Confounding in the Association of Proton Pump Inhibitor Use With Risk of Community-Acquired Pneumonia

ABSTRACT

BACKGROUND

Use of proton pump inhibitors (PPIs) is associated with community-acquired pneumonia (CAP), an association which may be confounded by unobserved patient and prescriber characteristics.

OBJECTIVE

We assessed for confounding in the association between PPI use and CAP by using a ‘falsification approach,’ which estimated whether PPI use is also implausibly associated with other common medical conditions for which no known pathophysiologic link exists.

DESIGN

Retrospective claims-based cohort study.

SETTING

Six private U.S. health plans.

SUBJECTS

Individuals who filled at least one prescription for a PPI (N = 26,436) and those who never did (N = 28,054) over 11 years.

INTERVENTIONS

Multivariate linear regression of the association between a filled prescription for a PPI and a diagnosis of CAP in each 3-month quarter. In falsification analyses, we tested for implausible associations between PPI use in each quarter and rates of osteoarthritis, chest pain, urinary tract infection (UTI), deep venous thrombosis (DVT), skin infection, and rheumatoid arthritis. Independent variables included an indicator for whether a prescription for a PPI was filled in a given quarter, and quarterly indicators for various co-morbidities, age, income, geographic location, and marital status.

KEY RESULTS

Compared to nonusers, those ever using a PPI had higher adjusted rates of CAP in quarters in which no prescription was filled (68 vs. 61 cases per 10,000 persons, p < 0.001). Similar associations were noted for all conditions (e.g. chest pain, 336 vs. 282 cases, p < 0.001; UTI, 151 vs. 139 cases, p < 0.001). Among those ever using a PPI, quarters in which a prescription was filled were associated with higher adjusted rates of CAP (111 vs. 68 cases per 10,000, p < 0.001) and all other conditions (e.g. chest pain, 597 vs. 336 cases, p < 0.001; UTI, 186 vs. 151 cases, p < 0.001), compared to quarters in which no prescription was filled.

CONCLUSION

PPI use is associated with CAP, but also implausibly associated with common medical conditions. Observed associations between PPI use and CAP may be confounded.

This is a preview of subscription content, access via your institution.

Figure 1.
Figure 2.
Figure 3.

REFERENCES

  1. 1.

    Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292(16):1955–1960.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med. 2008;149(6):391–398.

    PubMed  Google Scholar 

  3. 3.

    Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case–control study. Arch Intern Med. 2007;167(9):950–955.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Howden CW, Hunt RH. Relationship between gastric secretion and infection. Gut. 1987;28(1):96–107.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Giannella RA, Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections. A perspective. Ann Intern Med. 1973;78(2):271–276.

    PubMed  CAS  Google Scholar 

  6. 6.

    Ruddell WS, Axon AT, Findlay JM, Bartholomew BA, Hill MJ. Effect of cimetidine on the gastric bacterial flora. Lancet. 1980;1(8170):672–674.

    PubMed  CAS  Google Scholar 

  7. 7.

    IMS. Leading Therapy Classes in 2002 Global Pharmaceutical Sales. IMS World Review. Vol. 2010; 2010.

  8. 8.

    Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology. 2010;139(4):1115–1127.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Logan IC, Sumukadas D, Witham MD. Gastric acid suppressants–too much of a good thing? Age and ageing. 2010;39(4):410–411.

    PubMed  Article  Google Scholar 

  10. 10.

    Lodato F, Azzaroli F, Turco L, et al. Adverse effects of proton pump inhibitors. Best Pract Res Clin Gastroenterol. 2010;24(2):193–201.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Trifiro G, Gambassi G, Sen EF, et al. Association of community-acquired pneumonia with antipsychotic drug use in elderly patients: a nested case–control study. Ann Intern Med. 2010;152(7):418–25, W139-40.

  12. 12.

    Popper KR. The Logic of Scientific Discovery Routledge; 2002.

  13. 13.

