Plavix

Generic Name: Clopidogrel Bisulfate
Class: Platelet-Aggregation Inhibitors
ATC Class: B01AC04

• 
  

  Clopidogrel is a prodrug; requires activation by CYP enzyme system (principally by CYP2C19) to produce its pharmacologically active metabolite.^{1 2 6 8 11 121}

  
  


• 
  

  Genetic variations of CYP2C19 can result in impaired metabolism and reduced effectiveness of clopidogrel.^{1 121} (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions.) Higher rates of major adverse cardiovascular events (e.g., death, MI, stroke) have been reported in poor metabolizers of CYP2C19 receiving clopidogrel at recommended dosages following acute coronary syndrome or PCI compared with those who have normal CYP2C19 function.^{1 121}

  
  


• 
  

  Genetic tests are available to determine a patient's CYP2C19 genotype; results of such tests may be used to guide treatment decisions.^{1 20 121 122}

  
  


• 
  

  Consider use of other antiplatelet agents or alternative dosing strategies for clopidogrel in patients with variant CYP2C19 genotypes.^{1 121}

  
  

REMS:

FDA approved a REMS for clopidogrel to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Platelet-aggregation inhibitor; thienopyridine derivative.¹

Uses for Plavix

Cardiovascular Risk Reduction Following Recent Myocardial Infarction or Stroke or in Established Peripheral Arterial Disease

Reduction of the risk of cardiovascular or cerebrovascular events (new MI, new ischemic stroke, and vascular death) in patients with a history of recent MI, recent ischemic stroke, or established peripheral arterial disease.^{1 2 6 8 15 23 25 27} Recommended as an alternative to aspirin in those with aspirin allergy.^{10 14 17 21 25 26 28 30}

Clopidogrel monotherapy or aspirin in combination with dipyridamole may be preferable to aspirin monotherapy for secondary prevention of stroke based on a somewhat greater absolute risk reduction for stroke; weigh benefit against additional costs of therapy.^{25 63}

In patients with peripheral arterial disease, clopidogrel recommended over ticlopidine or no antiplatelet therapy for prevention of death and disability from stroke or MI.²⁹

In children who have recurrent arterial ischemic strokes or TIAs despite aspirin therapy, ACCP suggests changing from aspirin therapy to clopidogrel or an anticoagulant, such as a low molecular weight heparin or warfarin.⁶³

Use of aspirin rather than clopidogrel for most patients requiring long-term antiplatelet therapy is suggested by many clinicians because of lower cost and modest additional benefit of clopidogrel over aspirin.^{5 8 10 20 23 29 66 71}

Acute Coronary Syndromes: Unstable Angina or Non-ST-Segment Elevation MI

Used in combination with aspirin for reduction of the risk of cardiovascular or cerebrovascular events in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (NSTE ACS), including unstable angina and non-ST-segment-elevation MI (NSTEMI).^{1 5 10 14 17 18 21 26 28 30 34 35 39 64 65 66} Used in patients who are managed medically or with coronary intervention (e.g., PCI with or without coronary artery stenting, CABG).^{1 5 10 18 21 26 28 30 34 35 39 40}

Long-term use recommended by ACCP as an alternative to aspirin in patients with unstable angina or NSTEMI, including those undergoing CABG, who are allergic to aspirin†.^{10 14 17 26 28 30}

Recommended by ACC/AHA and other clinicians as an adjunct to acute therapy with heparin and aspirin in patients with NSTE ACS who are managed medically and in those undergoing PCI who are not at high risk for bleeding.^{18 21 34 39}

Dual-drug antiplatelet therapy (aspirin plus clopidogrel or prasugrel) recommended by ACC/AHA for patients with definite or likely NSTEMI in whom an invasive approach is selected.¹³⁴ Begin treatment as early as possible before or at the time of PCI and continue for ≥1 month, ideally ≤1 year in patients who are not at high risk for bleeding.¹³⁴

Balance potential benefit of pretreatment with clopidogrel in patients undergoing PCI against increased risk of bleeding should emergency CABG be needed.^{28 34 35} Temporarily discontinue therapy 5–10 days prior to CABG and reinitiate therapy in conjunction with aspirin after the procedure.^{26 30 35 40 66 69}

In patients undergoing PCI with an absolute contraindication to aspirin†, ACCP states that pretreatment with clopidogrel and/or a GP IIb/IIIa-receptor inhibitor is reasonable.⁶⁴ (See General under Dosage and Administration.)

