Table 2.

Key assumptions of the case–crossover and the self-controlled case series (SCCS) methods^a and consequences of their violations in the context of interacting drugs

Design		Key Assumptions	Consequences of violation
Case–crossover	SCCS
✓	✓	No within-person, time-varying confounding (e.g., confounding by drug indication)	Both designs are affected to the same extent. Magnitude of bias depends on the magnitude of the confounder–outcome association, confounder–exposure association, and prevalence of the confounder.
✓		Constant drug exposure probability in population: no time-trends in the exposure	Biased estimates with the case–crossover design
✓		Transient drug exposure	Evaluating persistent exposures leads to upward bias in the case–crossover design; no bias when prolonged, but finite exposures are evaluated
	✓	Outcome does not affect subsequent drug exposure	We did not evaluate violation of this assumption independent of event-dependent censoring in the current study
	✓	Observation time is not affected by the outcome	In SCCS design nested within person–time exposed to an object drug, discontinuation of the object drug following an outcome will lead to censoring and biased estimates, particularly when discontinuation occurs in more than 50% of the patients. Bias may be larger when chronic precipitant drugs are evaluated.
	✓	Independent recurrent events or rare if independence cannot be assumed	We did not evaluate violation of this assumption in the current study

^aAs conventionally implemented in studies of drug effects: case–crossover with right censoring at an outcome (unidirectional) and SCCS that makes use of exposure information before and after outcome(s) of interest.