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Adverse Outcomes Associated With Use of Proton Pump Inhibitors and Clopidogrel

Young Kwang Chae, MD, MPH, MBA; Jongoh Kim, MD
JAMA. 2009;302(1):29-31. doi:10.1001/jama.2009.896
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To the Editor: Dr Ho and colleagues1 reported that concomitant use of clopidogrel and a proton pump inhibitor (PPI) after discharge from hospital for acute coronary syndrome (ACS) was associated with an increased risk of rehospitalization for ACS, compared with use of clopidogrel without PPI. Based on their observations, the authors concluded that, although causality cannot be claimed, PPIs should be used based on clear clinical indications rather than prophylactic prescription. Reconsideration of prophylactic prescription of PPIs in patients with ACS has been ongoing.2 However, the recent American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) guidelines still recommend using PPIs for aspirin users with a history of myocardial infarction, many of whom are also using clopidogrel.3

The study by Ho et al found differences only in hospitalization for ACS, not in mortality. We therefore suggest that the authors compare the incidences of gastrointestinal hemorrhage and related hospitalization rates between clopidogrel users with and without routine prophylactic PPI use within their cohort.

In addition, authors should be more cautious in using the general term PPI. They found an increased risk of adverse outcomes among ACS patients using clopidogrel that was related only to use of omeprazole and labeprazole. This may not be due to a PPI class effect. Pantoprazole and esomeprazole, other PPIs also widely used in different institutions, do not inhibit CYP450 2C19.4 Moreover, in a Canadian trial including more than 13 000 patients, omeprazole, rabeprazole, and lansoprazole were associated with an increased risk of reinfarction, but there was no association for pantoprazole.5

Finally, the main purpose of this study was to investigate the interaction effect between PPI and clopidogrel on adverse outcomes in patients with ACS. However, the authors have only shown the effect of PPI on the odds ratios of adverse outcome in 2 groups: clopidogrel users and nonusers. We believe that it would also be clinically meaningful to demonstrate the effect of clopidogrel on the odds ratios of adverse outcome among PPI users and nonusers, since it may better quantify the interactive effect of PPI on the cardioprotective effect of clopidogrel.

AUTHOR INFORMATION

Financial Disclosures: None reported.

REFERENCES

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(9):937-944
PubMedCrossRef
Barada K, Karrowni W, Abdallah M, Shamseddeen W, Sharara AI, Dakik HA. Upper gastrointestinal bleeding in patients with acute coronary syndromes: clinical predictors and prophylactic role of proton pump inhibitors.  J Clin Gastroenterol. 2008;42(4):368-372
PubMedCrossRef
Bhatt DL, Scheiman J, Abraham NS,  et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.  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(18):1894-1909
PubMedCrossRef
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(1):148,e1-e5
PubMedCrossRef
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(7):713-718
PubMedCrossRef

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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(9):937-944
PubMedCrossRef
Barada K, Karrowni W, Abdallah M, Shamseddeen W, Sharara AI, Dakik HA. Upper gastrointestinal bleeding in patients with acute coronary syndromes: clinical predictors and prophylactic role of proton pump inhibitors.  J Clin Gastroenterol. 2008;42(4):368-372
PubMedCrossRef
Bhatt DL, Scheiman J, Abraham NS,  et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.  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(18):1894-1909
PubMedCrossRef
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(1):148,e1-e5
PubMedCrossRef
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(7):713-718
PubMedCrossRef
July 1, 2009
Verena Schneider-Lindner, MD, MSc; Kristian B. Filion, MSc; James M. Brophy, MD, PhD
JAMA. 2009;302(1):29-31.
July 1, 2009
Habib A. Dakik, MD; Kassem Barada, MD
JAMA. 2009;302(1):29-31.
July 1, 2009
Stephen Hayes, MD
JAMA. 2009;302(1):29-31.
July 1, 2009
P. Michael Ho, MD, PhD; John S. Rumsfeld, MD, PhD; Li Wang, MS
JAMA. 2009;302(1):29-31.
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