The Role of Intention-to-Treat Analyses in Randomized Trials

To the Editor—Fritz et al recently examined 4 different approaches to eradicating Staphylococcus aureus carriage among patients with community-onset skin and soft-tissue infections (SSTIs). The increasing incidence of SSTIs—especially in the context of community-associated methicillin-resistant S. aureus—and the relative paucity of data on this subject make this an important investigation. The authors undertook an ambitious and rigorous approach to answering their research question, ultimately producing high-quality evidence supporting the use of dilute bleach bath, intranasal mupirocin, and hygiene education to eradicate carriage of S. aureus. In the course of their analysis, the authors describe using a "modified intention-to-treat analysis" to assess their outcomes. A recent investigation by Abraha and Montedori examined the use of the term "modified intention to treat" (ITT) in 475 publications of randomized and controlled trials; their conclusions revealed that significant variation exists in its definition, making its meaning nearly indiscernible. In the study by Fritz et al, the authors used the term to refer to their primary analysis, which included only subjects completing follow-up visits and may more commonly be characterized as a "perprotocol" or "as-treated" analysis. While it is easy to follow the methods the authors used in their modified ITT analysis, we feel use of this term should be avoided. One assessment not performed in this investigation was a strict ITT analysis, which treats subjects lost to follow-up as having experienced treatment failure. On the basis of information included in their publication, Table 1 presents the results from a strict ITT analysis alongside the results reported in Table 2 of the original publication. Although the original results presented in the article showed the combination of education, intranasal mupirocin, and bleach baths to be most effective at eradicating carriage of S. aureus, this group also had the highest attrition. In the strict ITT analysis, the advantage in this group disappears, and the eradication rate of S. aureus carriage is comparable to that of the control group as well as the other treatment groups. Both strict ITT and as-treated analyses should be used to inform the overall conclusions of any given randomized trial. Both analyses provide estimates of the true effect—which likely lies somewhere between the 2 estimates—while offering different trade-offs. Strict ITT analyses ensure that the benefits of randomization, most notably the equal distribution of unmeasured confounders, remain intact. However, by treating those lost to follow-up as having experienced treatment failure, strict ITT analyses may be overly conservative and likely dilute true effect sizes. As-treated analyses may more accurately represent the impact of a given treatment by including only those who actually received treatment in the analysis. The trade-off here is that selection bias may be introduced because of differential loss to follow-up if subjects are lost due to an unmeasured or unknown confounder. We applaud the work of these investigators and look forward to reading further work from them on this topic. We feel it necessary that clinicians are aware of the nuances in reporting clinical trials and the important role ITT analysis plays in assessing the results of randomized controlled trials.