|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
Special Alerts
Statement Released Regarding Clopidogrel-Proton Pump Inhibitor (PPI) Interaction
November 2010
The American College of Cardiology Foundation, in conjunction with the American College of Gastroenterology and the American Heart Association, has issued a consensus document regarding the concomitant use of PPIs and thienopyridines, specifically clopidogrel.
The following highlighted recommendations are discussed within this consensus statement:
- Clopidogrel alone, aspirin alone, and their combination are associated with an increased risk of GI bleeding.
- Risk of GI bleeding increases as the number of risk factors increase (eg, prior GI bleeding, advanced age, concurrent use of anticoagulants).
- PPIs are appropriate in patients with multiple risk factors for GI bleeding who are also receiving antiplatelet therapy (eg, clopidogrel).
- Although pharmacokinetic and pharmacodynamic studies have demonstrated varying effects of PPIs on the extent of clopidogrel metabolic conversion to the active metabolite, no evidence has established clinically meaningful differences in outcomes.
- A clinically-significant interaction cannot be excluded in subgroups who are poor metabolizers of clopidogrel.
- Until solid evidence exists to support staggering PPIs with clopidogrel, the dosing of PPIs should not be altered.
Healthcare professionals must evaluate the risks and benefits of concomitant use of PPIs and thienopyridines, considering both the cardiovascular and GI complications. For more information, healthcare professionals may refer to the following website: http://content.onlinejacc.org/cgi/reprint/j.jacc.2010.09.010v1.pdf
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(kloh PID oh grel)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM243349.pdf, must be dispensed with this medication.
REMS Components
Medication Guide
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Reduces rate of atherothrombotic events (myocardial infarction, stroke, vascular deaths) in patients with recent MI or stroke, or established peripheral arterial disease; reduces rate of atherothrombotic events in patients with unstable angina (UA) or non-ST-segment elevation (NSTEMI) managed medically or with percutaneous coronary intervention (PCI) (with or without stent) or CABG; reduces rate of death and atherothrombotic events in patients with ST-segment elevation MI (STEMI) managed medically
Use: Unlabeled/Investigational
In patients with allergy or major gastrointestinal intolerance to aspirin, initial treatment of acute coronary syndromes (ACS) or prevention of coronary artery bypass graft closure (saphenous vein)
Pregnancy Risk Factor
B
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. Use during pregnancy only if clearly needed.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to clopidogrel or any component of the formulation; active pathological bleeding such as peptic ulcer or intracranial hemorrhage
Canadian labeling: Additional contraindications (not in U.S. labeling): Significant liver impairment or cholestatic jaundice
Warnings/Precautions
Boxed warnings:
• Reduced CYP2C19 function: See “Special populations” below.
Concerns related to adverse effects:
• Bleeding: Clopidogrel increases the risk of bleeding. Use is contraindicated in patients with active pathological bleeding or intracranial hemorrhage. Additional risk factors for bleeding include age ≥75 years, propensity to bleed (eg, recent trauma or surgery, recent or recurrent GI bleeding, active PUD, severe hepatic impairment), body weight <60 kg, CABG or other surgical procedure, concomitant use of medications that increase risk of bleeding (eg, warfarin, NSAIDs). Bleeding should be suspected if patient becomes hypotensive after undergoing recent coronary angiography, PCI, CABG, or other surgical procedure even if overt signs of bleeding do not exist.
• Thrombotic thrombocytopenic purpura (TTP): Cases of TTP (usually occurring within the first 2 weeks of therapy), resulting in some fatalities, have been reported; urgent plasmapheresis is required.
Disease-related concerns:
• Bleeding disorders: Use with caution in patients with platelet disorders, bleeding disorders and/or at increased risk for bleeding (eg, PUD, trauma, or surgery).
• Hepatic impairment: Use with caution in patients with severe hepatic impairment (experience is limited). Use in patients with severe hepatic impairment or cholestatic jaundice is contraindicated in the Canadian labeling.
• Renal impairment: Use with caution in patients with severe renal impairment (experience is limited).
Concurrent drug therapy issues:
• Anticoagulants and platelet aggregation inhibitors: Use with caution in patients receiving either anticoagulants (eg, heparin, warfarin) or other platelet aggregation inhibitors; bleeding risk is increased.
• Aspirin: Concurrent use of aspirin and clopidogrel is not recommended for secondary prevention of ischemic stroke or TIA in patients unable to take oral anticoagulants due to hemorrhagic risk (Furie, 2011).
• CYP2C19 inhibitors: Concurrent use with drugs known to inhibit CYP2C19 (eg, proton pump inhibitors) may reduce levels of active metabolite and subsequently reduce clinical efficacy and increase the risk of cardiovascular events; if possible, avoid concurrent use of moderate-to-strong CYP2C19 inhibitors. In patients requiring antacid therapy, consider use of an acid-reducing agent lacking (eg, ranitidine) or with less CYP2C19 inhibition. If a PPI is necessary, the use of pantoprazole, a weak CYP2C19 inhibitor, has been shown to have less of an effect on the pharmacologic activity of clopidogrel. Of the PPIs, lansoprazole exhibits the most potent CYP2C19 inhibitory effects (Li, 2004).
Special populations:
• Reduced CYP2C19 function: [U.S. Boxed Warning]: Patients with one or more copies of the variant
CYP2C19*2
and/or
CYP2C19*3
alleles (and potentially other reduced-function variants) may have reduced conversion of clopidogrel to its active thiol metabolite. Lower active metabolite exposure may result in reduced platelet inhibition and, thus, a higher rate of cardiovascular events following MI or stent thrombosis following PCI. Although evidence is insufficient to recommend routine genetic testing, tests are available to determine CYP2C19 genotype and may be used to determine therapeutic strategy; alternative treatment or treatment strategies may be considered if patient is identified as a CYP2C19 poor metabolizer. Genetic testing may be considered prior to initiating clopidogrel in patients at moderate or high risk for poor outcomes (eg, PCI in patients with extensive and/or very complex disease). The optimal dose for CYP2C19 poor metabolizers has yet to be determined. After initiation of clopidogrel, functional testing (eg, VerifyNow® P2Y12 assay) may also be done to determine clopidogrel responsiveness (Holmes, 2010).
