Insights into the reporting of major adverse cardiovascular events in coronary artery disease trials
Authors: Lee E , Tan B , Chin Y H , Chan Y H , Ong J , Goh R S J , Chong B , Anand V V , Kong G , Wang J W , Muthiah M D , Loh P H , Chan M Y , Chew N W S , Mamas M A 
Published: October 2024

Abstract

Background and Purpose
Major adverse cardiovascular event (MACE) is one of the most used composite outcomes in coronary artery disease (CAD) trials, though its lack of a standardised definition has led to ambiguity and challenges in its interpretation. This study aims to elucidate the definition of MACE and guide future interpretation of MACE in the context of CAD trials.

Methods
A systematic review was conducted by searching Medline, Embase and Cochrane for double-blind pharmacological randomized-controlled trials among participants with CAD from 2012 to 2022 that reported MACE outcomes. Qualitative reviews were conducted based on the components of MACE, composite definitions, composite rationale, and the reporting of MACE.

Results
30 trials, consisting of 77,692 patients were included, from which a total of 41 MACE analyses were extracted. The most commonly included components were cardiac death (56%), unplanned revascularisation (56%), followed by fatal or non-fatal MI (54%), non-fatal MI (44%) and stroke (39%), with cardiac death, non-fatal MI and non-fatal stroke being the most commonly used conglomerate (14%). A third of trials did not provide definitions of MACE, and all MACE composites in included trials were determined within the investigating committees without justification nor citation from guidelines. Notably, 27% of studies constructed MACE outcomes post hoc, with 7% observing a resultant change in statistical significance of the overall results. A fifth of studies deviated from the original MACE definition that was proposed within their protocol. There were inconsistencies in the definitions of the composite components, with 22 trials (73%) failing to specify whether the MI component in MACE was fatal or non-fatal. Similarly, 16 trials (53%) did not specify if stroke was fatal. In terms of the timing of MACE in patients presenting with multiple events, the majority of the trials (77%) did not specify how the event was assessed with, seven trials (23%) described the approach to recording the time to the first MACE event, while none of the trials considered the time to the event that conferred greatest clinical significance, nor provided a definition for it.

Conclusion
There is substantial heterogeneity in MACE definitions within CAD trials, where rationale behind its adjudication is often inadequately described, with suboptimal specification, inconsistent reporting, and publication bias within and across studies. Clinicians should be cautious when interpreting conclusions related to MACE, as the intervention is unlikely to affect all components of MACE, due to the susceptibility to "cherry-picking" of components to improve statistical outcomes. Harmonising the MACE definition would enhance transparency in clinical trial reporting, ensuring a robust measure of intervention efficacy and safety that can be easily compared across different trials.