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Safety of Concomitant Use of Proton Pump Inhibitors and Clopidogrel

      To The Editor:
      We read with interest the article by Ali et al,
      • Ali T.
      • Roberts D.N.
      • Tierney W.M.
      Long-term safety concerns with proton pump inhibitors.
      “Long-term Safety Concerns with Proton Pump Inhibitors.” The article is a comprehensive review of potential safety concerns about proton pump inhibitors. However, the authors did not discuss the potential effect of proton pump inhibitors on concomitant use of clopidogrel, a medication that is widely used in patients with coronary artery disease, stroke, and other atherosclerotic diseases. Recently, there have been multiple conflicting reports about potential increase in cardiovascular events in patients taking these medications concomitantly.
      • Ho P.M.
      • Maddox T.M.
      • Wang L.
      • et al.
      Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.
      • Simon T.
      • Verstuyft C.
      • Mary-Krause M.
      • et al.
      Genetic determinants of response to clopidogrel and cardiovascular events.
      • O'Donoghue M.L.
      • Braunwald E.
      • Antman E.M.
      • et al.
      Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials.

      Bhatt DL, Cryer B, Contant CF, et al. The COGENT Trial; Transcatheter Cardiovascular Therapeutics; 2009: San Francisco, CA.

      A study by Ho et al
      • Ho P.M.
      • Maddox T.M.
      • Wang L.
      • et al.
      Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.
      of 8025 patients demonstrated increased death or rehospitalization for acute coronary syndrome occurring in concomitant clopidogrel and proton pump inhibitors use (29.8% vs 20.8%, respectively). Simon et al
      • Simon T.
      • Verstuyft C.
      • Mary-Krause M.
      • et al.
      Genetic determinants of response to clopidogrel and cardiovascular events.
      demonstrated similar findings (13% adverse events on concomitant clopidogrel and proton pump inhibitors vs 2.9% of patients on clopidogrel alone). In contrast, O'Donoghue et al
      • O'Donoghue M.L.
      • Braunwald E.
      • Antman E.M.
      • et al.
      Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials.
      did not show any significant difference in 6795 patients. Adverse cardiovascular events and deaths were seen in 11.29% on concomitant clopidogrel and proton pump inhibitors vs. 11.59% of patients on clopidogrel alone. Recently, Bhatt et al

      Bhatt DL, Cryer B, Contant CF, et al. The COGENT Trial; Transcatheter Cardiovascular Therapeutics; 2009: San Francisco, CA.

      demonstrated adverse cardiovascular events and death in 3.8% of patients on concomitant clopidogrel and proton pump inhibitors, and in 3.67% of those on clopidogrel alone.
      One of the proposed mechanisms of action has been the inhibition of the enzyme CYP2C19 responsible for the metabolism of clopidogrel. Certain proton pump inhibitors not only serve as a substrate for this enzyme but also can inhibit the enzyme CYP2C19.
      • Li X.Q.
      • Andersson T.B.
      • Ahlström M.
      • Weidolf L.
      Comparison of inhibitory effects of the proton-pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities.
      • Furuta T.
      • Ohashi K.
      • Kamata T.
      • et al.
      Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer.
      Proton pump inhibitors differ in their effect on the inhibition of the enzyme, which is potentially something to be looked for when selecting a proton pump inhibitor to be used in patients on clopidogrel.
      We believe that a dedicated powered randomized clinical trial is needed to answer this important clinical question.

      References

        • Ali T.
        • Roberts D.N.
        • Tierney W.M.
        Long-term safety concerns with proton pump inhibitors.
        Am J Med. 2009; 122: 896-903
        • Ho P.M.
        • Maddox T.M.
        • 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
        • 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
        • O'Donoghue M.L.
        • Braunwald E.
        • Antman E.M.
        • 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
      1. Bhatt DL, Cryer B, Contant CF, et al. The COGENT Trial; Transcatheter Cardiovascular Therapeutics; 2009: San Francisco, CA.

        • Li X.Q.
        • Andersson T.B.
        • Ahlström 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
        • Furuta T.
        • Ohashi K.
        • Kamata T.
        • et al.
        Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer.
        Ann Intern Med. 1998; 129: 1027-1030

      Linked Article

      • Long-term Safety Concerns with Proton Pump Inhibitors
        The American Journal of MedicineVol. 122Issue 10
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          Proton pump inhibitors (PPIs) are among the most widely prescribed medications worldwide. Their use has resulted in dramatic improvements in treatment of peptic ulcer disease and gastroesophageal reflux disease. Despite an acceptable safety profile, mounting data demonstrate concerns about the long-term use of PPIs. To provide a comprehensive review regarding the concerns of long-term PPI use, a literature search was performed to identify pertinent original and review articles. Despite study shortcomings, the collective body of information overwhelmingly suggests an increased risk of infectious complications and nutritional deficiencies.
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      • The Reply
        The American Journal of MedicineVol. 123Issue 4
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          We appreciate the thoughtful comments and critical appraisal by Khawaja et al of our article.1 We agree with the authors about the growing concern about the potential interaction between proton pump inhibitors (PPIs) and clopidogrel. However, our article was focused on long-term side effects of the medications and not the drug interactions and related complications. Also, our article was submitted for publication in January 2009, when articles about this potential interaction, as mentioned in Khawaja et al's references, were just being published.
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