The utility of major adverse cardiac events (MACE) as the primary endpoint in cardiovascular trials is under debate, with some experts suggesting it has outlived its usefulness. Speaking at the European Association for Cardio-Thoracic Surgery annual meeting, Mario Gaudino, MD, PhD, of Weill Cornell Medicine, argued that MACE, initially developed for exploratory trials, has become the gold standard despite significant limitations.
Gaudino and others propose replacing MACE with an endpoint that combines both hard outcomes like mortality and soft outcomes like quality of life, weighting these events appropriately. MACE's appeal has been its simplicity for trial design and power calculations, but its clinical relevance is now being questioned.
Limitations of MACE
A key criticism of MACE is that it assigns equal weight to all individual components, regardless of their impact on a patient's life. For example, myocardial infarction and mortality are treated equally, despite their vastly different consequences. Additionally, time-to-first-event analysis places undue emphasis on early clinical events, potentially skewing the overall results. "We have been designing clinical trials for trialists, not for patients," Gaudino stated.
Sigrid Sandner, MD, of the Medical University of Vienna, acknowledged the need for more education to convince the community about the benefits of non-MACE endpoints. She noted concerns among surgeons that focusing on quality of life might not adequately capture the impact of events like myocardial infarction and repeat revascularization.
The Win Ratio Approach
Gaudino, along with Eugene Braunwald, MD, and Gregg W. Stone, MD, advocate for a new composite endpoint that combines time-averaged quality of life with mortality, analyzed using the win ratio. This approach is being used in the ongoing RECHARGE trial, which compares CABG and PCI in underrepresented minority patients. The new endpoint aims to evaluate the patient's wellbeing globally, considering the impact of events on their overall quality of life.
According to Gaudino, while the conventional approach is suitable for studies comparing similar interventions, such as two stents, the new approach should be used when testing very different interventions, such as PCI and CABG or TAVR and SAVR, especially when those interventions affect not only cardiovascular outcomes but more general quality of life.
Concerns and Acceptance
Michael Borger, MD, PhD, of the Heart Center of Leipzig, raised concerns about the acceptance of the win ratio among surgeons, noting their limited experience with it and the difficulty in understanding and conveying its message. He worried that the complexity of the win ratio might lead to skepticism and misinterpretations.
However, Gaudino maintains that the win ratio's strength lies in its ability to weight disparate outcomes appropriately, ensuring that mortality, for instance, is given more importance than quality of life. He believes that the cardiac surgery community is innovative and will embrace the new approach once the rationale is clear.
Borger expressed interest in the RECHARGE trial's outcomes and how the win ratio is received within the community. He acknowledged MACE's weaknesses, such as the unequal weighting of components and variability across trials, but highlighted its resistance to the placebo effect.
Gaudino remains optimistic, stating that introducing new concepts always faces resistance but that the cardiac surgery community is generally cutting-edge and will be receptive to the rationale behind the change.