    Heckman JJ, Hotz VJ. Choosing among alternative nonexperimental methods for estimating the impact of social programs: the case of manpower training. J Am Stat Assoc. 1989;84(408):862–874.

    Article  Google Scholar 

  14. 14.

    Bertrand M, Duflo E, Mullainathan S. How much should We trust differences-in-differences estimates? Q J Econ. 2004;119(1):249–275.

    Article  Google Scholar 

  15. 15.

    Joyce GF, Escarce JJ, Solomon MD, Goldman DP. Employer drug benefit plans and spending on prescription drugs. JAMA. 2002;288(14):1733–1739.

    PubMed  Article  Google Scholar 

  16. 16.

    Goldman DP, Joyce GF, Lawless G, Crown WH, Willey V. Benefit design and specialty drug use. Health Aff (Millwood). 2006;25(5):1319–1331.

    Article  Google Scholar 

  17. 17.

    Goldman DP, Joyce GF, Escarce JJ, et al. Pharmacy benefits and the use of drugs by the chronically ill. JAMA. 2004;291(19):2344–2350.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Solomon MD, Goldman DP, Joyce GF, Escarce JJ. Cost sharing and the initiation of drug therapy for the chronically ill. Arch Intern Med. 2009;169(8):740–748. discussion 748–9.

    PubMed  Article  Google Scholar 

  19. 19.

    Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med. 2002;113(Suppl 1A):5S–13S.

    PubMed  Article  Google Scholar 

  20. 20.

    Ellis Simonsen SM, van Orman ER, Hatch BE, et al. Cellulitis incidence in a defined population. Epidemiol Infect. 2006;134(2):293–299.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    United States Department of H, Human Services. Centers for Disease C, Prevention. National Center for Health S. National Ambulatory Medical Care Survey, 2009. Inter-university Consortium for Political and Social Research (ICPSR) [distributor]; 2011.

  22. 22.

    Ware JH, Dockery DW, Louis TA, Xu XP, Ferris BG Jr, Speizer FE. Longitudinal and cross-sectional estimates of pulmonary function decline in never-smoking adults. Am J Epidemiol. 1990;132(4):685–700.

    PubMed  CAS  Google Scholar 

  23. 23.

    Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-suppressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology. 1997;8(5):571–574.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Neal KR, Scott HM, Slack RC, Logan RF. Omeprazole as a risk factor for campylobacter gastroenteritis: case–control study. BMJ. 1996;312(7028):414–415.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case–control studies. CMAJ. 2004;171(1):33–38.

    PubMed  Article  Google Scholar 

  26. 26.

    Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent clostridium difficile infection. Arch Intern Med. 2010;170(9):772–778.

    PubMed  Article  Google Scholar 

  27. 27.

    Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296(24):2947–2953.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N Engl J Med. 2007;357(4):370–379.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Cohen-Cole E, Fletcher JM. Detecting implausible social network effects in acne, height, and headaches: longitudinal analysis. BMJ. 2008;337:a2533.

    PubMed  Article  Google Scholar 

Download references

ACKNOWLEDGEMENTS

Contributors

All authors were involved in the study design and concept, interpretation of results and editing of manuscript. Drs. Jena and Sun analysed the data set and wrote the initial manuscript draft. Dr. Jena obtained ethical approval for the project. Dr. Goldman obtained funding. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

National Institute on Aging. The design, conduct, analysis, interpretation, and presentation of the data are the responsibility of the investigators, with no involvement from the funding sources.

Prior Presentations

None

Conflict of Interest

The authors declare that they do not have a conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Anupam B. Jena MD, PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 183 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jena, A.B., Sun, E. & Goldman, D.P. Confounding in the Association of Proton Pump Inhibitor Use With Risk of Community-Acquired Pneumonia. J GEN INTERN MED 28, 223–230 (2013). https://doi.org/10.1007/s11606-012-2211-5

Download citation

KEY WORDS

  • proton pump inhibitors
  • pneumonia
  • falsification testing