Unintended bias, clinical trial results, and the heparin post hoc crossover fallacy

OBJECTIVE: To describe the unintended pitfalls in the interpretation of postrandomization events in clinical trials. DESIGN: Analysis of patients enrolled in clinical trials for new sepsis interventions with postrandomization exposure to heparin. PATIENTS: Retrospective review of patients enrolled in large phase III sepsis trials after treatment with experimental anticoagulant therapies. INTERVENTIONS: Nonrandomized exposure to heparin therapy administered for a variety of clinical indications after enrollment in large phase III sepsis trials. RESULTS: The effect of heparin on overall survival in septic patients in trials that randomized patients into treatment assignments other than heparin is difficult to quantitatively analyze because of unintended selection bias and allocation bias. Both forms of bias overestimate the potential therapeutic value of heparin. This post hoc analysis of the data is functionally a crossover study in which only surviving patients can cross over in one direction (toward the heparin treatment arm). CONCLUSION: Great caution should be exercised in the post hoc interpretation of the potential efficacy of nonrandomized treatments such as heparin therapy derived from phase III clinical data of other drugs for sepsis. The therapeutic value of heparin as a treatment modality in severe sepsis can best be determined in a formal, randomized, prospective clinical trial. This will obviate the unavoidable selection bias and allocation bias intrinsic to postrandomization events in clinical trials with a high early mortality rate such as severe sepsis and septic shock.