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clopidogrel (Plavix)

Tradename: Plavix. Clopidogrel bisulfate. Generic May 2012 [33] Indications: 1) aspirin failure 2) stroke prophylaxis* - prevention of arterial thromboembolism 3) percutaneous coronary intervention (PCI) & s/p coronary stent (see CHARISMA trial) 4) antiplatelet prophylaxis prior to PTCA for STEMI [12] 5) post myocardial infarction (see COMMIT trial) - secondary prevention in patients with cardiovascular disease - patients with diabetes mellitus benefit less [36] 6) unstable angina (in combination with aspirin)# 7) cardiovascular risk reduction - may be more effective in smokers [37] * addition of aspirin NOT superior to clopidogrel alone [8] (see MATCH study) # increased risk of bleeding offset by lower mortality from cardiovascular events [4], see CHARISMA trial Contraindications: 1) hemorrhagic disorder (GI bleed, hemorrhagic stroke ...) 2) cardiovascular risk reduction (in combination with aspirin) (see CHARISMA trial) Benefit/risk: - secondary prevention of cardiovascular events [44] - number needed to treat (NNT) - 50 for 1 year to prevent 1 cardiovascular event - 77 for 1 year to prevent 1 non-fatal MI - 200 for 1 year to prevent 1 non-fatal stroke - 333 for 1 year to prevent 1 death [44] - in combination with aspirin - for 1 year following coronary stent - no mortality benefit [43] - number needed to treat (NNT) to prevent 1 non-fatal MI or 1 stroke = 27 [43] - number need to harm (major hemorrhage) = 117 - no benefit when added to aspirin for secondary prevention of cardiovascular events [45] - percutaneous coronary intervention (PCI) - number needed to harm: 275 to result in 1 serious hemorrhage [46] Dosage: 1) 75 mg PO QD - use in combination with aspirin 81 mg QD for coronary artery disease may be of benefit 2) stop Plavix 5-7 days prior to elective surgery 3) 600 mg once prior to percutaneous intervention (PCI),followed by 150 mg QD for 6 days, then 75 mg QD in combination with 81 mg aspirin [22] - see dual antiplatelet therapy 4) 2/3 of clopidogrel non-responders will respond to 150 mg/day [19] Tabs: 75 mg Pharmacokinetics: 1) rapidly absorbed after oral administration 2) absorbtion unaffected by food 3) activation dependent upon CYP3A4 & CYP2C19; a) reduced function CYP2C19 alleles inadequately activate clopidogrel & are associated with worse clinical outcomes [18] b) CYP2C19*1 allele fully functional metabolism of clopidogrel c) CYP2C19*2 & CYP2C19*3 alleles have no functional metabolism of clopidogrel* - these two alleles account for most of the reduced function alleles in patients of Caucasian (85%) & Asian (99%) descent classified as poor metabolizers d) CYP2C19*4, *5, *6, *7, & *8 & other alleles may be associated with absent or reduced metabolism of clopidogrel, but are less frequent than CYP2C19*2 & CYP2C19*3 alleles e) a patient with two loss-of-function alleles will have poor metabolizer status 4) cyt P450 2B metabolizes clopidogrel to inactive metabolites 5) steady state activity takes 3-7 days 6) once stopped, it takes 5 days for anti-platelet activity to stop 7) 600 mg achieves maximum platelet inhibition in 2 hours * ticagrelor & pasugrel not activated by CYP2C19 Monitor: - CYP2C19 allele