Other warnings/precautions:
• Coronary artery stents: Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. Duration of therapy, in general, is determined by the type of stent placed (bare metal or drug eluting) and whether an ACS event was ongoing at the time of placement.
• Elective surgery: Consider discontinuing 5 days before elective surgery (except in patients with cardiac stents that have not completed their full course of dual antiplatelet therapy; patient-specific situations need to be discussed with cardiologist; AHA/ACC/SCAI/ACS/ADA Science Advisory provides recommendations).
Adverse Reactions
As with all drugs which may affect hemostasis, bleeding is associated with clopidogrel. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the concurrent use of multiple agents which alter hemostasis and patient susceptibility.
3% to 10%:
Dermatologic: Rash (4%), pruritus (3%)
Hematologic: Bleeding (major 4%; minor 5%), purpura/bruising (5%), epistaxis (3%)
1% to 3%:
Gastrointestinal: GI hemorrhage (2%)
Hematologic: Hematoma
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Acute liver failure, agranulocytosis, anaphylactoid reaction, angioedema, aplastic anemia, arthralgia, arthritis, bronchospasm, bullous eruption, colitis (including ulcerative or lymphocytic), confusion, creatinine increased, eczema, erythema multiforme, fever, glomerulopathy, hallucination, hemorrhagic stroke (≤0.2%), hepatitis, hypersensitivity reaction, hypotension, interstitial pneumonitis, intracranial hemorrhage (≤0.4%), lichen planus, liver function tests (abnormal), musculoskeletal bleeding, myalgia, ocular bleeding (including conjunctival and retinal), pancreatitis, pancytopenia, pulmonary hemorrhage, rash (erythematous or maculopapular), retroperitoneal hemorrhage, serum sickness, Stevens-Johnson syndrome, stomatitis, taste disorder, thrombotic thrombocytopenic purpura (TTP), toxic epidermal necrolysis, vasculitis, wound hemorrhage
Metabolism/Transport Effects
Substrate of CYP2C19, 3A4, 1A2 (minor); Inhibits CYP2B6 (moderate), 2C9 (weak)
Drug Interactions
Amiodarone: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk C: Monitor therapy
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
Calcium Channel Blockers: May diminish the therapeutic effect of Clopidogrel. Exceptions: Clevidipine. Risk C: Monitor therapy
Collagenase (Systemic): Antiplatelet Agents may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
CYP2B6 Substrates: CYP2B6 Inhibitors (Moderate) may decrease the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
CYP2C19 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy
Dexlansoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Risk D: Consider therapy modification
Drotrecogin Alfa: Antiplatelet Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Management: When possible, avoid use of drotrecogin within 7 days of use of any IIb/IIIa antagonists, higher dose aspirin (more than 650 mg/day), or use of other antiplatelet agents. Risk D: Consider therapy modification
Esomeprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Risk D: Consider therapy modification
Glucosamine: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Antiplatelet Agents. Bleeding may occur. Risk D: Consider therapy modification
Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Lansoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Risk D: Consider therapy modification
Macrolide Antibiotics: May diminish the therapeutic effect of Clopidogrel. Exceptions: Azithromycin; Azithromycin (Systemic); Spiramycin. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Omeprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
Pantoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Risk D: Consider therapy modification
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
RABEprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Risk D: Consider therapy modification
Rifamycin Derivatives: May enhance the therapeutic effect of Clopidogrel. Risk C: Monitor therapy
Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy
Warfarin: Clopidogrel may enhance the anticoagulant effect of Warfarin. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, chamomile, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng (American), ginseng (Panax), ginseng (Siberian), grape seed, green tea, guggul, horse chestnut seed, horseradish, licorice, prickly ash, red clover, reishi, SAMe (S-adenosylmethionine), sweet clover, turmeric, white willow (all have additional antiplatelet activity).
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Clopidogrel requires in vivo biotransformation to an active thiol metabolite. The active metabolite irreversibly blocks the P2Y12 component of ADP receptors on the platelet surface, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation. Platelets blocked by clopidogrel are affected for the remainder of their lifespan (~7-10 days).
Pharmacodynamics/Kinetics
Onset of action: Inhibition of platelet aggregation (IPA): Dose-dependent:
300-600 mg loading dose: Detected within 2 hours
50-100 mg/day: Detected by the second day of treatment
Peak effect: Time to maximal IPA: Dose-dependent: Note: Degree of IPA based on adenosine diphosphate (ADP) concentration used during light aggregometry:
300-600 mg loading dose:
ADP 5 μmol/L: 20% to 30% IPA at 6 hours post administration (Montelescot, 2006)
ADP 20 μmol/L: 30% to 37% IPA at 6 hours post administration (Montelescot, 2006)
50-100 mg/day: ADP 5 μmol/L: 50% to 60% IPA at 5-7 days (Herbert, 1993)
Absorption: Well absorbed
Protein binding: Parent drug: 98%; Inactive metabolite: 94%
Metabolism: Extensively hepatic via esterase-mediated hydrolysis to a carboxylic acid derivative (inactive) and via CYP450-mediated (CYP2C19 primarily) oxidation to a thiol metabolite (active)
Half-life elimination: Parent drug: ~6 hours; Active metabolite: ~30 minutes
Time to peak, serum: ~0.75 hours
Excretion: Urine (50%); feces (46%)
Dosage
Oral: Adults:
Recent MI, recent stroke, or established arterial disease: 75 mg once daily
Acute coronary syndrome (ACS):
Unstable angina, non-ST-segment elevation myocardial infarction (UA/NSTEMI): Initial: 300 mg loading dose, followed by 75 mg once daily for at least 1 month and ideally up to 12 months (in combination with aspirin 75-162 mg once daily indefinitely) (Wright, 2011).
