Importance of swift event adjudication of endpoints for adequate reporting to data and safety monitoring boards in clinical trials—lessons from CULPRIT-SHOCK

Abstract

Conduction of randomized controlled clinical trials is costand time-consuming, especially if study enrolment is performed at multiple sites in multiple countries with different medical traditions, medical record systems, and language barriers. Typically, three distinct boards are created to coordinate these trials. First of all, the principal investigator and associated advisors form the Steering Committee, which is responsible for executive tasks such as trial design and oversight. Secondly, a Data Safety Monitoring Board (DSMB) is needed to review the event and outcome data. This board consists of independent members and is responsible for ongoing evaluation of participant safety, overall conduction as well as the progress of the trial and might even recommend to modify or terminate the trial in case of respective concerns. Thirdly, the Clinical Event Adjudication Committee (CEAC) reviews the anonymized participant data and adjudicates events and outcome data. While the DSMB has direct access to the random code, the CEAC remains blinded throughout the trial to guarantee unbiased adjudications. Whereas the latter is often considered a necessity for the final reporting and thus robustness of the conclusions it is also quite common that substantial delays occur between investigator reporting and final adjudication of events. There are practical and financial interests to have fewer CEAC gatherings. While this delay is commonly accepted by the steering committee as it occurs simultaneously with other activities before the data lock of a trial, this delay may have important consequences for the interpretation during interim analyses, i.e. for the DSMB. Cardiovascular outcomes trials often include interventions which could benefit patients but inherently also might incur harm. In recent years there have been several examples of clinical trials being stopped prematurely due to either benefit or risk, even with an unfavorable risk-benefit ratio [1–3]. Increasingly, clinical trials have endpoints which are a composite of two or more adverse outcomes with quite different pathophysiological mechanisms or end organ involvement. As a consequence, the particular endpoints in a clinical trial can trend in quite opposite directions, making the interpretation difficult. An example of possible causes of death trending in different directions was encountered during the conduction of the recently published CULPRIT-SHOCK trial [4]. This trial was the first large randomized trial which proved that the hitherto preferred strategy of immediate complete revascularization with PCI in cardiogenic shock led to more harm defined by the primary endpoint of death and need for renal replacement therapy with an absolute difference of 9.5%. These 30-day results were recently confirmed in the 12-month follow-up analysis [5]. The pre-specified interim analysis after inclusion of 342 patients presented to the DSMB already showed a significant difference in 30-day total mortality favoring culprit-lesion only versus immediate multivessel PCI (44.2% vs. 57.1%; p = 0.017). The primary outcome of the trial, which also included renal replacement therapy, displayed a similar difference (47.1% vs. 61.2%; p = 0.009). The protocol stated that the interim analysis should be performed according to the O’Brian-Fleming method. The trial was to be stopped “if the null