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Interpreting the TRITON Results in Light of the Event Adjudication Process

process of adjudication can be important to assure systematic application of the definition. Misclassification of events could lead to less reliable results due to inaccurate estimates of true treatment effects. The ‘universal’ definition of MI has evolved into a standard similar to that used by the TRITON investigators. Moreover, using the actual ‘universal’ definition of MI, prasugrel was associated with statistically significantly lower rates of spontaneous MIs and of procedurerelated MIs [8] . Two methods of identifying events to be adjudicated can differentially impact on overall event rates and treatment effect estimates. If the ‘triggers’ for event review are limited to events that are identified by the investigators, then the false positive rates will decrease, but the false negative rates will not be affected – and overall event rates will only be decreased by the process. On the other hand, when triggers identify events that the investigator has missed, then the number of events can increase. Assuming the newly detected events are similarly modified by the experimental treatment, the power of the trial will be increased. This latter approach was used in the TRITON trial – and the number of MIs increased by around 2-fold. Dr. Serebruany states that the additional MIs identified by the adjudication process were necessary to lead to a statistically significant trial result in the primary prespecified analysis. He raises the concern that MIs detected by adjudication (but not by the investigators) may be smaller and less clinically relevant. The EPIC trial provides another example of statistically significant results based on adjudicated, but not investigator-identified Based on the results of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel [1] , prasugrel has been approved by the Food and Drug Administration (FDA) for the treatment of moderateto high-risk acute coronary syndrome (ACS) patients who are managed with percutaneous coronary intervention. The primary endpoint of the TRITON trial was the composite of cardiovascular death, nonfatal myocardial infarction (MI) and stroke. Because the benefit of prasugrel was primarily driven by reduction in MI, Dr. Serebruany raised important questions about how MI events were ascertained and adjudicated [2] . Traditionally in large clinical trials, nonfatal primary outcomes are adjudicated through centralized reviews in order to more systematically apply standard definitions. In spite of limited empirical data that central adjudication improves the reliability of treatment assessment, regulatory authorities, including the FDA, have been supportive of this approach [3] . Because adjudication can consume major resources without clear evidence of improving trial reliability, some have argued that the process be streamlined and efficiently tied to a carefullyconstructed data collection form [3, 4] . In trials of cardiovascular disease, there is evidence that in certain circumstances, clinicians may be inaccurate in applying standard definitions [5, 6] . In addition, definitions for nonfatal events such as MI have varied between trials, although an international standard for universally defining MI now exists [7] . MI ascertainment by this definition depends on both systematic blood sampling and surveying for biomarker elevation. A central Received and accepted: August 21, 2009 Published online: November 7, 2009