ST-segment elevation myocardial infarction (STEMI): 75 mg once daily (in combination with aspirin 162-325 mg initially followed by 81-162 mg/day). Note: CLARITY-TIMI 28 used a 300 mg loading dose (with thrombolysis) demonstrating an improvement in patency rate of the infarct related artery and reduction in ischemic complications. The duration of therapy was <28 days (usually until hospital discharge) unless nonprimary percutaneous coronary intervention (PCI) was performed (Sabatine, 2005).
The American College of Chest Physicians (Goodman, 2008) recommends:
Patients ≤75 years: Initial: 300 mg loading dose, followed by 75 mg once daily for up to 28 days (in combination with aspirin)
Patients >75 years: 75 mg once daily for up to 28 days (with or without thrombolysis)
Percutaneous coronary intervention (PCI) for UA/NSTEMI or STEMI: Loading dose: 300-600 mg (600 mg may be preferred for early invasive strategy with UA/NSTEMI) given as early as possible before or at the time of PCI followed by 75 mg once daily; may consider a maintenance dose of 150 mg once daily for 6 days then 75 mg once daily thereafter in patients not at high risk for bleeding (CURRENT-OASIS 7 Investigators, 2010; Wright, 2011). Note: If an initial loading dose of 300 mg was given prior to PCI, a supplemental loading dose of 300 mg (total loading dose of 600 mg) may be administered (Kushner, 2009). For patients with UA/NSTEMI, it has been recommended that the loading dose be given at least 2 hours (or 24 hours in patients unable to take aspirin) prior to PCI (Chest guidelines, 2008).
Duration of clopidogrel (in combination with aspirin) after stent placement: Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. With STEMI, clopidogrel for at least 12 months regardless of stent type (ie, either bare metal or drug eluting stent) is recommended (Kushner, 2009). With UA/NSTEMI, at least 12 months of clopidogrel is recommended in patients receiving a drug eluting stent (DES) unless the risk of bleeding outweighs the benefits. For bare metal stent (BMS) placement, at least 1 month and ideally up to 12 months duration is recommended unless the risk of bleeding outweighs the benefits then a minimum of 2 weeks is recommended (Wright, 2011). In either setting, a duration >15 months may be considered in patients with DES placement (Kushner, 2009; Wright 2011). For patients without ongoing ACS, clopidogrel should be continued for at least 1 month (for BMS) or at least 12 months (for DES) (Becker, 2008).
CYP2C19 poor metabolizers (ie, CYP2C19*2 or *3 carriers): An appropriate regimen for this patient population has not been established in clinical outcome trials; however, a higher dose regimen of 600 mg loading dose followed by 150 mg once daily has demonstrated an increase in antiplatelet response in this patient population.
Prevention of coronary artery bypass graft closure (saphenous vein) [Chest guidelines, 2008]: Aspirin-allergic patients (unlabeled use): Loading dose: 300 mg administered 6 hours following procedure; maintenance: 75 mg/day
Dosing adjustment in renal impairment and elderly: None necessary
Dosing adjustment in hepatic impairment: Use with caution; experience is limited. Note: Inhibition of ADP-induced platelet aggregation and mean bleeding time prolongation were similar in patients with severe hepatic impairment compared to healthy subjects after repeated doses of 75 mg once daily for 10 days.
Administration: Oral
May be administered without regard to meals.
Monitoring Parameters
Signs of bleeding; hemoglobin and hematocrit periodically. Consider platelet function testing to determine platelet inhibitory response if results of testing may alter management (Wright, 2011).
Dietary Considerations
May be taken without regard to meals.
Patient Education
May cause headache or dizziness. It may take longer than usual to stop bleeding. Inform prescribers and dentists that you are taking this medication prior to scheduling any surgery or dental procedure. Report immediately unusual or acute chest pain or respiratory difficulties; skin rash; unresolved bleeding, diarrhea, or GI distress; nosebleed; or acute headache.
Geriatric Considerations
Plasma concentrations of the main metabolite of clopidogrel were significantly higher in the elderly (≥75 years). This was not associated with changes in bleeding time or platelet aggregation. No dosage adjustment is recommended.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information:
Perioperative Management of Clopidogrel:
In patients with coronary stents, the risk of stent thrombosis becomes elevated depending on the type of stent deployed (bare metal vs drug-eluting stent) and the time from implantation. According to the American College of Chest Physicians (Becker, 2008), the recommended length of therapy for clopidogrel is at least 12 months in patients with ACS who undergo PCI with a bare metal stent (BMS) or drug-eluting stent (DES). In patients receiving a BMS without ongoing ACS, clopidogrel may be continued for at least 1 month. Early discontinuation of clopidogrel may result in stent thrombosis leading to nonfatal and fatal myocardial infarction. The perioperative recommendations for clopidogrel are below (Douketis, 2008):
Patients undergoing noncardiac surgery (low risk of cardiac event without coronary stent): Clopidogrel and other antiplatelet agents should be temporarily discontinued 5-10 days prior to surgery and resumed ~24 hours (or the next morning) after the procedure when adequate hemostasis is achieved.
Patients without coronary stent undergoing cardiac surgery (eg, CABG) or noncardiac surgery (high risk of cardiac event): Discontinue clopidogrel at least 5 days and, preferably, 10 days prior to surgery while continuing aspirin up to and beyond the time of surgery. If aspirin is interrupted, it should be reinitiated 6-48 hours after surgery; may resume clopidogrel ~24 hours (or the next morning) after the procedure when adequate hemostasis is achieved.
Patients undergoing cardiac surgery (eg, CABG) or noncardiac surgery (with coronary stent): Based on the risk of stent thrombosis, patients with a BMS who require surgery within 6 weeks of implantation or with a DES who require surgery within 12 months of implantation should continue on both aspirin and clopidogrel during the perioperative period.
