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Clopidogrel

Classification: A

Drug products: Clopidogrel Accord, Clopidogrel Actavis, Clopidogrel Aliud, Clopidogrel Aristo, Clopidogrel Aurobindo, Clopidogrel Krka, Clopidogrel Mylan, Clopidogrel Orion, Clopidogrel Pensa, Clopidogrel ratiopharm, Clopidogrel Sandoz, Clopidogrel STADA, Clopidogrel Teva, Clopidogrel Teva Pharma, Clopidogrel Teva Pharma B.V., Clopidogrel Viatris, Clopidogrel Zentiva, Cloriocard, Grepid, Klopidogrel Arrow, Plavix

ATC code: B01AC04

Substances: clopidogrel, clopidogrel besylate, clopidogrel hydrobromide monohydrate, clopidogrel hydrochloride, clopidogrel hydrogensulphate

Summary

Clopidogrel as secondary prevention lowers the risk of cardiovascular disease equally overall in men and women. In men, the risk of myocardial infarction, stroke, and total mortality of cardiovascular disease is decreased while in women the lowered risk of myocardial infarction is more pronounced. In the large COMMIT-study patients with suspected myocardial infarction was treated with clopidogrel or placebo in combination with aspirin. The addition of clopidogrel was found to lower the relative risk of death by all causes and the risk of re-infarction, stroke, or death in a similar way in men and women.

Additional information

Pharmacokinetics and dosing

Clopidogrel is a prodrug and it is reported that AUC and Cmax of the active metabolite are similar in healthy adult men and women (79 men, 77 women) [1].

Effects

A large sex-specific meta-analysis (in total 56 091 men, 23 522 women) reports that clopidogrel is effective in reducing cardiovascular events in both men and women. Women achieved cardiovascular benefit mainly by a reduced risk of myocardial infarction (MI), while men had reductions of the risks of suffering MI, stroke and all-cause mortality. Among women, the absolute risk reduction was 0.8% for the composite end point (cardiovascular event, MI, stroke, cardiovascular mortality, all-cause mortality) and 0.7% for MI alone. Among men, the absolute risk reduction was 1.2% for the composite end point and 0.6% for MI [2]. . More recent meta-analyses on P2Y12 inhibitors (prasugrel, ticagrelor, cangrelor) compared to clopidogrel confirms these findings [3, 4].

In the large COMMIT study (in total 45,852, 28% women), which was included in one of the meta-analysis, patients admitted to hospital within 24 h of suspected acute MI onset were randomly allocated clopidogrel 75 mg daily or matching placebo in addition to aspirin 162 mg daily for 4 weeks or until hospital discharge. Clopidogrel reduced the relative risk of death from any cause with 7% and the relative risk of composite outcome of death, re-infarction or stroke with 9%. This benefit was consistent across age and patient’s sex [5].

Men and women with acute coronary syndrome treated with clopidogrel had similar reduction rates of cardiovascular death, MI or stroke in the PLATO clinical trial, also included in the meta-analyses  [6], in two other clinical trials [7, 8], and a cohort study [9].

Some studies describe a higher platelet reactivity  [10-14] and more clopidogrel resistance in women [15-19], although other studies report no sex differences in platelet response to clopidogrel [20-25]. However, it is unclear whether this is explained by sex differences in pharmacodynamic response to clopidogrel [13, 14, 20, 22] or by a higher baseline pre-treatment platelet activity in women [10, 11]. Furthermore, frequency of clopidogrel resistance may vary between populations.

Adverse effects

The risk of major bleeding from clopidogrel treatment was similar in men and women in a large meta-analysis [2].  In a US register-based study in IBS patients (1489 men, 5728 women), treatment with clopidogrel was associated with a higher incidence of GI symptoms in women but not in men [26].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Updated: 2020-08-28

