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COX-2 Selective Nonsteroidal Anti-inflammatory Drugs and Risk of Gastrointestinal Tract Complications and Myocardial Infarction: An Instrumental Variable Analysis

Davies, Neil M.a; Smith, George Daveya; Windmeijer, Frankb; Martin, Richard M.a

doi: 10.1097/EDE.0b013e318289e024
Pharmacoepidemiology

Objective: Instrumental variable analysis can estimate treatment effects in the presence of residual or unmeasured confounding. We compared ordinary least squares regression versus instrumental variable estimates of the effects of selective cyclooxygenase-2 inhibitors (COX-2s) relative to nonselective nonsteroidal anti-inflammatory drug (NSAID) prescriptions on incidence of upper gastrointestinal complications and myocardial infarction (MI).

Methods: We sampled a cohort of 62,933 first-time users of COX-2s or nonselective NSAIDs older than 60 years in the Clinical Practice Research Datalink. The instruments were physicians’ previous prescriptions of COX-2s or nonselective NSAIDs, which are surrogates for physician preferences. We estimated risk differences of incident upper gastrointestinal complications and MI within 180 days of first COX-2 versus nonselective NSAID prescription.

Results: Using ordinary least squares regression, adjusted for baseline confounders, we observed little association of COX-2 prescriptions with incident upper gastrointestinal complications (risk difference = −0.08 [95% confidence interval = −0.20 to 0.04]) or MI (0.06 [−0.06 to 0.17]) per 100 patients treated. Our adjusted instrumental variable results suggested 0.46 per 100 (−0.15 to 1.07) fewer upper gastrointestinal complications and little difference in acute MIs (0.08 per 100 [−0.61 to 0.76]), within 180 days of being prescribed COX-2s. Estimates were more precise when we used 20 previous prescriptions; the instrumental variable analysis implied 0.74 (0.28 to 1.19) fewer MIs per 100 patients prescribed COX-2s.

Conclusions: Using instrumental variable analysis, we found some evidence that COX-2 prescriptions reduced the risk of upper gastrointestinal complications, consistent with randomized controlled trials. Our results using multiple instruments suggest that COX-2s may have heterogeneous within-class effects on MI.

From the aMedical Research Council Centre for Causal Analyses and Translational Epidemiology, School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Barley House, Oakfield Grove, Bristol, United Kingdom; and bCentre for Market and Public Organisation, Department of Economics, Faculty of Social Science and Law, University of Bristol, Bristol, United Kingdom.

N.D. is the recipient of a Medical Research Council 4-year PhD studentship with the Medical Research Council Centre for Causal Analysis in Translational Epidemiology and the data were obtained using funding from the Medical Research Council. G.D.S. and R.M.M. work within the Centre for Causal Analysis in Translational Epidemiology, which is supported by the Medical Research Council and the University of Bristol. This study is based, in part, on data from the Full Feature Clinical Practice Research Datalink obtained under license from the United Kingdom Medicines and Healthcare Products Regulatory Agency. Access to the Clinical Practice Research Datalink was funded through the Medical Research Council’s license agreement with Medicines and Healthcare Products Regulatory Agency. Supported by the European Research Council DEVHEALTH grant (269874 to G.D.S., F.W., and N.D.).

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author.

Editors’ note:Related articles appear on pages 363 and 370.

Correspondence: Neil Davies, Medical Research Council Centre for Causal Analyses and Translational Epidemiology, School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Barley House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. E-mail: neil.davies@bristol.ac.uk.

Received July 19, 2011

Accepted November 27, 2012

© 2013 by Lippincott Williams & Wilkins, Inc