The Use of Estimands in the Design and Analysis of Comparative Effectiveness Trials: The PEPPER Trial

Pragmatic trials have gained popularity in recent years because of their applicability to practical clinical situations. In contrast to traditional explanatory trials, which are tightly controlled and designed to define the effects of treatments under ideal circumstances, pragmatic trials are intended to reveal differences between established treatments in real-world situations. Although the intention-to-treat principle remains the cornerstone of explanatory trials, it may not reliably identify the treatment effect of greatest relevance in pragmatic trials. The estimand approach to trial design and analysis provides for specification and handling of various important intercurrent events that characterize pragmatic trials and arguably allows clearer definition of the treatment effects of interest for assorted real-world populations. Since pragmatic trials have considerable relevance to orthopaedics, we share the rationale for design and upcoming analysis of the Pulmonary Embolism Prevention after Hip and Knee Replacement Trial using an estimand framework.