Date of litterature search: 2018-11-12

References

  1. Frelinger AL, Bhatt DL, Lee RD, Mulford DJ, Wu J, Nudurupati S et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;61(8):872-9. PubMed
  2. Berger JS, Bhatt DL, Cannon CP, Chen Z, Jiang L, Jones JB et al. The relative efficacy and safety of clopidogrel in women and men a sex-specific collaborative meta-analysis. J Am Coll Cardiol. 2009;54:1935-45. PubMed
  3. Zaccardi F, Pitocco D, Willeit P, Laukkanen JA. Efficacy and safety of P2Y12 inhibitors according to diabetes, age, gender, body mass index and body weight: systematic review and meta-analyses of randomized clinical trials. Atherosclerosis. 2015;240(2):439-45. PubMed
  4. Lee KK, Welton N, Shah AS, Adamson PD, Dias S, Anand A et al. Differences in relative and absolute effectiveness of oral P2Y12 inhibition in men and women: a meta-analysis and modelling study. Heart. 2018;104(8):657-664. PubMed
  5. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1607-21. PubMed
  6. Husted S, James SK, Bach RG, Becker RC, Budaj A, Heras M et al. The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2014;35(23):1541-50. PubMed
  7. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK 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. PubMed
  8. Ntalas IV, Kalantzi KI, Tsoumani ME, Bourdakis A, Charmpas C, Christogiannis Z et al. Salts of Clopidogrel: Investigation to Ensure Clinical Equivalence: A 12-Month Randomized Clinical Trial. J Cardiovasc Pharmacol Ther. 2016;21(6):516-525. PubMed
  9. Xanthopoulou I, Davlouros P, Deftereos S, Hamilos M, Sitafidis G, Kanakakis I et al. Gender-related differences in antiplatelet treatment patterns and outcome: Insights from the GReekAntiPlatElet Registry. Cardiovasc Ther. 2017;35(4):-. PubMed
  10. Bozzi LM, Mitchell BD, Lewis JP, Ryan KA, Herzog WR, O'Connell JR et al. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study: Variation in Platelet Response to Clopidogrel and Aspirin. Curr Vasc Pharmacol. 2016;14(1):116-24. PubMed
  11. Hobson AR, Qureshi Z, Banks P, Curzen N. Gender and responses to aspirin and clopidogrel: insights using short thrombelastography. Cardiovasc Ther. 2009;27(4):246-52. PubMed
  12. Bobbert P, Stellbaum C, Steffens D, Schütte C, Bobbert T, Schultheiss HP et al. Postmenopausal women have an increased maximal platelet reactivity compared to men despite dual antiplatelet therapy. Blood Coagul Fibrinolysis. 2012;23(8):723-8. PubMed
  13. Park JJ, Park KW, Kang J, Jeon KH, Kang SH, Ahn HS et al. Genetic determinants of clopidogrel responsiveness in Koreans treated with drug-eluting stents. Int J Cardiol. 2013;163(1):79-86. PubMed
  14. Bouman HJ, Harmsze AM, van Werkum JW, Breet NJ, Bergmeijer TO, Ten Cate H et al. Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting. Heart. 2011;97(15):1239-44. PubMed
  15. Osmancik P, Paulu P, Tousek P, Kocka V, Widimsky P. High leukocyte count and interleukin-10 predict high on-treatment-platelet-reactivity in patients treated with clopidogrel. J Thromb Thrombolysis. 2012;33:349-54. PubMed
  16. Staritz P, Kurz K, Stoll M, Giannitsis E, Katus HA, Ivandic BT. Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene. Int J Cardiol. 2009;133:341-5. PubMed
  17. Al-Azzam SI, Alzoubi KH, Khabour OF, Nusair MB, Al-Hadidi H, Awidi A et al. Factors that contribute to clopidogrel resistance in cardiovascular disease patients: environmental and genetic approach. Int J Clin Pharmacol Ther. 2013;51:179-86. PubMed
  18. Ivandic BT, Schlick P, Staritz P, Kurz K, Katus HA, Giannitsis E. Determination of clopidogrel resistance by whole blood platelet aggregometry and inhibitors of the P2Y12 receptor. Clin Chem. 2006;52:383-8. PubMed
  19. Feher G, Feher A, Pusch G, Koltai K, Tibold A, Gasztonyi B et al. Clinical importance of aspirin and clopidogrel resistance. World J Cardiol. 2010;2:171-86. PubMed
  20. Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302(8):849-57. PubMed
  21. Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study. J Am Coll Cardiol. 2012;59(22):1928-37. PubMed
  22. Kassimis G, Davlouros P, Xanthopoulou I, Stavrou EF, Athanassiadou A, Alexopoulos D. CYP2C19*2 and other genetic variants affecting platelet response to clopidogrel in patients undergoing percutaneous coronary intervention. Thromb Res. 2012;129(4):441-6. PubMed
  23. Koltai K, Papp J, Kenyeres P, Feher G, Tibold A, Alexy T et al. Gender differences in hemorheological parameters and in in vitro platelet aggregation in acetylsalicylic acid and clopidogrel treated vascular patients. Biorheology. 2014;51(2):197-206. PubMed
  24. Verdoia M, Pergolini P, Rolla R, Nardin M, Barbieri L, Daffara V et al. Gender Differences in Platelet Reactivity in Patients Receiving Dual Antiplatelet Therapy. Cardiovasc Drugs Ther. 2016;30(2):143-50. PubMed
  25. Lev EI, Bliden KP, Jeong YH, Pandya S, Kang K, Franzese C et al. Influence of race and sex on thrombogenicity in a large cohort of coronary artery disease patients. J Am Heart Assoc. 2014;3(5):e001167. PubMed
  26. Soghomonyan S, Abdel-Rasoul M, Zuleta-Alarcon A, Grants I, Davila V, Yu J et al. Clopidogrel IBS Patients Have Higher Incidence of Gastrointestinal Symptoms Influenced by Age and Gender. Dig Dis Sci. 2017;62(10):2728-2743. PubMed
  27. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2017 [cited 2019-01-30.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson

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