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Primer: administrative health databases in observational studies of drug effects—advantages and disadvantages

Abstract

Observational studies are important tools for providing information on the safety and benefit of approved medications; they provide data on real-life use, rare outcomes and long-term effects that were undetectable in randomized controlled trials. We review various administrative databases in the US and Canada, in addition to European medical records databases, which have been used extensively to assess drug safety. We present their advantages, which include their large size and the availability of systematic and accurate medication data from pharmacies and extensive outcome data from hospital records, and limitations, including the questionable validity of diagnostic information and absence of information on confounders (e.g. disease severity) and over-the-counter drugs. We illustrate these challenges in the investigation of the cardiovascular risks of the cyclo-oxygenase 2 inhibitor rofecoxib and highlight important methodological issues, beyond the limitations of the databases, which could explain the contradictory findings from three observational studies that used these databases. We show that issues relating to the duration of drug use, immortal time, depletion of susceptibles and overadjustment were problematic sources of bias in these studies and discuss remedies to avoid these pitfalls. With careful attention to their design and analysis, observational database studies are powerful and modern tools for providing crucial data on drug effects.

Key Points

  • Observational studies provide important information on the safety and benefit of medications that complements data from randomized controlled trials

  • Administrative health databases offer large sources of rapidly accessible data for these studies, with accurate medication records from pharmacies and extensive outcome information from hospital records

  • These databases can contain invalidated diagnostic information, sometimes lack information on important confounders and have no data on over-the-counter drugs

  • Improper methodological aspects of observational studies, beyond the limitations of the databases, can lead to contradictory findings—for example, the cardiovascular risks of cyclo-oxygenase 2 inhibitors

  • With careful attention to design and analysis, observational database studies can be powerful and modern tools for providing crucial data on drug effects

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Figure 1: The cumulative time-to-event curves for confirmed serious thrombotic cardiovascular events in the Vioxx® Gastrointestinal Outcomes Research trial for users of rofecoxib and naproxen.17
Figure 2: The approximate hazard functions (instantaneous rate per 100 people per year), corresponding to the curves in Figure 1, for users of rofecoxib and naproxen in the Vioxx® Gastrointestinal Outcomes Research trial Research trial.13
Figure 3: Approximate hazard functions (instantaneous rate per 100 people per year) for users and nonusers of rofecoxib in the VIGOR trial, with estimates from the Tennessee study, according to the duration of new use of lower-dose (2 months) and higher-dose (1.5 months) rofecoxib use.14

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Acknowledgements

S Suissa's research is funded by the Canadian Institute of Health Research (CIHR).

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Correspondence to Samy Suissa.

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Competing interests

S Suissa has acted as a consultant for Bristol-Myers Squibb, Merck, Pfizer and Sanofi-Aventis, and has received grants or research support from Sanofi-Aventis and Wyeth. E Garbe has declared no competing interests

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Suissa, S., Garbe, E. Primer: administrative health databases in observational studies of drug effects—advantages and disadvantages. Nat Rev Rheumatol 3, 725–732 (2007). https://doi.org/10.1038/ncprheum0652

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