testing (research, see Pharmacokinetics) - clinical utility of CYP2C19 genotyping uncertain [31,32] Adverse effects: 1) overall tolerability is similar to aspirin 2) 13% of patients will experience adverse effects sufficient to withdraw therapy 3) neutropenia 0.8% 4) gastrointestinal 27% a) abdominal pain b) dyspepsia c) gastritis & upper GI bleeding [11] - proton pump inhibitor may reduce risk [16,29] - esomeprazole more effective than famotidine in preventing GI bleed when clopidogrel is used in combination with aspirin [34] - although not a primary cause of gastroduodenal ulcers, may impair healing of existing ulcers & erosions by inhibiting angiogenesis - 150 mg QD may increase risk relative to 75 mg QD [38] d) constipation e) diarrhea 5) dermatologic 16% (higher than aspirin) a) rash b) pruritus c) 1.5% severe enough for withdrawal of therapy 6) hemorrhage 7) headache 8) chest pain 9) dizziness 10) thrombotic thrombocytopenic purpura (TTP) (0.001-0.006%) [10] 11) increased risk of major bleeding if given within 5 days of CABG [20]; - discontinue clopidogrel & postpone surgery if feasible [20] 12) increased risk of severe postoperative wound complications after cutaneous surgery (3% vs 0.5% for aspirin) [30] 13) long-term treatment with clopidogrel does not increase or decrease overall risk of mortality in patients with or at risk for heart disease [48] Drug interactions: 1) in vitro, high concentrations of clopidogrel inhibit cytochrome P450 2C9 2) clopidogrel may potentially interfere with metabolism of: a) phenytoin b) tamoxifen c) tolbutamide d) warfarin e) torsemide f) NSAIDs 3) administration with heparin has not been studied 4) drugs that inhibit CYP3A4 & CYP2C19 may inhibit activation of clopidogrel & diminish antiplatelet effect a) proton pump inhibitors [22,25] 1] omeprazole > rabeprazole, pantoprazole, lansoprazole; 2] prasugrel may have less interaction with PPIs [24] 3] omeprazole may cut the effect of clopidogrel in half [26] 4] interaction of clopidogrel with proton pump inhibitors "clinically unimportant" [35] 5] no increase in risk for adverse cardiovascular events with addition of a PPI to a clopidogrel [47] b) other CYP2C19 inhibitors not recommended for use with clopidogrel 1] cimetidine 2] esomeprazole 3] fluoxetine 4] fluvoxamine 5] fluconazole 6] ketoconazole 7] voriconazole 8] etravirine 9] felbamate 10] ticlopidine [25] 5) No significant interactions of clopidogrel with statins - atorvastatin, simvastatin, lovastatin, fluvastatin .. [6,7] 6) increased risk of serious bleeding when used in combination with aspirin 81 mg QD [8] 7) smoking induces CYP 3A4 that converts clopidogrel into its active metabolite thus enhances platelet inhibition by clopidogrel [15,21] Mechanism of action: 1) inhibits platelet aggregation by irreversibly binding the platelet ADP receptor 2) biotransformation of Clopidogrel is necessary for anti-platelet activity, but the active metabolite is unknown 3) prolongs bleeding time 4) 40-100 times more potent than ticlopidine 5) reduces vascular smooth muscle contraction 6) prevents reocclusion rather than facilitates early reperfusion after fibrinolysis [13] 7) impairs angiogenesis Notes: cost $110/month in US (2001), $150/month (2009)

