Three noted cardiovascular trialists have called for a reappraisal of major adverse cardiovascular events (MACE) as a primary endpoint in cardiovascular clinical trials, in a viewpoint published in the European Heart Journal, favouring those with greater emphasis on patient-centred outcomes such as quality of life.
After more than three decades since MACE was first used as an outcome for measuring the safety and efficacy of interventions in cardiovascular medicine, Mario Gaudino (Weill Cornell Medicine, New York, USA), Eugene Braunwald (Harvard Medical School, Boston, USA) and Gregg W Stone (Icahn School of Medicine at Mount Sinai, New York, USA) state that its continued use “warrants re-evaluation”.
In their paper, published in late July, the trio note that the use of MACE—typically defined as the composite of non-fatal stroke, non-fatal myocardial infarction (MI) and cardiovascular death—was adopted to enable innovative treatment approaches to be evaluated for early safety and efficacy in relatively small trials, given the vast number of patients needed to effectively power trials to assess improved survival alone.
Subsequent to its first use in the early 1990s, a composite MACE endpoint was widely adopted in cardiology trials, Gaudino, Braunwald—who was among the original proponents of MACE—and Stone write, but from the outset, it was never envisioned that “MACE would become the standard on which regulatory and clinical decisions were based”.
According to the authors, MACE has a number of limitations, including that different events such as MI, stroke or death have varying degrees of severity and causes; definitions of individual components can differ across trials, making comparisons difficult; that combining multiple outcomes can obscure the effects of individual components; and, that some components may not be as clinically relevant to patients.
The authors go on to suggest several alternatives to MACE as a primary endpoint, including the use of a hierarchical composite endpoint that prioritises the most critical events, an approach that is being adopted in the REvascularization CHoices Among under-Represented Groups Evaluation (RECHARGE) trial, in which Gaudino and Stone are both investigators.
RECHARGE is enrolling 1,200 patients in multiple sites across the USA and Canada to compare coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI), focusing on female and minority populations. The trial is being funded through US$29.9 million from the Patient-Centered Outcomes Research Institute (PCORI), a US non-profit body that funds research focused on “outcomes that matter to patients”, according to its website.
The trial’s primary outcome measure is a combination of death and overall quality of life, assessed using 12-item short form surveys, designed for capturing the overall quality of life, at one, three, six, 12, 18, 24 and 36 months.
“RECHARGE will not only generate important data in patient groups that have been poorly represented in prior revascularisation trials, but also introduces a potentially transformative pathway for assessing the totality of the risks and benefits after cardiovascular interventions in an endpoint that is most meaningful to patients and overcomes the limitations of the traditional MACE endpoint,” Gaudino, Braunwald and Stone write of the trial in their European Heart Journal paper.
“Many physicians—and patients—have become increasingly frustrated with the traditional MACE endpoint,” Stone tells Cardiovascular News. “Because of its numerous limitations MACE does not inform the outcomes that are meaningful for patients after PCI versus CABG. Particularly, as we describe in this perspective, the discrete non-fatal components of the MACE endpoint often have a fleeting, if any, impact on a patient’s life.
“For example, a small MI defined only by a biomarker elevation may not be prognostic important, neither shortening life expectancy or impairing quality of life. Most repeat revascularisations are four-hour outpatient procedures that many patients don’t even recall. The traditional MACE endpoint favours the early occurrence of often minor events; does not overcome ascertainment or indication bias; ignores recurrent events; and does not account for many outcomes that are equally or more important as those included, such as new onset atrial fibrillation requiring oral anticoagulation; progressive kidney disease; heart failure; other causes of hospitalization; bleeding or vascular complications, etc.
“Patients want to live longer and live better, and the patient centred outcome that we are testing in RECHARGE is designed to reflect the overall risks and benefits of revascularization as it affects the patient’s life, time-averaged over five years to comprehensively reflect the entire journey of each patient.”
