Variability of relative treatment effect among populations with low, moderate and high control group event rates: a...

The current practice in guideline development is to use the control group event rate (CR) as a surrogate of baseline risk and to assume portability of the relative treatment effect across populations with low, moderate and high baseline risk. We sought to emulate this practice in a very large sample of meta-analyses.

We retrieved data from all meta-analyses published in the Cochrane Database of Systematic Reviews (2003-2020) that evaluated a binary outcome, reported 2 × 2 data for each individual study and included at least 4 studies. We excluded studies with no events. We conducted meta-analyses with odds ratios and relative risks and performed subgroup analyses based on tertiles of CR. In sensitivity analyses, we evaluated the use of total event rate (TR) instead of CR and using quartiles instead of tertiles.

The analysis included 2,531 systematic reviews (27,692 meta-analyses, 226,975 studies, 25,669,783 patients).The percentages of meta-analyses with statistically significant interaction (P < 0.05) based on CR tertile or quartile ranged 12-18% across various sensitivity analyses. This percentage increased as the number of studies or range of CR per meta-analysis increased, reflecting increased power of the subgroup test. The percentages of meta-analyses with statistically significant interaction (P < 0.05) with TR quantiles were lower than those with CR but remained higher than expected by chance.

This analysis suggests that when CR or TR are used as surrogates for baseline risk, relative treatment effects may not be portable across populations with varying baseline risks in many meta-analyses. Categroization of the continuous CR variable and not addressing measurement error limit inferences from such analyses and imply that CR is an undesirable source for baseline risk. Guideline developers and decision-makers should be provided with relative and absolute treatment effects that are conditioned on the baseline risk or derived from studies with similar baseline risk to their target populations.