Widely differing estimates of the treatment effect (i.e. heterogeneity or variability in results) across studies suggest true differences in underlying treatment effect. When heterogeneity exists, but investigators fail to identify a plausible explanation, the quality of evidence should be downgraded by one or two levels, depending on the magnitude of the inconsistency in the results.
Inconsistency may arise from differences in:
- Populations (e.g. drugs may have larger relative effects in sicker populations);
- Interventions (e.g. larger effects with higher drug doses);
- Outcomes (e.g. diminishing treatment effect with time).
Guideline panels or authors of systematic reviews should also consider the extent to which they are uncertain about the underlying effect due to the inconsistency in results and they may downgrade the quality rating by one or even two levels.
GRADE suggests rating down the quality of evidence if large inconsistency (heterogeneity) in study results remains after exploration of a priori hypotheses that might explain heterogeneity.