Discussion
T2D, death, CVOTs, Thrombolysis, Myocardial Infarction, T2D CVOTs
DISEASE, EVENT, MYOCARDIAL INFARCTION, EVENTS, EVENTS
The TECOS data show that, for patients with T2D and known CV disease, the real-time hazard rates for MACE-4 and other important CV outcomes remained constant over the duration of the trial. Hazard rates for death (ACM and CV mortality) increased slightly over time, but not to an extent that indicates the need for complex modelling assumptions to predict events—exponential models that assume a constant hazard rate over time fit the data well. Examination of the within-trial event accrual pattern shows an “adjudication gap” that reflects the efficiency of trial processes for detecting events and confirming them with independent adjudication. Efficiency improved as the trial progressed, reflected by shorter adjudication times and impacted by event type.Broadly stated, demonstration of a constant event hazard rate shows that trial participants were at an equal risk of experiencing a nonfatal CV event, including the MACE-4 composite, at all time points within the follow-up. This observation provides confidence in traditional modelling approaches for within-trial event rates. Even the event types with Weibull shape parameter estimates > 1 (CV death and ACM) were not sufficiently divergent from a constant hazard rate to require alternate assumptions. The reason for a small increase in hazard rate for fatal events is unclear and was not explained by adjusting the models for age. It is possible that a history of previous CV events, as required by the TECOS entry criteria, increases risk for subsequent death to a greater extent than for subsequent nonfatal events [With important trial events occurring at a constant rate, the next most pressing issue is to ensure robust trial processes to define, ascertain, and confirm relevant events. CVOTs benefit from internationally agreed definitions for most important CV events [Critical decisions about trial design and resource allocation are affected by the adjudication gap. Understanding what influences the adjudication gap is an important part of clinical trial management and operations, and could have implications for key trial milestones. In an ongoing trial, the length of the adjudication gap affects how quickly a determination can be made that projected event rates are higher or lower than anticipated, which might prompt protocol amendments to the sample size trial entry criteria. In an event-driven trial, reliable forecasting of accrual time for the final events is required to effectively plan and conduct resource-intensive end-of-trial activities, such as monitoring visits and data cleaning. Monitoring of patient safety could also be hampered if underreporting, delayed reporting, or delayed adjudication of potential events impede the ability of a data and safety monitoring committee to review unblinded event data.Interpretation of this analysis is limited by its inclusion of only TECOS data, making generalizability beyond populations defined by T2D and established CV disease unwise. Primary outcome event rates recorded in the placebo group of other completed T2D CVOTs vary widely, ranging from 24.2 per 1000 patient years in the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 trial to 58.7 per 1000 patient years in the Harmony Outcomes study [