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      Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans

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          Abstract

          Objective

          Proton pump inhibitors (PPIs) are widely used, and their use is associated with increased risk of adverse events. However, whether PPI use is associated with excess risk of death is unknown. We aimed to examine the association between PPI use and risk of all-cause mortality.

          Design

          Longitudinal observational cohort study.

          Setting

          US Department of Veterans Affairs.

          Participants

          Primary cohort of new users of PPI or histamine H2 receptor antagonists (H2 blockers) (n=349 312); additional cohorts included PPI versus no PPI (n=3 288 092) and PPI versus no PPI and no H2 blockers (n=2 887 030).

          Main outcome measures

          Risk of death.

          Results

          Over a median follow-up of 5.71 years (IQR 5.11–6.37), PPI use was associated with increased risk of death compared with H2 blockers use (HR 1.25, CI 1.23 to 1.28). Risk of death associated with PPI use was higher in analyses adjusted for high-dimensional propensity score (HR 1.16, CI 1.13 to 1.18), in two-stage residual inclusion estimation (HR 1.21, CI 1.16 to 1.26) and in 1:1 time-dependent propensity score-matched cohort (HR 1.34, CI 1.29 to 1.39). The risk of death was increased when considering PPI use versus no PPI (HR 1.15, CI 1.14 to 1.15), and PPI use versus no PPI and no H2 blockers (HR 1.23, CI 1.22 to 1.24). Risk of death associated with PPI use was increased among participants without gastrointestinal conditions: PPI versus H2 blockers (HR 1.24, CI 1.21 to 1.27), PPI use versus no PPI (HR 1.19, CI 1.18 to 1.20) and PPI use versus no PPI and no H2 blockers (HR 1.22, CI 1.21 to 1.23). Among new PPI users, there was a graded association between the duration of exposure and the risk of death.

          Conclusions

          The results suggest excess risk of death among PPI users; risk is also increased among those without gastrointestinal conditions and with prolonged duration of use. Limiting PPI use and duration to instances where it is medically indicated may be warranted.

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          Most cited references39

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          High-dimensional propensity score adjustment in studies of treatment effects using health care claims data.

          Adjusting for large numbers of covariates ascertained from patients' health care claims data may improve control of confounding, as these variables may collectively be proxies for unobserved factors. Here, we develop and test an algorithm that empirically identifies candidate covariates, prioritizes covariates, and integrates them into a propensity-score-based confounder adjustment model. We developed a multistep algorithm to implement high-dimensional proxy adjustment in claims data. Steps include (1) identifying data dimensions, eg, diagnoses, procedures, and medications; (2) empirically identifying candidate covariates; (3) assessing recurrence of codes; (4) prioritizing covariates; (5) selecting covariates for adjustment; (6) estimating the exposure propensity score; and (7) estimating an outcome model. This algorithm was tested in Medicare claims data, including a study on the effect of Cox-2 inhibitors on reduced gastric toxicity compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). In a population of 49,653 new users of Cox-2 inhibitors or nonselective NSAIDs, a crude relative risk (RR) for upper GI toxicity (RR = 1.09 [95% confidence interval = 0.91-1.30]) was initially observed. Adjusting for 15 predefined covariates resulted in a possible gastroprotective effect (0.94 [0.78-1.12]). A gastroprotective effect became stronger when adjusting for an additional 500 algorithm-derived covariates (0.88 [0.73-1.06]). Results of a study on the effect of statin on reduced mortality were similar. Using the algorithm adjustment confirmed a null finding between influenza vaccination and hip fracture (1.02 [0.85-1.21]). In typical pharmacoepidemiologic studies, the proposed high-dimensional propensity score resulted in improved effect estimates compared with adjustment limited to predefined covariates, when benchmarked against results expected from randomized trials.
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            Two-stage residual inclusion estimation: addressing endogeneity in health econometric modeling.

            The paper focuses on two estimation methods that have been widely used to address endogeneity in empirical research in health economics and health services research-two-stage predictor substitution (2SPS) and two-stage residual inclusion (2SRI). 2SPS is the rote extension (to nonlinear models) of the popular linear two-stage least squares estimator. The 2SRI estimator is similar except that in the second-stage regression, the endogenous variables are not replaced by first-stage predictors. Instead, first-stage residuals are included as additional regressors. In a generic parametric framework, we show that 2SRI is consistent and 2SPS is not. Results from a simulation study and an illustrative example also recommend against 2SPS and favor 2SRI. Our findings are important given that there are many prominent examples of the application of inconsistent 2SPS in the recent literature. This study can be used as a guide by future researchers in health economics who are confronted with endogeneity in their empirical work.
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              Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis.

              Observational studies and randomized controlled trials have yielded inconsistent findings about the association between the use of acid-suppressive drugs and the risk of pneumonia. We performed a systematic review and meta-analysis to summarize this association. We searched three electronic databases (MEDLINE [PubMed], Embase and the Cochrane Library) from inception to Aug. 28, 2009. Two evaluators independently extracted data. Because of heterogeneity, we used random-effects meta-analysis to obtain pooled estimates of effect. We identified 31 studies: five case-control studies, three cohort studies and 23 randomized controlled trials. A meta-analysis of the eight observational studies showed that the overall risk of pneumonia was higher among people using proton pump inhibitors (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.11-1.46, I(2) 90.5%) and histamine(2) receptor antagonists (adjusted OR 1.22, 95% CI 1.09-1.36, I(2) 0.0%). In the randomized controlled trials, use of histamine(2) receptor antagonists was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI 1.01-1.48, I(2) 30.6%). Use of a proton pump inhibitor or histamine(2) receptor antagonist may be associated with an increased risk of both community- and hospital-acquired pneumonia. Given these potential adverse effects, clinicians should use caution in prescribing acid-suppressive drugs for patients at risk.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Open (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2017
                4 July 2017
                : 7
                : 6
                : e015735
                Affiliations
                [1 ] departmentClinical Epidemiology Center, Research and Education Service , VA Saint Louis Health Care System , Saint Louis, Missouri, USA
                [2 ] departmentDepartment of Medicine , Washington University School of Medicine , Saint Louis, Missouri, USA
                [3 ] departmentDepartment of Biostatistics, College for Public Health and Social Justice , Saint Louis University , Saint Louis, Missouri, USA
                [4 ] departmentDivision of Public Health Sciences, Department of Surgery , Washington University School of Medicine , Saint Louis, Missouri, USA
                [5 ] departmentRenal Section, Medicine Service , VA Saint Louis Health Care System , Saint Louis, Missouri, USA
                [6 ] departmentInstitute for Public Health , Washington University in Saint Louis , Saint Louis, Missouri, USA
                Author notes
                [Correspondence to ] Dr Ziyad Al-Aly;      zalaly@ 123456gmail.com
                Author information
                http://orcid.org/0000-0002-2600-0434
                Article
                bmjopen-2016-015735
                10.1136/bmjopen-2016-015735
                5642790
                28676480
                70534d47-5e62-4d15-89b9-42cad2133293
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 23 December 2016
                : 20 March 2017
                : 22 March 2017
                Categories
                Public Health
                Research
                1506
                1724
                Custom metadata
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                Medicine
                clinical pharmacology,epidemiology,gastroduodenal disease,health & safety,public health,adverse events

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