Journal of General Internal Medicine

, Volume 28, Issue 2, pp 223–230 | Cite as

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

Original Research

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.

KEY WORDS

proton pump inhibitors pneumonia  falsification testing 

Supplementary material

11606_2012_2211_MOESM1_ESM.pdf (184 kb)
ESM 1(PDF 183 kb)

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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle Scholar
  4. 4.
    Howden CW, Hunt RH. Relationship between gastric secretion and infection. Gut. 1987;28(1):96–107.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedGoogle Scholar
  7. 7.
    IMS. Leading Therapy Classes in 2002 Global Pharmaceutical Sales. IMS World Review. Vol. 2010; 2010.Google Scholar
  8. 8.
    Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology. 2010;139(4):1115–1127.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.Google Scholar
  12. 12.
    Popper KR. The Logic of Scientific Discovery Routledge; 2002.Google Scholar
  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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar
  19. 19.
    Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med. 2002;113(Suppl 1A):5S–13S.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.Google Scholar
  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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Cohen-Cole E, Fletcher JM. Detecting implausible social network effects in acne, height, and headaches: longitudinal analysis. BMJ. 2008;337:a2533.PubMedCrossRefGoogle Scholar

Copyright information

© Society of General Internal Medicine 2012

Authors and Affiliations

  1. 1.Department of Health Care PolicyHarvard Medical SchoolBostonUSA
  2. 2.Department of MedicineMassachusetts General HospitalBostonUSA
  3. 3.Department of MedicineNational Bureau of Economic ResearchCambridgeUSA
  4. 4.Department of AnesthesiaStanford University HospitalsStanfordUSA
  5. 5.Leonard D. Schaeffer Center for Health Policy and 7 EconomicsUniversity of Southern CaliforniaLos AngelesUSA

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