The AHA/ACC/SCAI/ACS/ADA Science Advisory (2007) published recommendations (Circulation, February 13, 2007) to prevent premature discontinuation of dual antiplatelet therapy (clopidogrel and aspirin) in patients with coronary artery stents. The advisory panel agreed with the 2004 ACC/AHA guidelines stressing the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent (DES) in patients who are not at high risk of bleeding. The advisory panel included these recommendations. Minor surgery, teeth cleaning, and tooth extraction can usually be performed without increased bleeding on the dual antiplatelet regimen. If increased bleeding is anticipated, then the procedure should be delayed until the antiplatelet regimen is completed. Elective procedures with a significant risk of bleeding should be postponed until the antiplatelet regimen is completed. The advisory panel recommends healthcare providers who perform invasive or surgical procedures contact the patient's cardiologist before discontinuing antiplatelet therapy. For patients with drug-eluting stents who must undergo a procedure that requires discontinuation of thienopyridine therapy, aspirin should be continued if possible and the thienopyridine restarted as soon as possible after the procedure. “Bridging” stent patients with warfarin, other antithrombins, or glycoprotein IIb/IIIa agents is not supported by the Advisory Committee.
For the complete review and additional recommendations, refer to http://www.acc.org/qualityandscience/clinical/pdfs/Final_Dual_Antiplatelet_Statement_010507.pdf
Cardiovascular Considerations
Acute Coronary Syndrome (ACS): The 2007 ACC/AHA guidelines for unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) recommend administration of clopidogrel to hospitalized patients who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance (Class I; level of evidence B). In certain situations, patients may even be desensitized to aspirin so that they may receive aspirin and clopidogrel concurrently. The CURE trial demonstrated that clopidogrel reduced major cardiovascular events in patients with ACS without ST-segment elevation (Yusuf S, 2001). In this trial, the risk of major bleeding was significantly increased in the clopidogrel group although life-threatening bleeding and hemorrhagic strokes were similar in both groups. In hospitalized UA/NSTEMI patients in whom an early noninvasive strategy is planned, clopidogrel should be added to aspirin and anticoagulant therapy as soon as possible after admission, administered for at least 1 month and ideally up to 1 year (Class I, level of evidence B).
ST-Segment Elevation Myocardial Infarction (STEMI): The COMMIT trial (Chen, 2005), randomized 45,852 patients with an acute MI (supporting ECG abnormalities), presenting within 24 hours of onset of symptoms, to clopidogrel 75 mg daily or placebo. All patients received aspirin and standard medical care (eg, thrombolytics if appropriate, ACEI). Clopidogrel was continued for 28 days or until hospital discharge whichever came first. The primary outcome measure was a composite of death, MI, or stroke. Patients in the clopidogrel arm had a significantly lower death rate (7.5% clopidogrel, 8.1% placebo; p=0.002).The CLARITY trial (Scirica BM, 2006) evaluated clopidogrel in the setting of thrombolysis and its relationship to ST-segment resolution. The randomized, double blind, placebo-controlled trial included 3491 patients within 12 hours of the onset of STEMI who were candidates for thrombolytic therapy. Patients were randomized to receive clopidogrel (300 mg loading dose, then 75 mg daily) or placebo until angioplasty, discharge, or Day 8. Patients also received aspirin (loading dose followed by 75-162 mg/day). The ECG was monitored at baseline, and 90- and 180 minutes after thrombolysis. There was no difference in ECG resolution (none, partial, complete) between the groups at 90 minutes. Patients with partial (30% to 70%) and complete (>70%) ST-segment resolution on clopidogrel had significantly improved patency on discharge angiogram over placebo patients with similar ST-segment resolution. The clopidogrel group with partial ST segment resolution had a significantly lower rate of in-hospital death and MI than their placebo counterparts. The clopidogrel group with complete resolution of ST-segments showed a trend toward a reduction of in-hospital death and MI, but it was not statistically significant (p=0.056). Mortality was followed for 30 days; the clopidogrel group with complete resolution of ST-segment abnormalities had a significant reduction in the rate of death compared to its placebo counterpart.
Percutaneous Coronary Intervention (PCI): In UA/NSTEMI patients in whom an invasive strategy will be employed, dual-antiplatelet therapy with ASA and a second agent should be initiated prior to diagnostic angiography. If initiated before PCI, the second agent may include clopidogrel or a glycoprotein IIb/IIIa inhibitor (eptifibatide or tirofiban are preferred) (Class I, level of evidence A). If initiated at the time of PCI, prasugrel may be selected as the second antiplatelet agent in place of clopidogrel or an I.V. glycoprotein IIb/IIIa inhibitor (Class I, level of evidence: B). For patients with STEMI, clopidogrel should be administered as early as possible before or at the time of primary/nonprimary PCI. Prasugrel should be given as soon as possible for primary PCI.
The PCI-CURE trial, a substudy of the CURE trial, suggested that in patients with ACS undergoing PCI receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term therapy (9 months) is beneficial in reducing major cardiovascular events, compared with placebo (Mehta, 2001). In the CREDO trial, long-term (1 year) clopidogrel treatment (75 mg daily) following PCI, significantly reduced the risk of adverse ischemic events (Steinhubl, 2002). In CREDO, the issue of timing was evaluated and a 300 mg loading dose of clopidogrel must be given at least 6 hours before PCI. More recently, however, a 600 mg loading dose of clopidogrel was shown to result in maximal platelet inhibition at 2 hours (Hochholzer, 2005).
In patients taking clopidogrel in whom elective CABG is planned, clopidogrel should be withheld for at least 5 days before elective CABG. If urgent CABG is required, the benefits of revascularization and/or the net benefit of the thienopyridine should outweigh the potential risks of excess bleeding (Wright, 2011).