Interactions

drug interactions drug adverse effects (more general classes)

Related

CHARISMA trial MATCH study

General

amine ester P2Y12-receptor inhibitor sulfur compound thienopyridine

Properties

INHIBITS: P2Y12 purinoceptor SIZE: MW = 322 G/M MISC-INFO: elimination route KIDNEY LIVER 1/2life 8 HOURS

Database Correlations

PUBCHEM correlations

References

  1. Lancet 348:9038
  2. Bristol-Myers Squibb package insert
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Prescriber's Letter 8(4):20 2001 Clopidogrel In The Treatment Of Acute Coronary Syndromes Detail-Document#: 170422 (subscription needed) http://www.prescribersletter.com
  5. Prescriber's Letter 9(4):20 2002
  6. Prescriber's Letter 10(1):1 2003
  7. Journal Watch 23(20):161, 2003 Saw J et al, Circulation 108(Aug 26):921, 2003 PMID: 12925453
  8. Journal Watch 24(17):133, 2004 Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo- controlled trial. Lancet. 2004 Jul 24;364(9431):331-7. PMID: 15276392
  9. Prescriber's Letter 11(10): 2004 Concomitant use of Aspirin and Clopidogrel (Plavix) in Cerebrovascular Disease Detail-Document#: 201002 (subscription needed) http://www.prescribersletter.com
  10. Ovbiagele B, In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
  11. Prescriber's Letter 12(3): 2005 Safety of Clopidogrel (Plavix) in Patients at Risk for Ulcers Detail-Document#: 210304 (subscription needed) http://www.prescribersletter.com - Journal Watch 25(4):29, 2005 Chan FK, Ching JY, Hung LC, Wong VW, Leung VK, Kung NN, Hui AJ, Wu JC, Leung WK, Lee VW, Lee KK, Lee YT, Lau JY, To KF, Chan HL, Chung SC, Sung JJ. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005 Jan 20;352(3):238-44. PMID: 15659723 - Cryer B. Reducing the risks of gastrointestinal bleeding with antiplatelet therapies. N Engl J Med. 2005 Jan 20;352(3):287-9. No abstract available. PMID: 15659730
  12. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005 Sep 14;294(10):1224-32. Epub 2005 Sep 4. PMID: 16143698
  13. Scirica BM et al, The role clopidogrel in early and sustained arterial patency after fibrinolysis for ST segment elevation myocardial infarction The ECG CLARITY-TIMI 29 Study J Am Coll Cardiol 2006, 48:37 PMID: 16814646
  14. Prescriber's Letter 15(3): 2008 Is abrupt discontinuation of Plavix (Clopidogrel) Safe? Detail-Document#: 240305 (subscription needed) http://www.prescribersletter.com - Ho PM et al, Indidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008, 299:532 PMID: 18252883
  15. Bliden KP et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 2008 Aug 12; 52:531. PMID: 18687246
  16. Prescriber's Letter 15(21): 2008 Reducing the Risk for GI Bleeding with Antiplatelet Drugs Detail-Document#: 241205 (subscription needed) http://www.prescribersletter.com
  17. Bhatt DL et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol 2008 Nov; 103:2890. - Bhatt DL et al, ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008 Oct 28;52(18):1502-17. PMID: 19017521 - Bhatt DL et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008 Oct 28; 118:1894. PMID: 18836135
  18. Mega JL et al Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2008 Dec 22; [e-pub ahead of print] PMID: 19106084 http://dx.doi.org/10.1056/NEJMoa0809171 - Simon T et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2008 Dec 22; [e-pub ahead of print] PMID: 19106083 http://dx.doi.org/10.1056/NEJMoa0808227 - Collet JP et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: A cohort study. Lancet 2008 Dec 23; [e-pub ahead of print]. PMID: 19108880 http://dx.doi.org/10.1016/S0140-6736(08)61845-0
  19. Aleil B et al Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: Results from the VASP-02 (vasodilator- stimulated phosphoprotein-02) randomized study. J Am Coll Cardiol Intv 2008 Dec; 1:631 PMID: 19463377 http://interventions.onlinejacc.org/cgi/content/full/1/6/631 - Cuisset T et al Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: A prospective, randomized study. J Am Coll Cardiol Intv 2008 Dec; 1:649 http://interventions.onlinejacc.org/cgi/content/full/1/6/649 - Bhatt DL Resisting the temptation to oversimplify antiplatelet resistance. J Am Coll Cardiol Intv 2008 Dec; 1:660 http://interventions.onlinejacc.org/cgi/content/full/1/6/660
  20. Berger JS et al Impact of clopidogrel in patients with acute coronary syndromes requiring coronary artery bypass surgery: A multicenter analysis. J Am Coll Cardiol 2008 Nov 18; 52:1693. PMID: 19007688
  21. Desai NR et al. Interaction between cigarette smoking and clinical benefit of clopidogrel. J Am Coll Cardiol 2009 Apr 14; 53:1273. PMID: 19358940
  22. Prescriber's Letter 16(7): 2009 Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: 250706 (subscription needed) http://www.prescribersletter.com - Prescriber's Letter 16(11): 2009 Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: 251107 (subscription needed) http://www.prescribersletter.com
  23. Prescriber's Letter 16(10): 2009 The Case for a Higher Maintenance Dose of Clopidogrel (Plavix) Detail-Document#: 251004 (subscription needed) http://www.prescribersletter.com
  24. O'Donoghue ML 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 Sep 19; 374:989. PMID: 19726078