Following implantation of a bare-metal coronary artery stent in patients at low risk for bleeding, ACC/AHA currently recommend use in combination with aspirin for ≥1 month, ideally for ≤12 months.¹³⁴

In patients at low atherosclerotic risk, ACCP recommends combination therapy with aspirin for ≥2 weeks after implantation of a bare-metal stent.²⁸

Following bare-metal stent placement in patients at high risk for bleeding, ACC/AHA recommend short-term (a minimum of 2 weeks) therapy with clopidogrel and aspirin.¹³⁴

Prolonged dual-drug therapy (≥12 months) with clopidogrel and aspirin recommended in patients with drug-eluting stents (DES) who are not at high risk of bleeding.^{43 44 45 46 50 51 52 54 134} (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.)

Acute Coronary Syndromes: ST-Segment Elevation MI

Used in combination with aspirin for reduction of the rate of ischemic cardiovascular and cerebrovascular events in patients with ST-segment elevation MI (STEMI).^{1 10 27 31 36 67 134} Net benefits of a particular thienopyridine (clopidogrel or prasugrel) in patients with STEMI undergoing PCI not fully elucidated; ACC/AHA state that choice of clopidogrel or prasugrel in individual patients should take into account antithrombotic efficacy, bleeding risk, and clinician experience with a given drug.¹³⁴

Recommended by ACCP, ACC, AHA, and other clinicians for 14–28 days in addition to aspirin, with or without reperfusion therapy (i.e., thrombolytic therapy, primary PCI), in patients with suspected acute STEMI.^{67 68} ACCP suggests continuance of clopidogrel and aspirin beyond 28 days and up to 1 year in patients with STEMI who have not undergone stent implantation.⁶⁷

In patients in whom CABG is planned, withhold clopidogrel for at least 5 days and preferably for 7–10 days prior to surgery unless urgency of revascularization outweighs risks of excess bleeding.^{69 134}

Suggested as adjunct to thrombolytic therapy in patients with acute STEMI who are allergic to aspirin or in whom aspirin is otherwise contraindicated.^{10 23 27}

In patients with STEMI in whom PCI is planned, ACC/AHA and ACCP recommend pretreatment with a loading dose of a thienopyridine derivative (e.g., clopidogrel, prasugrel) before or at the time of PCI in conjunction with aspirin therapy.^{67 134}

Recommended by ACC/AHA in combination with aspirin as short-term prophylaxis (≥ 1 month) in patients with STEMI who have undergone PCI with bare-metal coronary artery stent implantation.^{39 134}

Ideally, use long term (≥12 months) in conjunction with aspirin therapy in patients with STEMI who have undergone PCI with bare-metal stent implantation and are at low risk of bleeding.¹³⁴

Recommended as short-term (minimum of 2 weeks) therapy with aspirin in patients with STEMI who have undergone PCI with bare-metal stent implantation and are at high risk of bleeding.¹³⁴

Prolonged (≥12 months) prophylaxis in combination with aspirin strongly recommended in patients who have undergone PCI with DES implantation and are not at high risk of bleeding.^{43 44 45 46 50 51 52 54 134} (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.) Consider continuation of thienopyridine therapy beyond 15 months in patients with drug-eluting stents; may use abbreviated period of thienopyridine therapy (less than 12 months) in patients with STEMI and a drug-eluting stent in whom the risk of morbidity due to bleeding outweighs the anticipated benefit of such therapy.¹³⁴

Triple antithrombotic therapy with clopidogrel, low-dose aspirin, and warfarin anticoagulation† (target INR 2–2.5) recommended, based on case studies or expert opinion, in patients who have indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical heart valves) and who require clopidogrel and aspirin after PCI.^{23 42 65} In patients who have undergone stent placement and have indications for anticoagulation, warfarin (INR 2–3) and aspirin suggested in addition to clopidogrel;^{23 42 66} continue clopidogrel therapy for 4 weeks or 1 year following bare-metal or drug-eluting stent implantation, respectively, in addition to warfarin and aspirin.⁶⁶ Such triple antithrombotic regimens are associated with an increased risk of bleeding; monitor closely.^{65 70}

