The Korean Journal of Medicine

  • 제80권4호
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  • Pages.434-442
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  • 2011
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  • 1738-9364(pISSN)
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  • 2289-0769(eISSN)
대한내과학회 (The Korean Association of Internal Medicine)
권호 표지

허혈성 심장 환자에서 프로톤펌프억제제와 Clopidogrel 병용투여 효과

Effect of Proton Pump Inhibitor and Clopidogrel Combination on the Outcome of Patients with Ischemic Heart Disease

  • 김원희 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 홍성표 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 김용훈 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 김도형 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 정준구 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 박일 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 이중민 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 권창일 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 고광현 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 황성규 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 박필원 (CHA의과학대학교 분당차병원 소화기센터) ;
  • 임규성 (CHA의과학대학교 분당차병원 소화기센터)
  • Kim, Won-Hee (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Hong, Sung-Pyo (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Kim, Yong-Hun (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Kim, Do-Hyung (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Chung, Jun-Gu (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Park, Il (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Lee, Jung-Min (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Kwon, Chang-Il (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Ko, Kwang-Hyun (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Hwang, Seong-Gyu (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Park, Pil-Won (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine) ;
  • Rim, Kyu-Seong (Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine)
  • 발행 : 2011.04.01
⟨ 이전 논문 다음 논문 ⟩

초록

목적: 허혈성 심장환자에서 clopidogrel과 프로톤펌프억제제를 함께 사용하는 경우 임상적 예후에 영향을 미친다는 것이 최근 연구에서 밝혀지고 있으나 아직 국내 자료는 없는 실정이다. 이에 저자들은 국내 단일 기관을 내원한 환자를 대상으로 두 약제의 사용이 허혈성 심장환자의 임상경과에 미치는 영향을 살펴보고자 하였다. 방법: 2003년 1월부터 2007년 12월까지 협심증과 심근경색증으로 분당차병원에 내원한 환자 중 clopidogrel 투약을 시작한 환자를 대상으로 하였다. 프로톤펌프억제제를 함께 투여한 환자군을 실험군, clopidogrel만 단독으로 투여한 환자군을 대조군으로 하여 의무기록 분석을 통한 후향적 연구를 시행하였다. 결과: 흉통으로 인한 재입원이나 사망률은 실험군에서 42.4%, 대조군에서 24.2%로 유의하게 차이가 있었으며, 다변량 분석에서 프로톤펌프억제제의 병용투여는 clopidogrel을 사용하는 허혈성 심장환자에서 프로톤펌프억제제를 투여하지 않는 환자에 비해 재입원이나 사망의 위험을 높이는 것으로 나타났다(adjusted HR 2.51, 95% CI 1.43~4.40, p = 0.001). 약제 별 하위집단 분석에서는 lansoprazole의 병용투여가 그렇지 않은 환자에 비해 2.66배의 위험도를 나타내었다(adjusted HR 2.66, 95% CI 1.45~4.89, p = 0.002). 약제 사용 기간이나 용량은 재입원이나 사망의 위험도에 영향을 주지 않았다. 흉통으로 재입원 한 환자 중 재관류 요법을 다시 시행한 경우는 13.1%와 11.1%로 차이가 없었다. H. pylori의 감염 유무에 따른 primary outcome의 차이는 없었다. 결론: 허혈성 심장환자에서 재관류요법 후 clopidogrel을 투여할 때, 프로톤펌프억제제를 함께 투여하는 경우에는 흉통으로 인한 재입원이나 사망률 및 재관류요법의 시행률을 높이므로 약제의 사용에 주의를 기울여야 할 것으로 보인다.

Background/Aims: It has recently been suggested that proton pump inhibitors (PPIs) might reduce the inhibitory effect of clopidogrel on platelet aggregation. Co-administration of a PPI and clopidogrel in patients with ischemic heart disease may thus alter clinical outcome. We investigated the effect of concomitant use of a PPI with clopidogrel in Korean patients with ischemic heart disease. Methods: This is a retrospective cohort study of 99 patients with acute coronary syndrome taking clopidogrel and PPIs after discharge from CHA Bundang Medical Center between January 1, 2003, and December 31, 2007. The control group consisted of 99 patients who were matched for age and sex but were not taking PPIs. Results: Patients who received clopidogrel plus PPI had a greater than two times higher risk of re-admission or death (adjusted hazard ratio 2.51; 95% confidence interval [CI] 1.43~4.40; p = 0.001) than those who received clopidogrel alone. Lansoprazole use was associated with an increased risk of re-admission or death (adjusted hazard ratio 2.66; 95% CI 1.45~4.89; p = 0.002). Combined period of administration or Helicobacter pylori infection did not affect the risk of re-admission or death. Conclusions: Particular attention should be paid when patients with ischemic heart disease are prescribed a combination of clopidogrel and a PPI, since this combination was associated with an elevated risk of re-admission or death.

