Using Danish population databases, Dr Schmidt and colleagues have performed a careful analysis of the possible effects of proton pump inhibitor (PPI) co-therapy among patients given clopidogrel following percutaneous coronary intervention.1 Their study is strengthened by the reliability, size and inclusiveness of these databases. Their main finding – that PPI co-therapy did not modify the protective effect of clopidogrel – is in keeping with our recent analyses of the literature.2, 3 Hopefully, their findings will go some way towards resolving the ongoing controversy about the use of PPIs by patients on clopidogrel.

Although the authors claim that theirs is the first study to have examined an interaction between PPIs and clopidogrel taking into account possible discontinuation and re-commencement of treatment, others have also attempted to do this.4–6 The important study by Ray et al. found no detrimental effect of PPI co-therapy on cardiovascular outcomes and a likely beneficial influence on gastrointestinal outcomes.4

The conclusion by Schmidt et al. that PPI treatment was associated with worse cardiovascular outcomes, regardless of clopidogrel use, deserves further comment. The 95% confidence interval on their adjusted hazard ratio for long-term PPI use in clopidogrel non-users encompassed unity (0.97–1.63). It would therefore be inappropriate to conclude that PPI use was a risk factor for adverse cardiovascular outcomes. As the authors discuss, there is strong possibility of confounding; patients receiving PPIs had worse cardiovascular risk profiles than patients not given a PPI.

We agree with the authors that PPI co-therapy is unlikely to adversely affect cardiovascular outcomes in patients on clopidogrel. In accordance with recent consensus-based recommendations,7 patients on clopidogrel should be given PPI co-therapy if they have additional risk factors for upper GI bleeding.


  1. Top of page
  2. Acknowledgements
  3. References

Declaration of personal interests: Dr. Leontiadis has served as a consultant to AstraZeneca. Dr. Howden is a consultant to Takeda and Otsuka, and has received honoraria from Takeda, Otsuka and GlaxoSmithKline. Declaration of funding interests: None.


  1. Top of page
  2. Acknowledgements
  3. References
  • 1
    Schmidt M, Johansen MB, Robertson DJ, et al. Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation. Aliment Pharmacol Ther 2012; 35: 16574.
  • 2
    Leontiadis GI, Yuan Y, Howden CW. The interaction between proton pump inhibitors and clopidogrel and upper gastrointestinal bleeding. Gastrointest Endosc Clin N Am 2011; 21: 63756.
  • 3
    Chen J, Yuan Y, Leontiadis GI, Howden CW. Recent safety concerns with proton pump inhibitors. J Clin Gastroenterol 2012; in press.
  • 4
    Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med 2010; 152: 33745.
  • 5
    Banerjee S, Weideman RA, Weideman MW, et al. Effect of concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention. Am J Cardiol 2011; 107: 8718.
  • 6
    Ortolani P, Marino M, Marzocchi A, De Palma R, Branzi A. One-year clinical outcome in patients with acute coronary syndrome treated with concomitant use of clopidogrel and proton pump inhibitors: results from a regional cohort study. J Cardiovasc Med (Hagerstown) 2011 [Epub ahead of print].
  • 7
    Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol 2010; 105: 253349.