Suggested by American Diabetes Association (ADA) as alternative to aspirin for primary prevention of MI† 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, and elevated blood cholesterol or triglyceride concentrations).⁹⁵ Recommended by ACCP for primary prevention of cardiovascular events as an alternative to aspirin for aspirin-allergic patients who are at moderate to high risk for cardiovascular events.⁶⁶

Chronic Stable Angina

Use in combination with aspirin suggested by ACCP for reduction of the risk of AMI in high-risk patients with symptomatic chronic stable angina†.²⁶

Used as an alternative to aspirin in patients with symptomatic chronic stable angina who cannot tolerate aspirin†.⁹⁶

Other Uses

Aspirin generally recommended for all clinical conditions in which antiplatelet prophylaxis has a favorable benefit-to-risk profile.^{5 8 10 11} However, use recommended by ACCP as alternative and/or adjunctive antithrombotic therapy in selected patients with a number of atherosclerotic and ischemic conditions,^{13 14 15 16 17} including rheumatic mitral valve disease† ^{13 24} and saphenous vein CABG†.^{14 26 30 40}

Use in combination with aspirin in patients undergoing brachytherapy for restenosis following PCI and coronary artery stent implantation† suggested by ACC/AHA.³⁴

Considered a reasonable choice for antiplatelet therapy in high-risk patients with prosthetic heart valves in whom aspirin cannot be used† or in patients with prosthetic heart valves receiving aspirin who have breakthrough embolic events†.⁴¹

Plavix Dosage and Administration

General

Timing of Treatment in Relation to PCI or CABG

• 
  

  In patients with ACS in whom PCI is planned, ACC/AHA recommend administration of a loading dose of clopidogrel as early as possible before or at the time of the procedure.¹³⁴

  
  


• 
  

  Temporarily discontinue therapy 5–10 days prior to CABG and reinitiate clopidogrel in conjunction with aspirin after the procedure.^{26 30 35 40 69 134}

  
  

Administration

Administer orally without regard to meals.^{1 6 8}

Dosage

Available as clopidogrel bisulfate; dosage expressed in terms of clopidogrel.¹

Pharmacogenomic factors can influence response to clopidogrel; although a higher dosage or administration of additional loading doses may increase the antiplatelet response in patients who are poor metabolizers, manufacturer states that an appropriate dosage of the drug in such patients has not been determined.^{1 121 123 130} (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions.)

Adults

Cardiovascular Risk Reduction Following Recent MI or Stroke or in Established Peripheral Arterial Disease

Oral

75 mg once daily.^{1 2 3 5 6 8 23 25 26}

Acute Coronary Syndromes

Unstable Angina or Non-ST-Segment Elevation MI

Oral

300-mg initial loading dose promptly at diagnosis, then 75 mg daily given with aspirin daily for ≥1 month, ideally for ≤1 year in patients at low risk of bleeding.^{1 17 18 20 21 22 26 34 39 64 66}

Most patients generally have received concomitant heparin acutely.^{1 18}

Patients allergic to or intolerant of aspirin†: 300-mg loading dose, then 75 mg daily continued indefinitely.^{10 14 17 21 26 28 30 64}

Planned PCI: 300–600 mg as loading dose as early as possible prior to or at time of the procedure with aspirin, then 75 mg once daily for ≤1 year in patients at low risk of bleeding.^{64 66 134} Larger loading doses (e.g., ≥900 mg) used to achieve higher level of antiplatelet activity more rapidly, but efficacy and safety not established.^{64 134}

Planned PCI in patients unable to tolerate aspirin†: 600-mg loading dose ≥24 hours prior to procedure, followed by 75 mg once daily.⁶⁴

Patients undergoing CABG: 75 mg once daily with aspirin, beginning postoperatively and continuing for 9–12 months.⁶⁶

Patients undergoing CABG who are allergic to aspirin: ACCP recommends initiation of a 300-mg loading dose of clopidogrel 6 hours after the procedure, followed by 75 mg once daily, continued indefinitely.⁶⁶

Following bare-metal stent implantation: 75 mg once daily with aspirin for ≥1 month.¹³⁴ Ideally, continue for ≤12 months in conjunction with daily aspirin therapy in patients at low risk for bleeding.¹³⁴ In patients in whom a high risk of bleeding is deemed to outweigh anticipated benefit, administer clopidogrel with aspirin for a minimum of 2 weeks.¹³⁴

Following drug-eluting stent (DES) implantation: 75 mg once daily with aspirin for ≥12 months in patients not at high risk for bleeding.^{43 44 45 46 50 51 52 54 66 134} (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.)

