clopidogrel (Plavix)

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Introduction

Tradename: Plavix. Clopidogrel bisulfate. Generic May 2012[33]

Indications

* 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

Benefit/risk

Dosage

Tabs: 75 mg

Pharmacokinetics

  • rapidly absorbed after oral administration
  • absorbtion unaffected by food
  • activation dependent upon CYP3A4 & CYP2C19;
    • reduced function CYP2C19 alleles inadequately activate clopidogrel & are associated with worse clinical outcomes[18]
    • CYP2C19*1 allele fully functional metabolism of clopidogrel
    • 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
    • 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
    • a patient with two loss-of-function alleles will have poor metabolizer status
  • cyt P450 2B metabolizes clopidogrel to inactive metabolites
  • steady state activity takes 3-7 days
  • once stopped, it takes 5 days for anti-platelet activity to stop
  • 600 mg achieves maximum platelet inhibition in 2 hours

* ticagrelor & pasugrel not activated by CYP2C19

elimination via kidney

elimination via liver

1/2life = 8 hours

Monitor

Adverse effects

Drug interactions

Mechanism of action

Notes

cost $110/month in US (2001), $150/month (2009)

More general terms

Additional terms

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. ↑ 4.0 4.1 Prescriber's Letter 8(4):20 2001 Clopidogrel In The Treatment Of Acute Coronary Syndromes Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=170422&pb=PRL (subscription needed) http://www.prescribersletter.com
  5. ↑ Prescriber's Letter 9(4):20 2002
  6. ↑ 6.0 6.1 Prescriber's Letter 10(1):1 2003
  7. ↑ 7.0 7.1 Journal Watch 23(20):161, 2003 Saw J et al, Circulation 108(Aug 26):921, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12925453
  8. ↑ 8.0 8.1 8.2 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: https://www.ncbi.nlm.nih.gov/pubmed/15276392
  9. ↑ Prescriber's Letter 11(10): 2004 Concomitant use of Aspirin and Clopidogrel (Plavix) in Cerebrovascular Disease Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=201002&pb=PRL (subscription needed) http://www.prescribersletter.com
  10. ↑ 10.0 10.1 Ovbiagele B, In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
  11. ↑ 11.0 11.1 Prescriber's Letter 12(3): 2005 Safety of Clopidogrel (Plavix) in Patients at Risk for Ulcers Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=210304&pb=PRL (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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/15659730
  12. ↑ 12.0 12.1 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: https://www.ncbi.nlm.nih.gov/pubmed/16143698
  13. ↑ 13.0 13.1 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: https://www.ncbi.nlm.nih.gov/pubmed/16814646
  14. ↑ Prescriber's Letter 15(3): 2008 Is abrupt discontinuation of Plavix (Clopidogrel) Safe? Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=240305&pb=PRL (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: https://www.ncbi.nlm.nih.gov/pubmed/18252883
  15. ↑ 15.0 15.1 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: https://www.ncbi.nlm.nih.gov/pubmed/18687246
  16. ↑ 16.0 16.1 Prescriber's Letter 15(21): 2008 Reducing the Risk for GI Bleeding with Antiplatelet Drugs Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=241205&pb=PRL (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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/18836135
  18. ↑ 18.0 18.1 Mega JL et al Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2008 Dec 22; [e-pub ahead of print] <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19106084 <Internet> 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] <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19106083 <Internet> 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]. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19108880 <Internet> http://dx.doi.org/10.1016/S0140-6736(08)61845-0
  19. ↑ 19.0 19.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19463377 <Internet> 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. ↑ 20.0 20.1 20.2 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: https://www.ncbi.nlm.nih.gov/pubmed/19007688
  21. ↑ 21.0 21.1 Desai NR et al. Interaction between cigarette smoking and clinical benefit of clopidogrel. J Am Coll Cardiol 2009 Apr 14; 53:1273. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19358940
  22. ↑ 22.0 22.1 22.2 Prescriber's Letter 16(7): 2009 Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250706&pb=PRL (subscription needed) http://www.prescribersletter.com
    Prescriber's Letter 16(11): 2009 Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=251107&pb=PRL (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#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=251004&pb=PRL (subscription needed) http://www.prescribersletter.com
  24. ↑ 24.0 24.1 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: https://www.ncbi.nlm.nih.gov/pubmed/19726078
  25. ↑ 25.0 25.1 25.2 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. ↑ 26.0 26.1 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#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260112&pb=PRL (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. ↑ 29.0 29.1 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: https://www.ncbi.nlm.nih.gov/pubmed/21144850
  30. ↑ 30.0 30.1 Cook-Norris RH et al. Complications of cutaneous surgery in patients taking clopidogrel-containing anticoagulation. J Am Acad Dermatol 2011 Apr 22 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/21514003 <Internet> http://www.sciencedirect.com/science/article/pii/S0190962211002386
  31. ↑ 31.0 31.1 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: https://www.ncbi.nlm.nih.gov/pubmed/21816733
  32. ↑ 32.0 32.1 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: https://www.ncbi.nlm.nih.gov/pubmed/22203539
    Nissen SE. Pharmacogenomics and clopidogrel: Irrational exuberance? JAMA 2011 Dec 28; 306:2727. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22203545
  33. ↑ 33.0 33.1 Prescriber's Letter 19(4): 2012 CHART: Anticipated Availability of First-Time Generics Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=280401&pb=PRL (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. ↑ 34.0 34.1 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: https://www.ncbi.nlm.nih.gov/pubmed/22108447
  35. ↑ 35.0 35.1 Douglas IJ et al Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. BMJ 2012;345:e4388 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22782731 <Internet> http://www.bmj.com/content/345/bmj.e4388
    Targownik LE Prescribing proton pump inhibitors with clopidogrel BMJ 2012;345:e4558 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22782732 <Internet> http://www.bmj.com/content/345/bmj.e4558
  36. ↑ 36.0 36.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22948698 <Internet> 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22948703 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=1356337
  37. ↑ 37.0 37.1 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. ↑ 38.0 38.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/20653354
  43. ↑ 43.0 43.1 43.2 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. ↑ 44.0 44.1 44.2 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. ↑ 45.0 45.1 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/18359315
  46. ↑ 46.0 46.1 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. ↑ 47.0 47.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26196021 <Internet> http://openheart.bmj.com/content/2/1/e000248
  48. ↑ 48.0 48.1 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

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