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Integrative Medicine on Optimizing Clopidogrel and Aspirin Therapy

Abstract

This article reviews the available published data on optimizing clopidogrel and aspirin therapy using translational and integrative medicine. Translational and evidence-based medical studies show that the CYP2C19 gene mutation (CYP2C19*2 and CYP2C19*3) could affect > 50% of the Chinese population, and that this mutation is closely associated with clopidogrel resistance and an increased risk of major adverse cardiovascular events, particularly stent thrombosis in patients following percutaneous coronary intervention (PCI). Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation (AF), and warfarin is substantially more efficacious than aspirin. However, a poor compliance is a big problem in warfarin use especially in China. The genetic variants of vitamin K expoxide reductase might account for the universally lower warfarin dosage used in Chinese population. The available evidence indicates that the integrating mainstream treatments (e.g., clopidogrel, CYP2C19 genotyping) and non-mainstream medicines [e.g., Chinese medicines, Naoxintong Capsule (脑心通胶囊, NXT)] to treat CYP2C19 gene mutation patients following PCI can be effective. Aspirin combined NXT and the adjusted-dose warfarin was equally effective in elderly patients with non-valvular AF in prevention of ischemic stroke.

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References

  1. Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet 2012;379:1705–1711.

    Article  CAS  PubMed  Google Scholar 

  2. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354–362.

    Article  CAS  PubMed  Google Scholar 

  3. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010;121:512–518.

    Article  CAS  PubMed  Google Scholar 

  4. Dai ZL, Chen H, Wu XY. Relationship between cytochrome P450 2C19*17 genotype distribution, platelet aggregation and bleeding risk in patients with blood stasis syndrome of coronary artery disease treated with clopidogrel. J Integr Med 2012;10:647–654.

    Google Scholar 

  5. Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2010;56:321–341.

    Article  CAS  PubMed  Google Scholar 

  6. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, et al. French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363–375.

    CAS  PubMed  Google Scholar 

  7. Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dörrler K, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009;30:916–922.

    Article  CAS  PubMed  Google Scholar 

  8. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 2010;304:1821–1830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Man M, Farmen M, Dumaual C, Teng CH, Moser B, Irie S, et al. Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol 2010;50:929–940.

    Article  CAS  PubMed  Google Scholar 

  10. Chen H, Yan W, Wu XY. Relationships of blood stasis syndrome, CYP2C19 gene polymorphism with clopidogrel resistance and post-PCI prognosis. Chin J Integr Tradit West Med (Chin) 2010;30:1245–1249.

    Google Scholar 

  11. Sun H, Qu Q, Chen ZF, Tan SL, Zhou HJ, Qu J, et al. Impact of CYP2C19 variants on clinical efficacy of clopidogrel and 1-year clinical outcomes in coronary heart patients undergoing percutaneous coronary intervention. Front Pharmacol 2016;7:453.

    PubMed  PubMed Central  Google Scholar 

  12. Jang JS, Cho KI, Jin HY, Seo JS, Yang TH, Kim DK, et al. Meta-analysis of cytochrome P450 2C19 polymorphism and risk of adverse clinical outcomes among coronary artery disease patients of different ethnic groups treated with clopidogrel. Am J Cardiol 2012;110:502–508.

    Article  CAS  PubMed  Google Scholar 

  13. Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007;115:708–716.

    Article  CAS  PubMed  Google Scholar 

  14. Mega JL, Hochholzer W, Frelinger AL 3rd, Kluk MJ, Angiolillo DJ, Kereiakes DJ, et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA 2011;306:2221–2228.

    Article  CAS  PubMed  Google Scholar 

  15. Price MJ, Murray SS, Angiolillo DJ, Lillie E, Smith EN, Tisch RL, et al. GIFT Investigators. 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. Am Coll Cardiol 2012;59:1928–1937.