ST-Segment Elevation MI

Oral

Usual recommended dosage: 75 mg once daily with or without a loading dose in combination with aspirin.^{1 39 67 134} ACCP recommends a clopidogrel loading dose of 300 mg in patients ≤75 years of age;⁶⁷ loading dose for patients >75 years of age not established.¹³⁴

ACC/AHA state that clopidogrel should be continued as the thienopyridine of choice in patients with STEMI who will undergo PCI and have already received clopidogrel and thrombolytic therapy.¹³⁴

Patients with STEMI who have received any thrombolytic agent (fibrin-specific or not) and in whom PCI is planned within 24 hours: ACC/AHA recommend a clopidogrel loading dose of 300 mg.¹³⁴

Patients with STEMI receiving a non-fibrin-specific thrombolytic agent who will undergo PCI within 24–48 hours: ACC/AHA recommend a clopidogrel 300-mg loading dose.¹³⁴

Patients with STEMI who have received a fibrin-specific thrombolytic agent and will undergo PCI >24 hours later: ACC/AHA recommend a clopidogrel loading dose of 300–600 mg.¹³⁴

Patients with STEMI who have received a non-fibrin-specific thrombolytic agent and will be undergoing PCI >48 hours later: ACC/AHA recommend a clopidogrel loading dose of 300–600 mg.¹³⁴

Patients with STEMI who have not received thrombolytic or thienopyridine therapy and who will undergo nonprimary PCI: ACC/AHA recommend a clopidogrel loading dose of 300–600 mg.¹³⁴

Patients allergic to or intolerant of aspirin†: 75 mg of clopidogrel once daily indefinitely as an adjunct to thrombolytic therapy.⁶⁶

Planned PCI: ACC/AHA recommend a loading dose of 300–600 mg as early as possible before or at the time of PCI in conjunction with aspirin therapy.¹³⁴ Larger loading doses (e.g., ≥900 mg) have been used to achieve higher level of antiplatelet activity more rapidly, but efficacy and safety not established.^{67 134}

Following bare-metal stent implantation: 75 mg once daily with aspirin for ≥1 month.^{66 134} Ideally, continue for ≤12 months in conjunction with daily aspirin therapy in patients at low risk for bleeding.^{66 134} In patients at high risk for bleeding, administer clopidogrel and aspirin for a minimum of 2 weeks.¹³⁴

Following DES implantation: 75 mg once daily with aspirin for ≤1 month.^{66 134} Continue for ≥12 months with aspirin in patients not at high risk for bleeding.^{28 43 44 45 46 50 51 52 54 66 134}

Special Populations

Geriatric Patients

No dosage adjustment necessary.¹

Hepatic Impairment

No dosage adjustment necessary.¹

Cautions for Plavix

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

Compliance with Therapy in Patients with Drug-eluting Stents

Stent thrombosis with potentially fatal sequelae, particularly with DES, associated with premature discontinuance of therapy with a thienopyridine derivative and aspirin.^{43 44 45 46 47 48 49 54} (See Acute Coronary Syndromes: Unstable Angina or Non-ST-Segment Elevation MI under Uses.)

Before implantation of a DES, carefully assess patients for likelihood of compliance with prolonged dual-drug antiplatelet therapy.^{45 59} Consider avoiding use of a DES in patients who are not expected to comply.^{45 59} (See Advice to Patients.) In patients who are likely to require invasive or surgical procedures ≤12 months after DES implantation, consider implantation of a bare-metal stent or use of balloon angioplasty with provisional stent implantation instead.⁴⁵

Clinicians performing invasive procedures must understand the consequences of premature discontinuance of thienopyridine derivative therapy in patients with DES.⁴⁵ If issues about a patient’s antiplatelet therapy are unclear (e.g., concern about periprocedural bleeding), such professionals should contact the patient’s cardiologist.⁴⁵ Defer elective procedures with substantial bleeding risk until completion of dual-drug antiplatelet therapy.⁴⁵ For non-elective procedures that mandate discontinuance of thienopyridine-derivative therapy, continue aspirin therapy if at all possible.⁴⁵ Restart thienopyridine therapy as soon as possible after the procedure.⁴⁵

Reduced Efficacy Associated with Impaired CYP2C19 Function

Possible reduced efficacy of clopidogrel (i.e., increased risk of cardiovascular events) due to genetic polymorphism of CYP2C19 or concurrent use of drugs (e.g., omeprazole) that inhibit CYP2C19.^{1 72 76 78 79 80 81 82 83 84 85 86 100 101 121} Consider use of other antiplatelet agents or alternative dosing strategies for clopidogrel in patients with variant CYP2C19 genotypes.^{1 121 123} (See Boxed Warning.)