  25. FDA MedWatch, Posted 11/17/2009 Clopidogrel (marketed as Plavix) and Omeprazole (marketed as Prilosec) - Drug Interaction http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm190848.htm
  26. FDA Alert, 11/17/2009 Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC) http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm
  27. Prescriber's Letter 17(1): 2010 Cytochrome P450 Drug Interactions CHART: Cytochrome P450 Drug Interactions COMMENTARY: Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: 260112 (subscription needed) http://www.prescribersletter.com
  28. FDA Medwatch Plavix (clopidogrel): Reduced effectiveness in patients who are poor metabolizers of the drug http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm204256.htm
  29. Hsu P-I et al. Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology 2011 Mar; 140:791. PMID: 21144850
  30. Cook-Norris RH et al. Complications of cutaneous surgery in patients taking clopidogrel-containing anticoagulation. J Am Acad Dermatol 2011 Apr 22 PMID: 21514003 http://www.sciencedirect.com/science/article/pii/S0190962211002386
  31. Bauer T et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: Systematic review and meta-analysis. BMJ 2011 Aug 4; 343:d4588 PMID: 21816733
  32. Holmes MV et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: A systematic review and meta-analysis. JAMA 2011 Dec 28; 306:2704. PMID: 22203539 - Nissen SE. Pharmacogenomics and clopidogrel: Irrational exuberance? JAMA 2011 Dec 28; 306:2727. PMID: 22203545
  33. Prescriber's Letter 19(4): 2012 CHART: Anticipated Availability of First-Time Generics Detail-Document#: 280401 (subscription needed) http://www.prescribersletter.com - FDA News Release: May 17, 2012 FDA approves generic versions of blood thinner Plavix http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm304489.htm
  34. Ng F-H et al. Esomeprazole compared with famotidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction. Am J Gastroenterol 2012 Mar; 107:389. PMID: 22108447
  35. Douglas IJ et al Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. BMJ 2012;345:e4388 PMID: 22782731 http://www.bmj.com/content/345/bmj.e4388 - Targownik LE Prescribing proton pump inhibitors with clopidogrel BMJ 2012;345:e4558 PMID: 22782732 http://www.bmj.com/content/345/bmj.e4558
  36. Andersson C et al Association of Clopidogrel Treatment With Risk of Mortality and Cardiovascular Events Following Myocardial Infarction in Patients With and Without Diabetes. JAMA. 2012;308(9):882-889 PMID: 22948698 http://jama.jamanetwork.com/article.aspx?articleid=1356353 - Bhatt DL Antiplatelet Therapy Following Myocardial Infarction in Patients With Diabetes JAMA. 2012;308(9):921-922 PMID: 22948703 http://jama.jamanetwork.com/article.aspx?articleid=1356337
  37. Gagne JJ et al Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison. BMJ 2013;347:f5307 http://www.bmj.com/content/347/bmj.f5307
  38. Lin CC et al Risk factors of gastrointestinal bleeding in clopidogrel users: A nationwide population-based study. Aliment Pharmacol Ther 2013 Nov; 38:1119 PMID: 24099473
  39. Deprecated Reference
  40. Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. J Am Coll Cardiol. 2011 Mar 15;57(11):1251-63. Review. PMID: 21392639
  41. Cuisset T, Frere C, Quilici J et al Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol. 2009 Sep 22;54(13):1149-53. PMID: 19761935
  42. 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 Aug;30(8):787-96 PMID: 20653354
  43. The NNT: Clopidogrel Added To Aspirin During and After a Coronary Event or a Stent Procedure. http://www.thennt.com/nnt/clopidogrel-added-to-aspirin-during-and-after-a-coronary-event-or-stenting/
  44. The NNT: Clopidogrel to Prevent Cardiovascular Disease for People Who Have Had Heart Attacks or Strokes. http://www.thennt.com/nnt/clopidogrel-for-cardiovascular-prevention-after-prior-heart-attack-or-stroke/
  45. The NNT: Clopidogrel Added to Aspirin to Prevent a Second Heart Attack Or Stroke. http://www.thennt.com/nnt/clopidogrel-with-aspirin-for-prevention-after-prior-heart-attack-or-stroke/ - Squizzato A, Keller T, Romualdi E, Middeldorp S Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD005158 PMID: 21249668 - Bowry AD, Brookhart MA, Choudhry NK. Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. Am J Cardiol. 2008 Apr 1;101(7):960-6 PMID: 18359315
  46. FDA News Release. June 22, 2015 FDA approves new antiplatelet drug used during heart procedure. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm452172.htm
  47. Cardoso RN et al. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: An updated meta-analysis. Open Heart 2015; 2:e000248 PMID: 26196021 http://openheart.bmj.com/content/2/1/e000248
  48. FDA Safety Alert. Nov 6, 2015 Plavix (clopidogrel): Drug Safety Communication - Long-term Treatment Does Not Change Risk of Death. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm471531.htm - FDA Drug Safety Communication. Nov 6, 2015 FDA review finds long-term treatment with blood-thinning medicine Plavix (clopidogrel) does not change risk of death. http://www.fda.gov/Drugs/DrugSafety/ucm471286.htm