The AHA/ACC/SCAI/ACS/ADA Science Advisory (2007) published recommendations (Circulation, February 13, 2007) to prevent premature discontinuation of dual antiplatelet therapy (clopidogrel, aspirin) in patients with coronary artery stents. This advisory panel agreed with the 2004 ACC/AHA guidelines stressing the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent (DES) in patients who are not at high risk of bleeding. The advisory panel included these recommendations. Minor surgery, teeth cleaning, and tooth extraction can usually be performed without increased bleeding on the dual antiplatelet regimen. If increased bleeding is anticipated, then the procedure should be delayed until the antiplatelet regimen is completed. Elective procedures with a significant risk of bleeding should be postponed until the antiplatelet regimen is completed. The Advisory panel recommends healthcare providers who perform invasive or surgical procedures contact the patient's cardiologist before discontinuing antiplatelet therapy. For patients with drug-eluting stents who must undergo a procedure that requires discontinuation of thienopyridine therapy, aspirin should be continued if possible and the thienopyridine restarted as soon as possible after the procedure. “Bridging” stent patients with warfarin, other antithrombins, or glycoprotein IIb/IIIa agents is not supported by the Advisory Committee.
For the complete review and additional recommendations, refer to http://www.acc.org/qualityandscience/clinical/pdfs/Final_Dual_Antiplatelet_Statement_010507.pdf.
High Cardiovascular-Event Risk Patients: The CHARISMA trial (Bhatt DL, 2006) evaluated the use of clopidogrel compared to placebo in 15,603 patients receiving low-dose aspirin (75-162 mg/day) who were at high risk of future cardiovascular events. This patient group included those with multiple atherothrombotic risk factors, documented coronary, cerebrovascular, or peripheral vascular disease. The primary outcome measure was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The primary outcome measure occurred in 6.8% of patients receiving clopidogrel and aspirin vs. 7.3% with placebo and aspirin (p=0.22). The rates of the secondary endpoints which included hospitalizations for ischemic events, was 16.7% and 17.9% (p=0.04). The rate of GUSTO-defined severe bleeding was 1.7% and 1.3% (p=0.09). A prespecified subgroup analysis divided patients into a “symptomatic” group (with documented cardiovascular disease) and an “asymptomatic” group (without documented cardiovascular disease). In the patients considered symptomatic, the primary event rate was lower in the clopidogrel group compared to placebo (6.9% vs 7.9%, p=0.046). In patients considered asymptomatic, there was a 20% relative increase in the primary event rate (6.6% vs 5.5%; p=0.20) if receiving clopidogrel. The rate of death from cardiovascular causes was also higher in this group (3.9% vs 2.2%, p=0.01). In summary, clopidogrel in addition to low-dose aspirin is not significantly more effective than low-dose aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular causes. Use of clopidogrel in addition to low-dose aspirin may be harmful in patients with multiple atherothrombotic risk factors without cardiovascular disease. The American College of Chest Physicians recommends against the routine use of clopidogrel (in addition to aspirin) for primary prevention unless the patient has an aspirin allergy and is at moderate-to-high risk for a cardiovascular event (Becker, 2008).
CYP2C19 Polymorphisms: CYP2C19 is the main isoenzyme responsible for the metabolism of clopidogrel to its active metabolite (thiol derivative). Genetic variants of CYP2C19 result in reduced function and less active metabolite formation. Two main gene variants have been identified which result in loss of function: CYP2C19*2 and CYP2C19*3 (CYP2C19*1 designates the gene coding for the functionally normal isoenzyme). The CYP2C19*2 polymorphism accounts for 75% to 85% of defective alleles seen in Caucasians and Asians. CYP2C19*3 alleles are rare in Caucasians, but account for the remaining loss of function alleles seen in Asians (Desta, 2002). Patients may be either heterozygous (eg, CYP2C19*1/*2) or homozygous (CYP2C19*2/*2). Regardless, residual platelet aggregation (RPA) will be higher if the patient is a carrier of at least one loss-of-function allele and may experience worse clinical outcomes (Frere, 2008; Trenk, 2008). In a cohort of patients from the TRITON-TIMI 38 trial (n=1477) where ~92% were self-reported as of white race, ~30% were carriers of at least one CYP2C19 loss-of-function allele (95% carried CYP2C19*2). As a result, patients who were carriers had lower concentrations of the active metabolite, diminished platelet inhibition, and higher rates of major adverse cardiovascular events including stent thrombosis (Mega, 2009).
Genetic testing to detect CYP2C19*2 or *3 alleles is available and might be considered for patients with UA/NSTEMI (or, after ACS and with PCI) on clopidogrel therapy, only if results of testing may alter management (Wright, 2011). Genetic testing may be considered prior to initiation of clopidogrel in those patients who are at moderate or high risk for poor outcomes (eg, PCI in patients with extensive and/or very complex disease). Functional testing, after initiation of clopidogrel, using any one of the available assays (eg, VerifyNow® P2Y12 assay) may also be done to determine clopidogrel responsiveness (Holmes, 2010). Of note, a number of independent predictors of clopidogrel responsiveness coexist with CYP2C19*2 carrier status including advanced age, presence of diabetes mellitus, and body mass index. However, combining these variables with CYP2C19*2 carrier status only explains 11.5% of the variability seen in on-clopidogrel RPA (Hochholzer, 2010).
The CYP2C19*17 polymorphism, which occurs in ~4% to 18% of the population, confers hypermetabolism and results in more active metabolite formation and enhanced antiplatelet response (Sim, 2006). CYP2C19*17 carriers in one trial, both heterozygotes and homozygotes for this polymorphism, demonstrated significantly lower ADP-induced platelet aggregation values compared to their wild-type counterparts and higher rates of bleeding with the highest risk of bleeding seen in those patients who were CYP2C19*17 homozygous (Sibbing, 2010).