Specific variant alleles of CYP2C19 (e.g., CYP2C19*2, CYP2C19*3) associated with reduced metabolism of and diminished antiplatelet response to clopidogrel; data on clinical outcomes are conflicting, but higher rates of major adverse cardiovascular events (e.g., death, MI, stroke, stent thrombosis) reported in patients receiving recommended dosages of clopidogrel who possess such alleles.^{1 76 78 79 80 82 83 88 89 90 92 104 117 118 121} (See Actions.) Genetic tests (e.g., Plavitest) are available to identify patients with variant CYP2C19 genotypes.^{1 20 121 122} While such tests are appropriate for any patient currently receiving or considering treatment with clopidogrel, the need for pharmacogenetic testing should be determined individually.^{121 122 123} Genetic variants of other CYP isoenzymes (e.g., CYP2C19*17, CYP2B6) also may affect response to clopidogrel.^{1 78 123 131} Role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and proton-pump inhibitors not established.¹³⁶

Concurrent use of clopidogrel and omeprazole, a potent inhibitor of CYP2C19, also shown to reduce antiplatelet effects of clopidogrel.^{1 72 79 84 88 89 98 100 101 102 103 109} (See Proton-Pump Inhibitors under Interactions.) Clinical importance not fully elucidated, but reduced effectiveness in preventing cardiovascular events possible.^{1 73 74 81 89 91 92 98 100 101 102 103 115} Concomitant use of other drugs that inhibit CYP2C19 also may decrease response to clopidogrel.^{1 100 101} (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.) Avoid concomitant therapy with known inhibitors of CYP2C19 activity.^{1 20 101}

Thrombotic Thrombocytopenic Purpura (TTP)

Rarely reported, sometimes after short exposure (<2 weeks) to the drug.^{1 11 12} Potentially fatal; requires urgent treatment, including plasmapheresis.¹

General Precautions

Bleeding

Increased risk of bleeding.^{1 136 138}

Discontinue clopidogrel 5–10 days prior to elective surgery if antiplatelet effect is undesirable.^{1 23 43 68 69}

May restore hemostasis with exogenous administration of platelets; however, platelet transfusions within 4 hours of a loading dose or within 2 hours of a maintenance dose may have reduced effectiveness.¹

Bleeding is unlikely to be resolved or prevented by withholding a dose of clopidogrel because of the drug's prolonged inhibitory effects on platelet function.¹

American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) recommends prophylactic proton-pump inhibitor therapy to reduce risk of ulcer complications and GI bleeding in patients with additional GI risk factors receiving clopidogrel and aspirin.^{81 87 89 136} However, consider possibility of reduced antiplatelet effects when clopidogrel is used concomitantly with a proton-pump inhibitor (e.g., omeprazole).^{1 76 100 101} (See Interactions: Proton-Pump Inhibitors.)

Risks of Interruption or Discontinuance of Therapy

In general, treatment with a thienopyridine derivative should not be discontinued prematurely because of the increased risk of cardiovascular events.¹ (See Compliance with Therapy in Patients with Drug-eluting Stents under Cautions.)

Advise patient to never stop clopidogrel therapy without first consulting prescribing clinician.^{1 45}

If temporary discontinuance is necessary (e.g., prior to surgery), reinitate therapy as soon as possible.¹ (See Advice to Patients.)

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Manufacturer states that safety and efficacy not established in patients <21 years of age.^{1 20}

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 reported.⁹⁷

Geriatric Use

In patients ≥75 years of age, no difference in platelet aggregation observed compared with younger healthy individuals.¹ In a clinical trial, geriatric patients were at greater risk for thrombotic events and major bleeding than younger 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 limited in patients with moderate or severe renal impairment.¹

Inhibition of ADP-induced platelet aggregation is decreased in patients with moderate (Cl_cr 30–60 mL/minute) or severe (Cl_cr 5–15 mL/minute) renal impairment.¹

