Heart and Vessels

, Volume 28, Issue 3, pp 292–300

Adverse cardiovascular outcomes associated with concurrent use of clopidogrel or ticlopidine and proton-pump inhibitors in patients undergoing percutaneous coronary intervention

Original Article

Abstract

Recent clinical studies reported the drug interaction between proton-pump inhibitors (PPI) and clopidogrel, which remains controversial. The aim of this study was to determine whether the concurrent use of PPI with clopidogrel or ticlopidine is associated with increased risk for adverse cardiovascular outcomes in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). In this retrospective cohort study, we assessed the cardiovascular outcomes associated with the concurrent use of PPI and clopidogrel or ticlopidine in the well-characterized 1286 patients with CAD undergoing PCI in the University of Tokyo Hospital. In the Japanese patients with CAD undergoing PCI, the concurrent use of PPI was significantly associated with increased risk for major adverse cardiovascular events in the ticlopidine users (hazard ratio 2.63; 95 % confidence interval 1.65–4.18; P < 0.001), but not in the clopidogrel users. In the clopidogrel users as well as the ticlopidine users, PPI use did not affect the occurrence of target lesion revascularization, but significantly increased the risk for new lesion formation in the coronary arteries, which required subsequent revascularization. The adverse cardiovascular effects of the concurrent use of PPI and ticlopidine were identified in the patients with CAD undergoing PCI. Also, new lesion formation in the coronary arteries was shown to be increased when PPI was coprescribed for the thienopyridine users.

Keywords

Proton-pump inhibitor Clopidogrel Ticlopidine Cardiovascular outcome 

References

  1. 1.
    Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DE Jr, Green LA, Hochman JS, Jacobs AK, Krumholz HM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL, Williams DO (2009) 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. Circulation 120:2271–2306PubMedCrossRefGoogle Scholar
  2. 2.
    Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction. Circulation 116:e148–e304PubMedCrossRefGoogle Scholar
  3. 3.
    Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF (2007) Guidelines for the early management of adults with ischemic stroke. Stroke 38:1655–1711PubMedCrossRefGoogle Scholar
  4. 4.
    Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG (2007) Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 45:S5–S67PubMedCrossRefGoogle Scholar
  5. 5.
    Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM (2008) ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation 118:1894–1909PubMedCrossRefGoogle Scholar
  6. 6.
    Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J (2008) 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 51:256–260PubMedCrossRefGoogle Scholar
  7. 7.
    Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS (2009) Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 301:937–944PubMedCrossRefGoogle Scholar
  8. 8.
    Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM (2009) A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 180:713–718PubMedCrossRefGoogle Scholar
  9. 9.
    Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, Ramsey S (2010) Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med 170:704–710PubMedCrossRefGoogle Scholar
  10. 10.
    O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD (2009) Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 374:989–997PubMedCrossRefGoogle Scholar
  11. 11.
    Rassen JA, Choudhry NK, Avorn J, Schneeweiss S (2009) Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 120:2322–2329PubMedCrossRefGoogle Scholar
  12. 12.
    Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty JR, Kaltenbach LA, Stein CM (2010) Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med 152:337–345PubMedCrossRefGoogle Scholar
  13. 13.
    Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP, COGENT Investigators (2010) Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 363:1909–1917PubMedCrossRefGoogle Scholar
  14. 14.
    Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360:363–375PubMedCrossRefGoogle Scholar
  15. 15.
    Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362PubMedCrossRefGoogle Scholar
  16. 16.
    Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G (2009) Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373:309–317PubMedCrossRefGoogle Scholar
  17. 17.
    Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302:849–857PubMedCrossRefGoogle Scholar
  18. 18.
    Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KA, Eikelboom JW (2010) Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 363:1704–1714PubMedCrossRefGoogle Scholar
  19. 19.
    Bhatt DL, Bertrand ME, Berger PB, L’Allier PL, Moussa I, Moses JW, Dangas G, Taniuchi M, Lasala JM, Holmes DR, Ellis SG, Topol EJ (2002) Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 39:9–14PubMedCrossRefGoogle Scholar
  20. 20.
    Tsukahara K, Kimura K, Morita S, Ebina T, Kosuge M, Hibi K, Iwahashi N, Endo M, Maejima N, Sugano T, Umemura S (2011) Impact of concomitant use of proton-pump inhibitors and thienopyridine derivatives on the antiplatelet effects. J Cardiol 57:275–282PubMedCrossRefGoogle Scholar
  21. 21.
    Fukushima K, Kobayashi Y, Kitahara H, Iwata Y, Kuroda N, Ooyama M, Kuwabara Y, Nomura F, Komuro I (2010) Antiplatelet effect of 50-mg maintenance dose of clopidogrel compared to 200 mg ticlopidine: a preliminary study. Heart Vessels 25:41–44PubMedCrossRefGoogle Scholar
  22. 22.
    Forgacs I, Loganayagam A (2008) Overprescribing proton pump inhibitors. BMJ 336:2–3PubMedCrossRefGoogle Scholar
  23. 23.
    el-Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE (1995) Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 109:681–691PubMedCrossRefGoogle Scholar
  24. 24.
    Haruma K, Kamada T, Kawaguchi H, Okamoto S, Yoshihara M, Sumii K, Inoue M, Kishimoto S, Kajiyama G, Miyoshi A (2000) Effect of age and Helicobacter pylori infection on gastric acid secretion. J Gastroenterol Hepatol 15:277–283PubMedCrossRefGoogle Scholar
  25. 25.
    Taha AS, McCloskey C, Prasad R, Bezlyak V (2009) Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial. Lancet 374:119–125PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  1. 1.Department of Cardiovascular Medicine, Graduate School of MedicineUniversity of TokyoTokyoJapan
  2. 2.Department of Translational Research for Healthcare and Clinical Science, Graduate School of MedicineUniversity of TokyoTokyoJapan
  3. 3.Department of Ubiquitous Health Informatics, Graduate School of MedicineUniversity of TokyoTokyoJapan
  4. 4.Department of Clinical Trial Data Management, Graduate School of MedicineUniversity of TokyoTokyoJapan

Personalised recommendations