    Article  CAS  Google Scholar 

  16. Valenti R, Marcucci R, Comito V, Marrani M, Cantini G, Migliorini, et al. Prasugrel in clopidogrel nonresponders undergoing percutaneous coronary intervention: The RECLOSE-3 Study (REsponsiveness to CLOpidogrel and StEnt Thrombosis). JACC Cardiovasc Interv 2015;8:1563–1570.

    Article  PubMed  Google Scholar 

  17. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 2013;94:317–323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jeong YH, Lee SW, Choi BR, Kim IS, Seo MK, Kwak CH, et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive Cilostazol Versus High Maintenance Dose Clopidogrel in Patients with Clopidogrel Resistance) randomized study. J Am Coll Cardiol 2009;53:1101–1109.

    Article  CAS  PubMed  Google Scholar 

  19. Ben-Dor I, Torguson R, Scheinowitz M, Li Y, Delhaye C, Wakabayashi K, et al. Incidence, correlates, and clinical impact of nuisance bleeding after antiplatelet therapy for patients with drug-eluting stents. Am Heart J 2010;159:871–875.

    Article  CAS  PubMed  Google Scholar 

  20. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057.

    CAS  PubMed  Google Scholar 

  21. Müller K, Aichele S, Herkommer M, Bigalke B, Stellos K, Htun P, et al. Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease. Atherosclerosis 2010;213:256–262.

    Article  CAS  PubMed  Google Scholar 

  22. Ge H, Zhou Y, Liu X, Nie X, Wang Z, Guo Y, et al. Relationship between plasma inflammatory markers and platelet aggregation in patients with clopidogrel resistance after angioplasty. Angiology 2012;63:62–66.

    Article  CAS  PubMed  Google Scholar 

  23. Antoniades C, Bakogiannis C, Tousoulis D, Antonopoulos AS, Stefanadis C. The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 2009;54:669–677.

    Article  CAS  PubMed  Google Scholar 

  24. Gavins FN, Li G, Russell J, Perretti M, Granger DN. Microvascular thrombosis and CD40/CD40L signaling. J Thromb Haemost 2011;9:574–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jin R, Zhang B. Analysis on complex characteristics of traditional Chinese medicine property theory. China J Chin Materia Med (Chin) 2012;37:3340–3343.

    Google Scholar 

  26. Lardizabal JA, Joshi BK, Ambrose JA.The balance between anti-ischemic efficacy and bleeding risk of antithrombotic therapy in percutaneous coronary intervention: a yin-yang paradigm. J Invasive Cardiol 2010;22:284–292.

    PubMed  Google Scholar 

  27. Zhang Y, Chen H, Li CD, Wu HX, Lin YC. Influence of syndrome of qi deficiency with blood stasis on the anti-thrombosis effect after percutaneous coronary intervention. J Traditional Chinese Med 2011;52:859–861.

    Google Scholar 

  28. Hao CZ, Wu F, Shen J, Lu L, Fu DL, Liao WJ, et al. Clinical efficacy and safety of Buyang Huanwu Decoction for acute ischemic stroke: a systematic review and meta-analysis of 19 randomized controlled trials. Evid Based Complement Alternat Med 2012;2012:630124.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yang G, Fang Z, Liu Y, Zhang H, Shi X, Ji Q, et al. Protective effects of Chinese traditional medicine Buyang Huanwu Decoction on myocardial injury. Evid Based Complement Alternat Med 2011;2011:930324.

    PubMed  PubMed Central  Google Scholar 

  30. Liu Y, Lin R, Shi X, Fang Z, Wang W, Lin Q, et al. The roles of Buyang Huanwu Decoction in anti-inflammation, antioxidation and regulation of lipid metabolism in rats with myocardial ischemia. Evid Based Complement Alternat Med 2011;2011:561396.

    PubMed  PubMed Central  Google Scholar 

  31. Huang MW, Wang H, Zhong WJ, Wu XY, Chen H. Chinese herbal medicine Naoxintong Capsule combined with dual antiplatelet therapy in a rat model of coronary microembolization induced by homologous microthrombi. J Integr Med 2011;9:38–48.

