From the Journals

A call to revamp revascularization trial endpoints



The time has come to rethink the conventional primary endpoints investigators use in coronary revascularization trials – a composite of major adverse cardiovascular events (MACE), death or MI, and other endpoints – and shift toward greater emphasis on quality of life, two clinical trial investigators say.

Gregg Stone, MD, and Mario Gaudino, MD, MSCE, PhD, made their case in the Journal of the American College of Cardiology, writing: “The classic academic exercise of comparing revascularization modalities in an elusive search for a clear ‘winner’ has failed.” Dr. Stone was the principal investigator of the landmark EXCEL trial and an investigator for the ISCHEMIA trial, the latter of which Dr. Gaudino was also an investigator. Both trials evaluated percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) as treatments for coronary artery disease.

Dr. Gregg W. Stone, Icahn School of Medicine at Mount Sinai, New York

Dr. Gregg W. Stone

In an interview, Dr. Stone, a cardiologist at the Icahn School of Medicine at Mount Sinai, New York, said: “We’re proposing a new endpoint called a composite endpoint measured in a hierarchical fashion of death or quality of life [QOL].” Dr. Gaudino is a cardiac surgeon at Weill Cornell Medicine, New York.

Quality of life as a validation tool

As a measure of revascularization after PCI or CABG, Dr. Stone said, QOL is ready for prime time. “Over the last 20 years there’s been a very rich literature of science developed linking certain quality of life instruments to improved outcomes, in particularly health but also heart failure.”

Those instruments include the Seattle Angina Questionnaire, the Minnesota Living with Heart Failure Questionnaire and the Kansas City Cardiomyopathy questionnaire. “All of these are sufficiently validated that the [Food and Drug Administration] considers them ‘validated tools’ for use in clinical trials.” Dr. Stone also noted that substudies of three landmark trials comparing PCI and CABG – EXCEL, SYNTAX, and FREEDOM – used those instruments to evaluate QOL as an endpoint alongside “hard” outcomes such as death, MI or stroke. “So quality of life already is being used and it is already widely accepted. What we’re saying is, when you think about the information you need for medical studies, we believe it’s time to elevate that from secondary supportive information to primary.”

He and Dr. Gaudino are putting their money where their mouths are. They’ve applied for a grant through the Patient-Centered Outcomes Research Institute to use QOL as an outcomes measure in a trial of revascularization strategies in women and minority patients.

Shortcomings with traditional endpoints

Dr. Stone explained some of the shortcomings with the traditional endpoints revascularization studies have used. “Everybody agrees that mortality or survival is the most important endpoint, but studies can never be large enough to be powered for that. So we always end up combining them with myocardial infarction, stroke, and often with repeat revascularization” into one MACE endpoint.

But those four types of events are “very, very different,” Dr. Stone said. The severity of MIs and strokes can range from minor, almost inconsequential events to major, debilitating events. “Some strokes resolve in a few days but we count them all the same.”

He ticked off a list of the other outcomes the traditional endpoints don’t account for: atrial fibrillation, kidney dysfunction, musculoskeletal disorders, depression, cognitive changes, and vascular complications. They all can all have a significant impact on a patient’s QOL, Dr. Stone said.

“We’ve now entered an era that is much more patient centered,” Dr. Stone said. “My goal as a physician is to try to impart my knowledge of the evidence that’s out there so that the patient can make the decision that gives them the best chance of meeting their life goals and objectives. When you ask patients what they want, they all want to live longer and they want to live better.”

Dr. Suzanne Baron, director of interventional cardiology research at Massachusetts General Hospital in Boston Mass General

Dr. Suzanne Baron

MACE as a composite endpoint has its shortcomings, but using QOL can also be fraught with problems, said Suzanne Baron, MD, director of interventional cardiology research at Massachusetts General Hospital, Boston.

With regards to MACE, she echoed some of Dr. Stone’s concerns. “Patients and clinicians likely would not consider a repeat stenting procedure to be the same as having a stroke, and so weighting these two outcomes equally within a composite endpoint can potentially result in a skewed trial conclusion.”

One potential issue with QOL as an endpoint is that it can vary from day to day. “If quality of life is only measured at a few time points, such as annually, it is possible that those measurements may only reflect a small portion of the patient’s overall quality of life,” she said. “Accordingly, I think that it will be important to incorporate frequent assessments of a patient’s quality of life if these measures will be used as a primary endpoint in cardiac revascularization trials.”

And, in a cost-conscious health care system, quantity (length) of life tends to carry more weight than QOL, she said. “So it will be important that a trial using quality-of-life improvement as a primary endpoint mandates that the degree of improvement be large enough to ensure that the treatment remains high-value from a health economics standpoint.”

Dr. Stone disclosed financial relationships with numerous pharmaceutical companies. Dr. Baron reported financial relationships with Abiomed, Acarix, Boston Scientific, Medtronic, Zoll Medical, Biotronik, Edwards Lifesciences, and Janssen.

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