This JAMA Guide to Statistics and Methods describes how intention-to-treat, per-protocol, and as-treated approaches to analysis differ with regard to the patient population and treatment assignments and their implications for interpretation of treatment effects in clinical trials.
Nonadherence in a randomized clinical trial (RCT) occurs when study participants do not follow the randomly assigned treatment protocol. Reasons for nonadherence may include the study participant not taking trial medications, crossing over to the other intervention being studied, or accessing treatment outside of the trial. Nonadherence also may occur when the clinician is unable to complete the assigned therapy (eg, a surgical procedure) as intended.
The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) clinical trial published in JAMA by Packer et al1 was difficult to interpret because of nonadherence with the treatment protocol that resulted from substantial crossover between groups. In this trial, patients with atrial fibrillation were randomized to either undergo catheter ablation or receive conventional medical therapy. Of the 1108 participants randomized to ablation, 102 (9%) did not receive the procedure. Of the 1096 patients randomized to drug therapy, 301 (27%) underwent ablation during the follow-up period, resulting in nonadherence to assigned treatment in both groups of the study. Interpretation of the effect of catheter ablation on atrial fibrillation differed based on alternate ways of analyzing the trials results. Intention-to-treat (ITT), per-protocol (PP), and as-treated (AT) approaches to analysis differ in how the included patient population and treatment assignments are defined, with important implications for interpretation of treatment effects in clinical trials.
ITT, PP, AND AT APPROACHES TO ANALYSES
The ITT principle is the most commonly used approach for the primary analysis of RCTs. It measures the effect of assigning patients to treatment, which includes differences in individuals’ adherence.2 With the ITT approach, all randomized patients are included in the analysis, based on the groups to which they were initially randomly assigned. The PP and AT analyses estimate the effect of receiving a treatment.3,4 Per-protocol only analyzes data from participants who follow the protocol, excluding their data after they become nonadherent. AT analyses consider the treatment actually received by the participant, without regard to adherence to their randomization assignment.
As-treated and PP analyses are not simple to interpret because of the potential loss of an important benefit of randomization: the elimination of systematic bias in treatment assignment. Selection bias and confounding in the treatment effect estimate arises if patients who are more adherent with the assigned treatment differ in ways that also influence their outcomes compared with those who are less adherent. Similarly, when comparing medical and procedure-based treatments, as occurred in the CABANA trial, patients who can have a procedure performed compared with those who cannot have the procedure may have differing prognoses. Consequently, PP and AT analyses must apply the types of statistical methods used in ...