Random treatment assignment using mathematical equipoise for comparative effectiveness trials

Abstract

In controlled clinical trials, random assignment of treatment is appropriate only when there is equipoise, that is, no clear preference among treatment options. However, even when equipoise appears absent because prior trials show, on average, one treatment yields superior outcomes, random assignment still may be appropriate for some patients and circumstances. In such cases, enrollment into trials may be assisted by real-time patient-specific predictions of treatment outcomes, to determine whether there is equipoise to justify randomization. The percutaneous coronary intervention thrombolytic predictive instrument (PCI-TPI) computes probabilities of 30-day mortality for patients having ST elevation myocardial infarction (STEMI), if treated with thrombolytic therapy (TT), and if treated with PCI. We estimated uncertainty around differences in their respective predicted benefits using the estimated uncertainty of the model coefficients. Using the 2,781-patient PCI-TPI development dataset, we evaluated the distribution of predicted benefits for each patient. For three typical clinical situations, randomization was potentially warranted for 70%, 93%, and 80% of patients. Predictive models may allow real-time patient-specific determination of whether there is equipoise that justifies trial enrollment for a given patient. This approach may have utility for comparative effectiveness trials and for application of trial results to clinical practice.

Figure 1

Predicted (PCI) survival benefit: p(live) with PCI minus p(live) with TT; * percutaneous coronary intervention (angioplasty), ** thrombolytic therapy.

Figure 2

Distribution of predicted mortality for ST elevation myocardial infarction by percutaneous coronary intervention (PCI) and thrombolytic therapy (TT) mortality for n = 2,781. Subjects in PCI–TPI development sample, together with line of equivalence and zone of equipoise (<20% benefit of either treatment compared to each other for given circumstance).