Retrospective analysis of the TOPPIC trial using DOOR methodology

Background Established analysis methods for composite outcomes can be complex to interpret, clinically and statistically. To counter this, composite outcomes are frequently reduced to a binary outcome. This can simplify interpretation but there exists a danger that deeper understanding of patient experience is lost. Rank-based DOOR methodology is emerging as an attractive option, using all components of a composite outcome. DOOR methodology has been employed retrospectively to the TOPPIC trial (ISRCTN89489788) to determine if making fuller use of data could enhance study results. Methods TOPPIC patients were assigned a clinical outcome rank (1 = most desirable to 8 = least desirable). DOOR methodology was applied, testing the null hypothesis of a DOOR probability of 50% (no difference). Additionally, smokers and non-smokers were considered separately. Win ratio and ordinal logistic regression provided supportive analyses. Results Employing DOOR methodology demonstrated the distribution of ranks differed between treatment groups - DOOR probability of a more desirable outcome with active treatment of 54.6% (95% CI 53.8% - 55.4%, p < 0.0001). Considering smokers and non-smokers separately, this difference was amplified in smokers (DOOR probability 66.1% (95% CI 62.7% - 69.4%, p < 0.0001). Win ratio methodology and ordinal logistic regression showed no difference between treatments. Conclusions DOOR methodology was applied successfully to a previously published trial and shows potential to discriminate clinical outcomes effectively by deconstructing a binary endpoint of component parts into an ordinal outcome. This approach should be considered when designing trials, either as principal analysis of a rank-based outcome or as a confirmatory sensitivity analysis.