Interaction with Proton Pump Inhibitors (PPIs): Clopidogrel is a prodrug requiring hepatic conversion via CYP3A4 and/or CYP2C19 to its active metabolite. Impaired clopidogrel conversion to its active metabolite may be due to either CYP450 polymorphisms or drug-drug interactions resulting in suboptimal antiplatelet activity. Omeprazole and other PPIs (eg, lansoprazole, pantoprazole, rabeprazole), which are all metabolized to at least some degree by CYP2C19, competitively inhibit CYP2C19-mediated conversion of clopidogrel to its active metabolite. Lansoprazole has the greatest degree of CYP2C19 inhibition, whereas pantoprazole has the least (Li, 2004). Several studies have reported greater clinical event rates (eg, myocardial infarction, death) or greater platelet reactivity associated with concurrent use of clopidogrel and a PPI (Gilard, 2006; Ho, 2008; Pezella, 2008; Kreutz, 2010). Similarly, a prospective, randomized, double-blind trial demonstrated a reduction in antiplatelet activity when omeprazole and clopidogrel are used concurrently (Gilard, 2008). Another controlled trial with the PPI lansoprazole also found evidence of a possible interaction resulting in less antiplatelet activity (Small, 2008). In contrast, one study with esomeprazole and pantoprazole did not find evidence of reduced antiplatelet activity when administered with clopidogrel (Siller-Matula, 2009).
The Clopidogrel Medco Outcomes Study was a retrospective cohort analysis evaluating integrated medical and pharmacy claims. Patients included (n=16,718) were those who had a coronary stent procedure with a new clopidogrel prescription claim within 1 month of procedure. Patients were segregated according to PPI use; newer PPIs (ie, rabeprazole, dexlansoprazole) were not included in the analysis. Those who received a PPI demonstrated a 51% increase in the risk of cardiovascular events (MI, unstable angina, stroke, and repeat coronary procedure) compared to those who did not receive a PPI (25% vs 17.9%, p<0.0001). Each individual PPI was analyzed for the occurrence of the primary endpoint: lansoprazole 24.3%; pantoprazole 29.2%; esomeprazole 24.9%; omeprazole 25.1% (Kreutz, 2010).
A retrospective analysis of the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial, an elective PCI trial for patients with angina, and the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel - Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) trial, a PCI trial for patients with moderate-high risk ACS. This analysis revealed that in the PRINCIPLE-TIMI 44 trial, which included 201 patients, 26.4% (n=53) were on a PPI at randomization and the mean inhibition of platelet aggregation at 6 hours after a 600 mg clopidogrel loading dose was significantly lower for patients receiving a concomitant PPI than for those not receiving a PPI (23.2 ± 19.5% vs 35.2 ± 20.9%, p=0.02). Those receiving a 60 mg loading dose of prasugrel demonstrated a modest difference (69.6 ± 13.5% vs 76.7 ± 12.4%, p=0.054).
In the TRITON-TIMI 38 trial, which included 13,608 patients, 33% (n=4529) were on a PPI at randomization (pantoprazole 40.7%; omeprazole 36.9%; esomeprazole 13.5 %; lansoprazole 9.7%; rabeprazole 1.4%). In contrast to the Clopidogrel Medco Outcomes Study, the authors found no association between the PPI use and occurrence of the primary endpoint, the composite of cardiovascular death, nonfatal MI, or nonfatal stroke. In addition, patients with a single reduced function CYP2C19 allele receiving a PPI did not demonstrate an increased risk of cardiovascular events. The authors concluded that these findings do not support the need to avoid concomitant use of PPIs, when indicated, in patients receiving clopidogrel or prasugrel (O'Donoghue, 2009).
The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) study randomized 3761 patients starting dual-antiplatelet therapy with ASA and clopidogrel to receive omeprazole or placebo. No difference was found in the primary composite cardiovascular endpoint between groups (p=0.98), and the rate of overt upper gastrointestinal bleeding was reduced with omeprazole as compared with placebo (HR 0.13, 0.03 to 0.56; P=0.001). The authors concluded, however, that these results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI because the study was halted prematurely due to study funding and limited power due to a small overall event rate (Bhatt, 2010).
However, in light of this conflicting information, clinicians should still evaluate the need for PPI therapy in patients requiring clopidogrel. If a PPI is necessary, consider the use of pantoprazole since its effects on clopidogrel's metabolism to its active metabolite is considerably less than other PPIs. Lansoprazole has the most potent CYP2C19 inhibitory activity and should be avoided. Some have advocated a strategy of staggering the dosing of the PPI and clopidogrel (Juurlink, 2009). Current manufacturer recommendations regarding omeprazole are that the concomitant use of clopidogrel be avoided even if staggered.
Dental Health: Effects on Dental Treatment
Aspirin and clopidogrel (Plavix®) in combination is the primary prevention strategy against stent thrombosis after placement of drug-eluting metal stents in coronary patients. Premature discontinuation of this combination antiplatelet therapy strongly increases the risk of a catastrophic event of stent thrombosis leading to myocardial infarction and/or death, so says a science advisory issued in January 2007 from the American Heart Association in collaboration with the American Dental Association and other professional healthcare organizations. The advisory stresses a 12-month therapy of aspirin and Plavix® combination after placement of a drug-eluting stent in order to prevent thrombosis at the stent site. Any elective surgery should be postponed for 1 year after stent implantation, and if surgery must be performed, consideration should be given to continuing the antiplatelet therapy during the perioperative period in high-risk patients with drug-eluting stents.
This advisory was issued from a science panel made up of representatives from the American Heart Association (AHA), the American College of Cardiology, the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons, the American Dental Association (ADA), and the American College of Physicians (Grines, 2007).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
There is no scientific evidence to warrant the discontinuance of clopidogrel prior to dental surgery. Patients taking one clopidogrel tablet daily as an antithrombotic and who require dental surgery should be given special consideration in consultation with physician.
Mental Health: Effects on Mental Status
May cause depression, dizziness, confusion, hallucinations, insomnia, or anxiety
Mental Health: Effects on Psychiatric Treatment
GI side effects are common; concurrent use with SSRIs and/or valproic acid may produce additive effects. Flu-like syndrome may occur and present like SSRI-discontinuation symptoms. Hematologic side effects have rarely been reported; monitor with clozapine, carbamazepine, and valproate.