    Google Scholar 

  32. Wang H, Zhong WJ, Huang MW, Wu XY, Chen H. Efficacy of dual antiplatelet therapy combined with Naoxintong Capsules following coronary microembolization induced by homologous microthrombi in rats. Chin J Integr Med 2011;17:917–924.

    Article  CAS  PubMed  Google Scholar 

  33. Sun H, Lou XY, Wu XY, Wang H, Qu Q, Tan SL, et al. Up-regulation of CYP2C19 expression by Buchang Naoxintong via PXR activation in HepG2 cells. PLoS One 2016;11:e0160285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen H, Wu XY, Wu HX, Wang H. A randomized controlled trial of adjunctive Naoxintong Capsule versus maintenance dose clopidogrel in patients with CYP2C19*2 polymorphism. Chin J Integr Med 2014;20:894–902.

    Article  PubMed  Google Scholar 

  35. Gao Q, Fu X, Wei JW, Chen X, Huang Y, Wang J, et al. China QUEST Study Investigators. Use of oral anticoagulation among stroke patients with atrial fibrillation in China: the ChinaQUEST (Quality evaluation of stroke care and treatment) registry study. Int J Stroke 2013;8:150–154.

    Article  PubMed  Google Scholar 

  36. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest 2010;137:263–272.

    Article  PubMed  Google Scholar 

  37. Zheng LF, Chen H. Investigation of anticoagulation therapy for elderly patients with high risk of nonvanular atrial fibrillation. Clin J Clinicians (Electronic ed). 2012;6:874–878.

    Google Scholar 

  38. Su L, Li Y, Lv B, Ji H, Ding H, Hu L, et al. Clinical study on Naoxintong Capsule for stroke recovery of qi-deficiency and blood-stasis syndrome. China J Chin Materia Med (Chin) 2011;36:1530–1533.

    Google Scholar 

  39. Chen C, Venketasubramanian N, Gan RN, Lambert C, Picard D, Chan BP, et al. Danqi Piantang Jiaonang (DJ), a traditional Chinese medicine, in poststroke recovery. Stroke 2009;40:859–863.

    Article  PubMed  Google Scholar 

  40. Chen D, Lu P, Zhang FB, Tang SH, Yang HJ. Molecular mechanism research on simultaneous therapy of brain and heart based on data mining and network analysis. China J Chin Mater Med (Chin) 2013;38:91–98.

    CAS  Google Scholar 

  41. Zhou GY, Hu XQ, Chen XH. Experimental study on effect of Naoxintong containing serum for antagonizing hypoxia-induced apoptosis of cortical neurons. Chin J Integr Tradit West Med (Chin) 2007;27:835–838.

    Google Scholar 

  42. Wang H, Zhou XK, Zheng LF, Wu XY, Chen H. Comparison of aspirin and Naoxintong Capsule with adjusted-dose warfarin in elderly patients with high-risk of non-valvularatrial fibrillation and genetic variants of vitamin K epoxide reductase. Chin J Integr Med 2018;24:247–253.

    Article  PubMed  Google Scholar 

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Correspondence to Hui Chen.

Additional information

Supported by the National Natural Science Fundation of China (No. 81373838), Ministry of Health of the People’s Republic of China of Fujian Province Health Education Union Scientific grants (No. WKJ 2008-2-59), and Provincial Natural Science Foundation of Fujian (No. 2011J0133)

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Chen, H. Integrative Medicine on Optimizing Clopidogrel and Aspirin Therapy. Chin. J. Integr. Med. 25, 395–400 (2019). https://doi.org/10.1007/s11655-017-2551-4

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  • DOI: https://doi.org/10.1007/s11655-017-2551-4

Keywords

  • integrative medicine
  • clopidogrel
  • aspirin
  • optimizing therapy
  • Chinese medicine