Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Comparison of Self-controlled Designs for Evaluating Outcomes of Drug–Drug Interactions

Simulation Study

Bykov, Katsiarynaa; Franklin, Jessica M.a; Li, Hub; Gagne, Joshua J.a

doi: 10.1097/EDE.0000000000001087

Background: Self-controlled designs, both case–crossover and self-controlled case series, are well suited for evaluating outcomes of drug–drug interactions in electronic healthcare data. Their comparative performance in this context, however, is unknown.

Methods: We simulated cohorts of patients exposed to two drugs: a chronic drug (object) and a short-term drug (precipitant) with an associated interaction of 2.0 on the odds ratio scale. We analyzed cohorts using case–crossover and self-controlled case series designs evaluating exposure to the precipitant drug within person-time exposed to the object drug. Scenarios evaluated violations of key design assumptions: (1) time-varying, within-person confounding; (2) time trend in precipitant drug exposure prevalence; (3) nontransient precipitant exposure; and (4) event-dependent object drug discontinuation.

Results: Case–crossover analysis produced biased estimates when 30% of patients persisted on the precipitant drug (estimated OR 2.85) and when the use of the precipitant drug was increasing in simulated cohorts (estimated OR 2.56). Self-controlled case series produced biased estimates when patients discontinued the object drug following the occurrence of an outcome (estimated incidence ratio [IR] of 2.09 [50% of patients stopping therapy] and 2.22 [90%]). Both designs yielded similarly biased estimates in the presence of time-varying, within-person confounding.

Conclusion: In settings with independent or rare outcomes and no substantial event-dependent censoring (<50%), self-controlled case series may be preferable to case–crossover design for evaluating outcomes of drug–drug interactions. With frequent event-dependent drug discontinuation, a case–crossover design may be preferable provided there are no time-related trends in drug exposure.

From the aDivision of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

bEli Lilly and Company, Indianapolis, IN.

Submitted October 1, 2018; accepted July 28, 2019.

This study was funded through Lilly Research Award Program. K.B. is supported by training grant from the National Institute of Child Health and Human Development (T32 HD40128-14).

K.B. has received support from a doctoral training grant from Takeda to Harvard T.H. Chan School of Public Health. J.J.G. was Principal Investigator of a grant from Novartis Pharmaceuticals Corporation to the Brigham and Women’s Hospital and is a consultant to Aetion Inc. and to Optum, Inc, all for unrelated work. H.L. is an employee of Lilly and Company, of which she also own equity.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (

Computing code is presented in the eAppendix (

Correspondence: Katsiaryna Bykov, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, 1620 Tremont St., Ste.3030, Boston, MA 02120. E-mail:

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.