Nursing: Physical Assessment/Monitoring
Monitor for unusual bleeding.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Plavix®: 75 mg, 300 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Plavix)
75 mg (30): $195.99
Extemporaneously Prepared
A 5 mg/mL oral suspension may be made using tablets. Crush four 75 mg tablets and reduce to a fine powder. Add a small amount of a 1:1 mixture of Ora-Sweet® and Ora-Plus® and mix to a uniform paste; mix while adding the vehicle in geometric proportions to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label "shake well". Stable 60 days at room temperature or under refrigeration.
Skillman KL, Caruthers RL, and Johnson CE, "Stability of an Extemporaneously Prepared Clopidogrel Oral Suspension," Am J Health Syst Pharm, 2010, 67(7):559-61.
References
“A Randomized, Blinded, Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). CAPRIE Steering Committee,” Lancet, 1996, 348(9083):1329-39.
Adams HP, del Zoppo G, Alberts MJ, et al, “Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups,” Stroke, 2007, 38(5):1655-1711.
Anderson JL, Adams CD, Antman EM, et al, “ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration With the American College of Emergency Physicians, The Society of Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons,” J Am Coll Cardiol, 2007, 50(7):1-157.
Antman EM, Anbe DT, Armstrong PW, et al. “ACC/AHA 2007 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” J Am Coll Cardiol, 2004, 44(3):671-719.
Bal dit Sollier C, Mahe I, Berge N, et al, “Reduced Thrombus Cohesion in an ex vivo Human Model of Arterial Thrombosis Induced by Clopidogrel Treatment: Kinetics of the Effect and Influence of Single and Double Loading-Dose Regimens,” Thromb Res, 2003, 111(1-2):19-27.
Becker RC, Meade TW, Berger PB, et al, “The Primary and Secondary Prevention of Coronary Artery Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):776-814.
Berger PB, Bell MR, Rihal CS, et al, “Clopidogrel Versus Ticlopidine After Intracoronary Stent Placement,” J Am Coll Cardiol, 1999, 34(7):1891-4.
Bertrand ME, Rupprecht HJ, Urban P, et al, “Double-Blind Study of the Safety of Clopidogrel With and Without a Loading Dose in Combination With Aspirin Compared With Ticlopidine in Combination With Aspirin After Coronary Stenting,” Circulation, 2000, 102(6):624-9.
Bhatt DL, Cryer BL, Contant CF, et al, “Clopidogrel With or Without Omeprazole in Coronary Artery Disease,” N Engl J Med, 2010, 363(20):1909-17.
Bhatt DL, Fox KA, Hacke W, et al, “Clopidogrel and Aspirin Versus Aspirin Alone for the Prevention of Atherothrombotic Events,” N Engl J Med, 2006, 354(16):1706-17.
Chen ZM, Jiang LX, Chen YP, et al, “Addition of Clopidogrel to Aspirin in 45,852 Patients With Acute Myocardial Infarction: Randomized Placebo-Controlled Trial. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group,” Lancet, 2005, 366(9497):1607-21.
Desta Z, Zhao X, Shin JG, et al, “Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism,” Clin Pharmacokinet, 2002, 41(12):913-58.
Douketis JD, Berger PB, Dunn AS, et al, “The Perioperative Management of Antithrombotic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):299-339.
Fraker TD, Fihn SD, Gibbons RJ, et al, “2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to Develop the Focused Update of the 2002 Guidelines for the Management of Patients With Chronic Stable Angina,” Circulation, 2007, 116(23):2762-72.
Frere C, Cuisset T, Morange PE, et al, “Effect of Cytochrome P450 Polymorphisms on Platelet Reactivity After Treatment with Clopidogrel in Acute Coronary Syndrome,” Am J Cardiol, 2008, 101(8):1088-93.
Furie KL, Kasner SE, Adams RJ, et al, “Guidelines for the Prevention of Stroke in Patients With Stroke or Transient Ischemic Attack: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association,” Stroke, 2011,42(1):227-76
Gibbons RJ, Abrams J, Chatterjee K, et al, “ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina),” Circulation, 2003, 107(1):149-58.
Gilard M, Arnaud B, Le Gal G, et al, “Influence of Omeprazol on the Antiplatelet Action of Clopidogrel Associated to Aspirin,” J Thromb Haemost, 2006, 4(11):2508-9.
Gilard M, Arnaud B, Cornily JC, et al, “Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated With Aspirin: The Randomized, Double-Blind Ocla (Omeprazole Clopidogrel Aspirin) Study,” J Am Coll Cardiol, 2008, 51(3):256-60.
Goodman SG, Menon V, Cannon CP, et al, “Acute ST-Segment Elevation Myocardial Infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):707-75.
Grines CL, Bonow RO, Casey DE, et al, “AHA/ACC/SCAI/ACS/ADA Science Advisory, Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients With Coronary Artery Stents. A Science Advisory From the American Heart Association, American College of Cardiology, Society of Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association With Representation from the Amercian College of Physicians,” Circulation, 2007, 115(6):813-8.
Harrington RA, Becker RC, Cannon CP, et al, “Antithrombotic Therapy for Non ST-Segment Elevation Acute Coronary Syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):670-707.
Herbert JM, Frehel D, Vallee E, et al, “Clopidogrel, A Novel Antiplatelet and Antithrombotic Agent,” Cardiovascular Drug Rev, 1993, 11(2):180-98.
Ho PM, Maddox TM, Wang L, et al, “Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome,” JAMA, 2009, 301(9):937-44.
Hochholzer W, Trenk D, Fromm MF, et al, “Impact of Cytochrome P450 2C19 Loss-of-Function Polymorphism and of Major Demographic Characteristics on Residual Platelet Function After Loading and Maintenance Treatment with Clopidogrel in Patients Undergoing Elective Coronary Stent Placement,” J Am Coll Cardiol, 2010, 55(22):2427-34.
Holmes DR, Dehmer GJ, Kaul S, et al, “ACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA “Boxed Warning.” A Report of the American College of Cardiology Foundation Task Force, 2010, 56(4):321-41.
