the antiplatelet activity of clopidogrel; therefore, concomitant use of omeprazole or esomeprazole with clopidogrel should be avoided.1,100,101,113,356 When administration of clopidogrel and omeprazole (at the same dosages) was separated by 12 hours, the amounts of reduced exposure to the active clopidogrel metabolite and reduced platelet inhibition were similar to when the drugs were administered at the same time.1,20,100,101,123,351,356

The decision to use any proton-pump inhibitor concomitantly with clopidogrel should be based on the assessed risks and benefits in individual patients.103,112,114,119,125,136 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 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.136 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.136 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 a 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.136 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.136

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.73,74,81,91,98,104,125 However, conflicting data have been reported,102,105,107,108,126 including results of a prematurely discontinued randomized controlled trial suggesting no effect of concomitant clopidogrel-proton-pump inhibitor therapy on cardiovascular outcomes;108,126 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.73,81,98,102,103,104,105,107,108,110,111,112,113,115,119,125,126

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.81,89,92,101,103,112,136 However, cimetidine should not be used as alternative therapy since it is a potent CYP2C19 inhibitor.89,100,101,112 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.76,100

Several observational studies involving large numbers of patients suggest that proton-pump inhibitors reduce the effectiveness of clopidogrel in preventing cardiovascular events.81,91,92,98,102,103,104,125 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 dischar this effect was not seen with pantoprazole, which does not inhibit CYP2C19.81,92,102,103,123 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.91,102,103,104 A subgroup analysis in one of these studies104 revealed that each proton-pump inhibitor (omeprazole, esomeprazole, pantoprazole, lansoprazole) was individually associated with an increased risk of cardiovascular events.103,104 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.98,102,103,125

Data discounting the clinical importance of a clopidogrel-proton-pump inhibitor interaction also have been reported.105,108,110,112,113 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.110 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.105 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.107 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.20,100,108,112,113,123,126

Repaglinide

A metabolite of clopidogrel is a strong inhibitor of CYP2C8, and can increase systemic exposure to drugs cleared by CYP2C8, including repaglinide.1 Avoid concomitant use or initiate repaglinide at 0.5 mg before each meal and do not exceed total daily dose of 4 mg.1

Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors

Potential pharmacodynamic interaction (increased risk of bleeding).1

Warfarin

Potential pharmacodynamic interaction (increased risk of bleeding).1,6 Caution is advised.6,8

Description

Clopidogrel bisulfate, a thienopyridine derivative structurally and pharmacologically related to ticlopidine,1,2,3,4,6,8 is a platelet-aggregation inhibitor.1,2,6,11 Clopidogrel is a prodrug with its platelet-aggregation inhibitory activity dependent on hepatic transformation to an active thiol metabolite.1,2,6,8,11

Biotransformation occurs through a 2-step process where clopidogrel is initially oxidized to a 2-oxo-clopidogrel intermediate metabolite, then subsequently metabolized to the active thiol metabolite.1 This metabolic pathway has been shown to be mediated by several cytochrome P-450 isoenzymes (e.g., CYP2C19, CYP3A, CYP2B6, CYP1A2).1 In particular, the CYP2C19 isoenzyme is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate.1

Clopidogrel is an ADP-receptor antagonist; the active metabolite of clopidogrel binds selectively and noncompetitively to a low-affinity, P2Y12 ADP-receptor binding site on the surface of platelets,1,2,4,6,11 thereby inhibiting ADP binding to the receptor and subsequent activation of the platelet glycoprotein (GP IIb/IIIa) complex necessary for fibrinogen-platelet binding.1,2,4,6,8 Clopidogrel also inhibits ADP-mediated release of platelet dense granule (e.g., ADP, calcium, and serotonin) and alpha granule (e.g., fibrinogen and thrombospondin) contents that augment platelet aggregation.1,6 The low-affinity ADP receptor is irreversibly modified by the drug, so platelets exposed to clopidogrel remain affected for the remainder of their lifespan (about 7-10 days).1,2,4,6,62 Unlike aspirin, thienopyridine platelet-aggregation inhibitors such as clopidogrel and ticlopidine do not inactivate platelet cyclooxygenase to prevent synthesis of prostaglandin endoperoxides and thromboxane A.2,6,8,11

Clopidogrel is rapidly absorbed after oral administration;1 at least 50% of an oral dose is absorbed.1 Peak plasma concentrations of the active metabolite occur approximately 30-60 minutes following an oral dose.1 When clopidogrel 75 mg is administered daily, inhibition of platelet aggregation is apparent on the first day of therapy, with 40-60% inhibition being achieved at steady state between days 3-7.1,2,6,62 Following discontinuance of the drug, platelet aggregation and bleeding time generally return to baseline values within about 5 days.1,2,6

Pharmacogenomics

Genetic polymorphism of CYP2C19 can affect the pharmacokinetic and pharmacodynamic response to clopidogrel.1,78,79,80,82,83 Patients with at least one loss-of-function variant CYP2C19 allele (e.g., CYP2C19*2, CYP2C19*3) are described as poor or intermediate metabolizers of clopidogrel and have been shown to have lower plasma concentrations of active metabolite and diminished antiplatelet response, which in turn can lead to a higher incidence of major adverse cardiovascular events.1,78,79,80,81,82,83,90,117,118 (See Reduced Efficacy in Poor CYP2C19 Metabolizers under Cautions.) The prevalence of reduced-function CYP2C19 genotypes in the general population differs according to race and ethnicity; an estimated 2% of Whites, 4% of Black, and 14% of Chinese individuals are poor CYP2C19 metabolizers.1,121

Advice to Patients

• Importance of counseling patients about potential risks versus benefits of clopidogrel.1
• Importance of informing patients that they may bleed more easily and that a longer than normal time will be required to stop bleeding when taking clopidogrel.1
• Importance of informing patient not to discontinue therapy without consulting their prescribing clinician.1
• Importance of patient informing clinician about any unanticipated, prolonged, or excessive bleeding, or blood in urine or stool.1,6
• Importance of patient informing clinician about clopidogrel therapy before any surgery is scheduled.1,6
• Advise patients not to take omeprazole or esomeprazole while taking clopidogrel.1
• Importance of patient informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, particularly omeprazole or esomeprazole and drugs that affect bleeding (e.g., warfarin, NSAIAs).1,76,100,101,102,114
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Sanofi-Aventis/Bristol-Myers Squibb. Plavix^®, (clopidogrel bisulfate) tablets prescribing information. New York, NY; 2021 Mar.

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