Common Adverse Effects

Chest pain,^{1 6} accidental injury,^{1 6} influenza-like symptoms,^{1 6} pain,^{1 6} headache,^{1 6} dizziness,^{1 6} abdominal pain,^{1 6 8} dyspepsia,^{1 2 3 6 8} diarrhea,^{1 2 3 6 8 10 11} nausea,^{1 2 3 6} arthralgia,^{1 6} back pain,^{1 6} purpura,^{1 6} upper respiratory tract infection,^{1 6} rash,^{1 2 3 6 8 10 11} pruritus.^{1 6}

Interactions for Plavix

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Appears to inhibit CYP2C9 isoenzyme in vitro at high concentrations.^{1 8 20}

Converted to active metabolite by CYP2C19.^{1 72 78 80 81 82 83} (See Metabolism under Pharmacokinetics.) Potential pharmacokinetic (decreased concentrations of active metabolite) and pharmacodynamic (reduced antiplatelet effects) interaction with inhibitors of CYP2C19.^{1 72 76 81 88 89} Avoid concomitant use of drugs (e.g., omeprazole) known to be potent inhibitors of CYP2C19.^{1 20 101}

Proton-Pump Inhibitors

Potential for reduced systemic exposure to clopidogrel's active metabolite and reduced antiplatelet effects with certain proton-pump inhibitors (via inhibition of CYP2C19 by proton-pump inhibitor).^{1 20 72 73 74 84 86 88 89 91 100 101 102 103 106 107 109} (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions and see Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.) Interaction demonstrated with omeprazole, but not consistently observed with other proton-pump inhibitors.^{1 20 72 79 84 88 102 103 106 109} Conflicting data on clinical outcomes reported, but increased risk of adverse cardiovascular events possible.^{1 72 73 74 81 91 98 102 103 104 105 107 108 110 111 112 113 115 119}

Based on currently available information, FDA and manufacturer of clopidogrel state that concomitant use (including separation of administration times) of clopidogrel and omeprazole should be avoided.^{1 100 101 113} FDA also states that esomeprazole should be avoided in patients receiving clopidogrel because of its potent CYP2C19-inhibitory activity.¹⁰¹ Extent to which other proton-pump inhibitors, which differ in CYP2C19-inhibitory potency, also may interfere with clopidogrel’s effects is unknown.^{100 106 114} If concomitant proton-pump inhibitor therapy is considered necessary, pantoprazole (which appears to be the weakest inhibitor of CYP2C19 among proton-pump inhibitors) has been suggested by some clinicians.^{81 89 92 102 103 109 111 112 114} However, weigh risks and benefits of concomitant use of any proton-pump inhibitor in individual patients.^{102 103 112 119} 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.¹³⁶ Risk/benefit tradeoff may favor concomitant use of dual antiplatelet therapy and a proton-pump inhibitor in stable patients with a history of GI bleeding who undergo coronary revascularization and receive a coronary stent.¹³⁶ ACCF/ACG/AHA 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 drugs (NSAIDs); H. pylori infection) and may outweigh potential reduction in cardiovascular efficacy of antiplatelet treatment associated with a drug–drug interaction.¹³⁶ In patients without such risk factors for GI bleeding, risk/benefit balance may favor use of antiplatelet therapy without a concomitant proton-pump inhibitor.¹³⁶ Alternatively, consider concomitant therapy with antacids or H₂-receptor antagonists (i.e., ranitidine, famotidine, nizatidine), except for cimetidine (also a potent CYP2C19 inhibitor).^{1 81 89 92 100 103 112}

Specific Drugs

Drug	Interaction	Comments
Antacids	Currently no evidence that antacids interfere with antiplatelet effects of clopidogrel101
Cilostazol	Potential additive antiplatelet effects93 94 Pharmacokinetic interaction unlikely19 93	Caution advised; monitor bleeding times during concurrent administration93
Dexlansoprazole	Reduced efficacy observed with concomitant clopidogrel and omeprazole; extent to which other proton-pump inhibitors also may interfere with clopidogrel’s effects is unknown1 100 101 106 114	FDA states that insufficient information available to make specific recommendations about concomitant use with clopidogrel100
Esomeprazole	Possible decreased plasma concentrations of clopidogrel's active metabolite and diminished antiplatelet effect101	FDA recommends that concomitant use be avoided101
Histamine H2-receptor antagonists (ranitidine, famotidine, nizatidine)	Currently no evidence that H2-receptor antagonists (except cimetidine) interfere with antipl