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Lack of Significant Interactions Between Clopidogrel and Proton Pump Inhibitor Therapy: Meta-Analysis of Existing Literature

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Abstract

Background

Published data regarding the effect of concomitant clopidogrel and proton pump inhibitor (PPI) therapy on cardiovascular outcomes have been conflicting.

Aim

To perform an updated meta-analysis in order to determine changes in risk differences (RD) between primary and secondary outcome analyses.

Methods

Primary analysis was based on definite vascular outcomes, including all cause mortality, cardiac death, myocardial infarction, and/or stroke. Secondary analysis also incorporated probable cardiac events, which included re-hospitalization for cardiac symptoms or revascularization procedures. RD were combined using a random-effects model.

Results

We reviewed 1,204 publications of which 26 studies (16 published articles, 10 abstracts) met inclusion criteria. The meta-analysis of outcomes from the two randomized controlled trials did not show an increased risk (RD 0.0, 95% CI −0.01, 0.01) for adverse outcomes. The meta-analysis of primary outcomes showed a RD of 0.02 (95% CI 0.01, 0.03) for all studies. The meta-analysis for secondary outcomes yielded a RD of 0.02 (95% CI 0.01–0.04) based on 19 published papers and abstracts. When primary and secondary outcomes were combined, the meta-analysis for published papers yielded an overall RD of 0.05 (95% CI 0.03–0.06).

Conclusions

In patients using concomitant clopidogrel and PPI therapy, the risk of adverse cardiac outcomes was 0% based on data from well-controlled randomized trials. Data from retrospective studies and the addition of probable vascular events significantly increased the RD estimates, likely due to lack of adjustment for potential confounders.

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Conflict of interest

Lauren B. Gerson MD, MSc: Consultant, Takeda, Eisai, Xenoport; grant support: Santarus, Inc. Donal McMahon, Ingram Olkin, Christopher Stave, and Stanley G. Rockson have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Medicine, Stanford University, Stanford, CA, USA

    Lauren B. Gerson, Christopher Stave & Stanley G. Rockson

  2. Division of Gastroenterology and Hepatology, Stanford University, 450 Broadway Street, Pavilion C, Mail Code 6341, Redwood City, CA, 94063, USA

    Lauren B. Gerson

  3. Department of Statistics, Stanford University, Stanford, CA, USA

    Donal McMahon & Ingram Olkin

  4. Department of Cardiology, Stanford University, Stanford, CA, USA

    Stanley G. Rockson

Authors
  1. Lauren B. Gerson
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  2. Donal McMahon
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  3. Ingram Olkin
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  4. Christopher Stave
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Corresponding author

Correspondence to Lauren B. Gerson.

Appendix—Search Strategy

Appendix—Search Strategy

PUBMED

Search Dates: 1947—October 27, 2010

MyNCBI: clopidrogel/clopidrogel

  1. 1.

    (“anti-ulcer agents” OR “Proton Pump Inhibitors” OR “proton pump”[tw] OR ppi[tw] OR omeprazole[tw] OR prilosec[tw] OR esomeprazole[tw] OR nexium[tw] OR lansoprazole[tw] OR prevacid[tw] OR pantoprazole[tw] OR protonix[tw] OR rabeprazole[tw] OR aciphex[tw] OR dexlansoprazole[tw] OR kapidex[tw])

  2. 2.

    (clopidogrel[tw] OR Iscover[tw] OR plavix[tw] OR “PCR 4099”[tw] OR “SR 25989”[tw])

  3. 3.

    1 AND 2 = 237

SCOPUS

Search Dates: 2009–October 27, 2010

  1. 1.

    (((TITLE((clopidogrel OR iscover OR plavix OR “PCR 4099” OR “SR 25989” OR “SR 25990” OR “SC 25989C”)) AND TITLE((“Proton Pump” OR omeprazole OR prilosec OR esomeprazole OR nexium OR lansoprazole OR prevacid OR pantoprazole OR protonix OR rabeprazole OR aciphex OR dexlansoprazole OR kapidex))))

  2. 2.

    ((ABS((clopidogrel OR iscover OR plavix OR “PCR 4099” OR “SR 25989” OR “SR 25990” OR “SC 25989C”)) AND ABS((“Proton Pump” OR omeprazole OR prilosec OR esomeprazole OR nexium OR lansoprazole OR prevacid OR pantoprazole OR protonix OR rabeprazole OR aciphex OR dexlansoprazole OR kapidex))))) AND (LIMIT-TO(PUBYEAR, 2010) OR LIMIT-TO(PUBYEAR, 2009))

  3. 3.

    1 OR 2 = 176 citations

BIOSIS

1926–October 27, 2010

  1. 1.

    (“Proton Pump” OR omeprazole or prilosec or esomeprazole or nexium or lansoprazole or prevacid or pantoprazole or protonix or rabeprazole or aciphex or dexlansoprazole or kapidex)

  2. 2.

    (clopidogrel or Iscover or plavix or “PCR 4099” or “SR 25989” or “SR 25990” or “SC 25989C”)

  3. 3.

    1 AND 2 = 257

EMBASE

1974–2009

  1. 1.

    Anti-ulcer agents! OR proton pump inhibitors! OR proton pump inhibitor! OR proton pumps!(L)AI OR omeprazole OR prilosec OR esomeprazole OR nexium OR lansoprazole OR prevacid OR pantoprazole OR protonix OR rabeprazole OR aiphex OR dexlansoprazole OR kapidex

  2. 2.

    Clopidogrel OR iscover OR plavix OR PCR(W)4099 OR SR(W)25989 OR SR(W)25990 OR SC(W)25989C OR ticlopidine

  3. 3.

    Heart infarction! OR heart death! OR drug safety! OR cardiovascular risk! OR acute coronary syndrome! OR kidney failure! OR comorbidity! OR gastrointestinal hemorrhage! OR bleeding! OR stent thrombosis! OR myocardial()infarction OR heart()attack OR cardiac()arrest OR cardiac()-death OR death OR survival OR stroke! OR graft occlusion! OR adverse OR stent?(2 N)occlu? OR angina OR ‘Complication’ OR ‘Adverse Drug Reaction’ OR ‘Drug Toxicity’

  4. 4.

    1 AND 2 AND 3 = 678

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Gerson, L.B., McMahon, D., Olkin, I. et al. Lack of Significant Interactions Between Clopidogrel and Proton Pump Inhibitor Therapy: Meta-Analysis of Existing Literature. Dig Dis Sci 57, 1304–1313 (2012). https://doi.org/10.1007/s10620-011-2007-1

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  • DOI: https://doi.org/10.1007/s10620-011-2007-1

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