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The Potential for Postrandomization Confounding in Randomized Clinical Trials

JoAnn E. Manson, MD, DrPH1; Chrisandra L. Shufelt, MD2; James M. Robins, MD3
[+] Author Affiliations
1Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
2Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute, Los Angeles, California
3Departments of Biostatistics and Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
JAMA. 2016;315(21):2273-2274. doi:10.1001/jama.2016.3676.
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In this Viewpoint, JoAnn Manson and colleagues discuss the risk of postrandomization “confounding,” a bias that can be introduced in long-duration trials of sustained interventions, using statin initiation after randomization in Women’s Health Initiative trials as an example.

Randomized clinical trials (RCTs) are considered the “gold standard” for evaluating an intervention’s efficacy and safety.1 Although large-scale RCTs are nearly always free of baseline confounding because randomization balances the distribution of measured and unmeasured risk factors across treatment groups, biases may emerge after randomization because of differential use of nonstudy medication or treatments, imbalanced rates of disease screening, differential loss to follow-up, and other differences between treatment groups. Such postrandomization “confounding” is more likely to occur in long-term trials or pragmatic trials taking place in typical patient care settings. Because community-based long-duration pragmatic trials are increasingly being used to evaluate sustained interventions, it is important for researchers to use available methodological approaches to assess the presence of such biases1 and for clinicians to be aware of potential sources of confounding when interpreting results of RCTs.

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Statin Use in the Women’s Health Initiative Hormone Therapy Trials, According to Treatment Group in Each Trial

Mean percentage of statin users at each annual visit by randomization group. Error bars indicate 95% CI; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate.

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