Juurlink DN, Gomes T, Ko DT, et al, “A Population-Based Study of the Drug Interaction Between Proton Pump Inhibitors and Clopidogrel,” CMAJ, 2009, 180(7):713-8.
Kastrati A, Mehilli J, Schuhlen H, et al, “A Clinical Trial of Abciximab in Elective Percutaneous Coronary Intervention After Pretreatment With Clopidogrel,” N Engl J Med, 2004, 350(3):232-8.
Kreutz RP, Stanek EJ, Aubert R, et al, “Impact of Proton Pump Inhibitors on the Effectiveness of Clopidogrel After Coronary Stent Placement: The Clopidogrel Medco Outcomes Study,” Pharmacotherapy, 2010, 30(8):787-96.
Kushner FG, Hand M, Smith SC, et al, “2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2009, 54(23):2205-41.
Lange RA and Hillis LD, “Antiplatelet Therapy for Ischemic Heart Disease,” N Engl J Med, 2004, 350(3):277-80.
Lidell C, Svedberg LE, Lindell P, et al, “Clopidogrel and Warfarin: Absence of Interaction in Patients Receiving Long-Term Anticoagulant Therapy for Nonvalvular Atrial Fibrillation,” Thromb Haemost, 2003, 89(5):842-6.
Li XQ, Andersson TB, Ahalström M, et al, “Comparison of Inhibitory Effects of the Proton Pump-Inhibiting Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole and Rabeprazole on Human Cytochrome P450 Activities,” Drug Metab Dispo, 2004, 32(8):821-7.
Mega JL, Close SL, Wiviott SD, et al, “Cytochrome P-450 Polymorphisms and Response to Clopidogrel,” N Engl J Med, 2009, 360(40):354-62.
Mehta SR, Yusuf S, Peters RJ, et al, “Effects of Pretreatment With Clopidogrel and Aspirin Followed by Long-Term Therapy in Patients Undergoing Percutaneous Coronary Intervention: The PCI-CURE Study,” Lancet, 2001, 358(9281):527-33.
Mishkel GJ, Aguirre FV, Ligon RW, et al, “Clopidogrel as Adjunctive Antiplatelet Therapy During Coronary Stenting,” J Am Coll Cardiol, 1999, 34(7):1884-90.
Montalescot G, Sideris G, Meuleman C, et al, “A Randomized Comparison of High Clopidogrel Loading Doses in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes,” J Am Coll Cardiol, 2006, 48(5):931-8.
Moussa I, Oetgen M, Roubin G, et al, “Effectiveness of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin in Preventing Stent Thrombosis After Coronary Stent Implantation,” Circulation, 1999, 99(18):2364-6.
O'Donoghue ML, Braunwald E, Antman EM, et al, “Pharmacodynamic Effect and Clinical Efficacy of Clopidogrel and Prasugrel with or without a Proton-pump Inhibitor: an Analysis of Two Randomised Trials,” Lancet, 2009, 374(9694):989-97.
Patrono C, Baigent C, Hirsh J, et al, “Antiplatelet Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):199-233.
Patti G, Colonna G, Pasceri V, et al, “Randomized Trial of High Loading Dose of Clopidogrel for Reduction of Periprocedural Myocardial Infarction in Patients Undergoing Coronary Intervention: Results From the ARMYDA-2 (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty) Study,” Circulation, 2005, 111(16):2099-106.
Pezalla E, Day D, and Pulliadath I, “Initial Assessment of Clinical Impact of a Drug Interaction Between Clopidogrel and Proton Pump Inhibitors,” J Am Coll Cardiol, 2008, 52(12):1038-9.
Sabatine MS, Cannon CP, Gibson CM, et al, “Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for Myocardial Infarction With ST-Segment Elevation,” N Engl J Med, 2005, 352(12):1179-89.
Scirica BM, Sabatine MS, Morrow DA, et al. “The Role of Clopidogrel in Early and Sustained Arterial Patency After Fibrinolysis for ST-segment Elevation Myocardial Infarction. The ECG Clarity-TIMI 28 Study,” J Am Coll Cardiol, 2006, 48(1):37-42.
Sibbing D, Koch W, Gebhard D, et al, “Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement,” Circulation, 2010, 121(4):512-18.
Siller-Matula JM, Spiel AO, Lang IM, et al, “Effects of Pantoprazole and Esomeprazole on Platelet Inhibition by Clopidogrel,” Am Heart J, 2009, 157(1):148.e1-5.
Sim SC, Risinger C, Dahl ML, et al, “A Common Novel CYP2C19 Gene Variant Causes Ultrarapid Drug Metabolism Relevant for the Drug Response to Proton Pump Inhibitors and Antidepressants,” Clin Pharmacol Ther, 2006, 79(1):103-13.
Small DS, Farid NA, Payne CD, et al, “Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel,” J Clin Pharmacol, 2008, 48(4):475-84.
Smith SC, Feldman TE, Hirshfeld JW, et al, “ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention),” J Am Coll Cardiol, 2006, 47(1):216-235.
Steinhubl SR, Berber PB, Mann JT, et al, “Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention. A Randomized Controlled Trial,” JAMA, 2002, 288(19):2411-20.
Trenk D, Hochholzer W, Fromm MF, et al, “Cytochrome P450 2C19 681G>A Polymorphism and High On-Clopidogrel Platelet Reactivity Associated With Adverse 1-Year Clinical Outcome of Elective Percutaneous Coronary Intervention With Drug Eluting or Bare-Metal Stents,” J Am Coll Cardiol, 2008, 51(20):1925-34.
Wright RS, Anderson JL, Adams CD, et al, “2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline) A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2011, 57(18) [epub ahead of print].
Yusef S, Zhao F, Mehta SR, et al, “Effects of Clopidogrel in Addition to Aspirin in Patients With Acute Coronary Syndromes Without ST-Segment Elevation,” N Engl J Med, 2001, 345(7):494-502.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
| 
