The Case-Crossover Design for Drug-Drug Interactions: Considerations for Implementation

Epidemiology. 2019 Mar;30(2):204-211. doi: 10.1097/EDE.0000000000000944.


Background: The case-crossover design may be useful for evaluating the clinical impact of drug-drug interactions in electronic healthcare data; however, experience with the design in this context is limited.

Methods: Using US healthcare claims data (1994-2013), we evaluated two examples of interacting drugs with prior evidence of harm: (1) cytochrome P450 (CYP)3A4-metabolized statins + clarithromycin or erythromycin and rhabdomyolysis; and (2) clopidogrel + fluoxetine or fluvoxamine and ischemic events. We conducted case-crossover analyses with (1) a three-parameter model with a product term and a six-parameter saturated model that distinguished initiation order of the two drugs; and (2) with or without active comparators.

Results: In the statin example, the three-parameter model produced estimates consistent with prior evidence with the active comparator (product term odds ratio [OR] = 2.05, 95% confidence interval [CI] = 1.00, 4.23) and without (OR = 1.99, 95% CI = 1.04, 3.81). In the clopidogrel example, this model produced results opposite of expectation (OR = 0.78, 95% = 0.68, 0.89), but closer to what was observed in prior studies when active comparator was used (OR = 1.03, 95% CI = 0.90, 1.19). The saturated model revealed heterogeneity of estimates across strata and considerable confounding; strata with concordant clopidogrel exposure likely produced the least biased estimates.

Conclusion: The three-parameter model assumes a common drug-drug interaction effect, whereas the saturated model is useful for identifying potential effect heterogeneity or differential confounding across strata. Restriction to certain strata or use of an active comparator may be necessary in the presence of within-person confounding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administrative Claims, Healthcare
  • Azithromycin / adverse effects
  • Azithromycin / therapeutic use
  • Clarithromycin / adverse effects
  • Clarithromycin / therapeutic use
  • Clopidogrel / adverse effects
  • Clopidogrel / therapeutic use
  • Cross-Over Studies*
  • Cytochrome P-450 CYP2C19 / metabolism
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Interactions*
  • Electronic Health Records / statistics & numerical data*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Implementation Science
  • Models, Statistical
  • Rhabdomyolysis / etiology
  • Rhabdomyolysis / metabolism
  • Risk Factors
  • Serotonin and Noradrenaline Reuptake Inhibitors / adverse effects
  • Serotonin and Noradrenaline Reuptake Inhibitors / therapeutic use
  • Treatment Outcome


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Serotonin and Noradrenaline Reuptake Inhibitors
  • Azithromycin
  • Clopidogrel
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Clarithromycin