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Sources of heterogeneity in case–control studies on associations between statins, ACE-inhibitors, and proton pump inhibitors and risk of pneumonia

  • PHARMACO-EPIDEMIOLOGY
  • Published:
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Abstract

The heterogeneity in case–control studies on the associations between community-acquired pneumonia (CAP) and ACE-inhibitors (ACEi), statins, and proton pump inhibitors (PPI) hampers translation to clinical practice. Our objective is to explore sources of this heterogeneity by applying a common protocol in different data settings. We conducted ten case–control studies using data from five different health care databases. Databases varied on type of patients (hospitalised vs. GP), level of case validity, and mode of exposure ascertainment (prescription or dispensing based). Identified CAP patients and controls were matched on age, gender, and calendar year. Conditional logistic regression was used to calculate odds ratios (OR) for the associations between the drugs of interest and CAP. Associations were adjusted by a common set of potential confounders. Data of 38,742 cases and 118,019 controls were studied. Comparable patterns of variation between case–control studies were observed for ACEi, statins and PPI use and pneumonia risk with adjusted ORs varying from 1.04 to 1.49, 0.82 to 1.50 and 1.16 to 2.71, respectively. Overall, higher ORs were found for hospitalised CAP patients matched to population controls versus GP CAP patients matched to population controls. Prevalence of drug exposure was higher in dispensing data versus prescription data. We show that case–control selection and methods of exposure ascertainment induce bias that cannot be adjusted for and to a considerable extent explain the heterogeneity in results obtained in case–control studies on statins, ACEi and PPIs and CAP. The common protocol approach helps to better understand sources of variation in observational studies.

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Acknowledgments

The authors thank Jan Vandenbroucke for his valuable discussions on methodology and interpretation of the analyses. This work was funded and performed within the framework of the Dutch Top Institute Pharma project T6-101-1 Mondriaan, The Dutch healthcare landscape as a ‘population laboratory’ (www.tipharma.com). We would like to thank the staff of all databases for their help in the data extraction.

Conflict of interest

Mark C. H. de Groot: The University of Utrecht has received funding from Top Institute Pharma to pay part of my salary. This public private partnership (funding: 50 % Government, 25 % Academia, 25 % pharmaceutical industry) supports project T6-101-1 Mondriaan, The Dutch healthcare landscape as a ‘population laboratory’ (www.tipharma.com). My employer received unrestricted support from the Innovative Medicine Initiative Joint Undertake (IMI-PROTECT: www.imi.europa.eu) under Grant Agreement No. 115004, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Olaf H. Klungel received unrestricted research support from IMI-PROTECT and IMI-EU2P for development of educational presentations. Hubert G. M. Leufkens has no personal funding to declare. Liset van Dijk has received unrestricted grants from Bristol Myers-Squibb, Astra Zeneca and Pfizer. Diederick E. Grobbee has nothing to declare. Ewoudt M. W. van de Garde has received unrestricted funding from the Netherlands Organisation for Health Research and Development (ZonMW) and GlaxoSmithKline that is not related to the present project.

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Authors and Affiliations

  1. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508 TB, Utrecht, The Netherlands

    Mark C. H. de Groot, Olaf H. Klungel, Hubert G. M. Leufkens, Liset van Dijk & Ewoudt M. W. van de Garde

  2. Nivel, Netherlands Institute for Healthcare Research, Utrecht, The Netherlands

    Liset van Dijk

  3. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

    Diederick E. Grobbee

  4. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

    Ewoudt M. W. van de Garde

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  1. Mark C. H. de Groot
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  2. Olaf H. Klungel
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  6. Ewoudt M. W. van de Garde
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Correspondence to Mark C. H. de Groot.

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de Groot, M.C.H., Klungel, O.H., Leufkens, H.G.M. et al. Sources of heterogeneity in case–control studies on associations between statins, ACE-inhibitors, and proton pump inhibitors and risk of pneumonia. Eur J Epidemiol 29, 767–775 (2014). https://doi.org/10.1007/s10654-014-9941-0

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