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.

Figure 1.

Unadjusted quarterly rates of community-acquired pneumonia, osteoarthritis, chest pain, and urinary tract infection medical claims among users and nonusers of proton pump inhibitors. Unadjusted quarterly rates of each condition were calculated for those never filling a prescription for a PPI (termed nonusers of PPIs), users (defined as persons who filled at least one prescription for a PPI) during quarters in which a prescription was not filled, and users during quarters in which a prescription was filled. Rates were determined from ICD-9 codes in administrative data and are displayed at the quarterly level per 10,000 persons. 95 % confidence intervals reported in graph.

Figure 2.

Adjusted quarterly rates of community-acquired pneumonia, osteoarthritis, chest pain, and urinary tract infection medical claims among users and nonusers of proton pump inhibitors. Adjusted estimates are from a multivariate linear probability model with individual fixed effects, quarterly indicators for various comorbidities, and demographic characteristics such as age, marital status, income, and geographic location. Rates are displayed at the quarterly level and are per 10,000 persons. 95 % confidence intervals reported in graph.

Figure 3.

Adjusted quarterly rates of community-acquired pneumonia, osteoarthritis, chest pain, and urinary tract infection medical claims, according to length of proton pump inhibitor use. This figure presents adjusted quarterly rates of each condition among users of PPIs according to tercile of use (based on number of quarters over the study period in which a prescription for a PPI was filled). Estimates are from a multivariate linear probability model with indicators for tercile of PPI use, quarterly indicators for various comorbidities, and demographic characteristics such as age, marital status, income, and geographic location. Rates are displayed at the quarterly level and are per 10,000 persons. 95 % confidence intervals reported in graph.