키워드

참고문헌

  1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. https://doi.org/10.1056/NEJMoa010746
  2. 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;358:527-533. https://doi.org/10.1016/S0140-6736(01)05701-4
  3. Jeong YH, Koh JS, Kang MK, et al. The impact of generic clopidogrel bisulfate on platelet inhibition in patients with coronary artery stents: results of the ACCEL-GENERIC Study. Korean J Intern Med 2010;25:154-161. https://doi.org/10.3904/kjim.2010.25.2.154
  4. Hollopeter G, Jantzen HM, Vincent D, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001;409:202-207. https://doi.org/10.1038/35051599
  5. Savi P, Combalbert J, Gaich C, et al. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost 1994;72:313-317.
  6. 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;101:1088-1093. https://doi.org/10.1016/j.amjcard.2007.11.065
  7. Miao J, Liu R, Li Z. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:2250-2251.
  8. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171-3175. https://doi.org/10.1161/01.CIR.0000130846.46168.03
  9. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-375. https://doi.org/10.1056/NEJMoa0808227
  10. Bhatt DL, Scheiman J, Abraham NS, 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;118:1894-1909. https://doi.org/10.1161/CIRCULATIONAHA.108.191087
  11. 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;51:256-260. https://doi.org/10.1016/j.jacc.2007.06.064
  12. van Boxel OS, van Oijen MG, Hagenaars MP, Smout AJ, Siersema PD. Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study. Am J Gastroenterol 2010;105:2430-2436. https://doi.org/10.1038/ajg.2010.334
  13. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-718. https://doi.org/10.1503/cmaj.082001
  14. 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;301:937-944. https://doi.org/10.1001/jama.2009.261
  15. Friesen MH. Interaction between clopidogrel and proton pump inhibitors. CMAJ 2009;180:1228. https://doi.org/10.1503/cmaj.1090017
  16. 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;374:989-997. https://doi.org/10.1016/S0140-6736(09)61525-7
  17. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003;107:32-37. https://doi.org/10.1161/01.CIR.0000047060.60595.CC
  18. Saw J, Steinhubl SR, Berger PB, et al. Clopidogrel for the Reduction of Events During Observation Investigators. Lack of adverse clopidogrel atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 2003;108:921-924. https://doi.org/10.1161/01.CIR.0000088780.57432.43
  19. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909-1917. https://doi.org/10.1056/NEJMoa1007964
  20. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010;31:810-823.
  21. Siller-Matula JM, Jilma B, Schrör K, Christ G, Huber K. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemost 2010;8:2624-2641. https://doi.org/10.1111/j.1538-7836.2010.04049.x
  22. Wu CY, Chan FK, Wu MS, et al. Histamine2-receptor antagonists are an alternative to proton pump inhibitor in patients receiving clopidogrel. Gastroenterology 2010;139:1165-1171. https://doi.org/10.1053/j.gastro.2010.06.067
  23. Fontes-Carvalho R, Albuquerque A, Arauju C, Nunes P, Gama-Ribeiro V. The clopidogrel: proton pump inhibitor's drug interaction is not a class effect: a randomized clinical study in patients after acute myocardial infarction under dual anti-platelet therapy. Gut 2010;59(suppl III):A2.
  24. Dunn SP, Macaulay TE, Brennan DM, et al. Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of cloidogrel in the CREDO trial. Circulation 2008;118(A:3999):815.
  25. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 2004;32:821-827. https://doi.org/10.1124/dmd.32.8.821
  26. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1-e5. https://doi.org/10.1016/j.ahj.2008.11.004
  27. Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol 2008;52:1038-1039.
  28. Kowalski M, Konturek PC, Pieniazek P, et al. Prevalence of helicobacter pylori infection in coronary artery disease and effect of its eradication on coronary lumen reduction after percutaneous coronary angioplasty. Dig Liver Dis 2001;33:222-229. https://doi.org/10.1016/S1590-8658(01)80711-8