CREST-2 Trial

Groundbreaking Crest-2 Trial to Determine Best Treatment for Carotid Atherosclerotic Stenosis

 When patients come to Brajesh Lal, M.D., with asymptomatic narrowing of the carotid artery — which places them at an increased risk for stroke — the vascular surgeon doesn’t know the very best way to treat them. That’s because the three established treatments for the condition — intensive medical management, carotid endarterectomy (CEA) or carotid artery stenting (CAS) — all produce excellent outcomes. Excellent, but not quite equal.

A multicenter trial known as CREST — Carotid Revascularization Endarterectomy versus Stenting Trial — published results in 2010, finding no major disparity in outcomes for the two surgical procedures, though “nuanced differences” included a slightly higher post-treatment stroke risk for those receiving stents and a slightly higher risk of heart attack in those undergoing CEA, an open surgery in use for the past 60 years.

Moreover, the most recent research evaluating intensive medical management dates from the early 1990s — comparing it only to CEA, since CAS had not yet been developed — and 20 years of improvements in the field renders that information nearly obsolete.

“I have almost a one-third split among all three methods of management in my clinical practice now,” says Dr. Lal, a professor of surgery at University of Maryland School of Medicine and director of the Center for Vascular Diagnostics at University of Maryland Medical Center. “So we’re really at a point of equipoise where we can’t really predict which treatment will be better.” 

That’s all about to change with the undertaking of the CREST-2 trial, which will be headed by UMMC and the Mayo Clinic and run at 120 clinical centers across the United States and Canada. The $39.5 million research, funded by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH), was fundamentally designed to be two parallel, randomized trials that build on the data collected by the CREST team but veers off in one crucial way.

Fundamental Difference in CREST-2 Trial

CREST-2 takes advantage of the infrastructure, network, expertise and goodwill built over the past decade by the CREST team, but uses the “CREST” acronym only because CREST-2 is the second trial to be conducted by the team. Otherwise, there’s a fundamental difference between the two trials: Instead of comparing one surgical procedure to the other, CREST-2 compares a combination of CEA and intensive medical management to intensive medical management alone, and CAS combined with intensive medical management to intensive medical management alone, in two separate arms.

Both arms will randomize 600 patients to each group for a total of 2,400 patients, all of whom have at least 70% or higher blockage of one of their carotid arteries but have not suffered a stroke from it. The research team will begin enrolling patients in early 2014, with UMMC running the imaging core facility that processes all imaging scans used in the research.

“One of the most important conclusions the first CREST trial came up with was that when you combined the outcomes of myocardial infarction, stroke and death and you looked at them together, CAS is no different than CEA,” says Dr. Lal, who is serving as one of two national principal investigators on the CREST-2 trial. “So purists would say, once you prove these are equivalent, all you need to do now is compare either of the procedures to medical management.

“My concern planning this trial was if we mixed these two procedures into a common arm, we would open ourselves to criticism from supporters of one or the other. And for a practicing physician, it would still leave some doubt as to which procedure was better or not better than medical management,” he adds. “I thought the best solution was to keep it clean and separate. Why do we do these expensive, effort-intensive trials? So when a patient walks in a [physician’s] door, they can categorically say ‘This is the best treatment for you.’ If we’re still going to come up with a cloudy result, we’ve not really done anyone any service.”

Dated Research Still Guides Treatment

Even now, Dr. Lal says, physicians refer to the recommendations of the Asymptomatic Carotid Atherosclerosis Study (ACAS) — which compared CEA to intensive medical management — to guide treatment of patients with asymptomatic carotid stenosis. But those results were published 20 years ago and intensive medical management combining medication with aggressive lifestyle modifications is much more advanced today.

“The reason we need to do this research again is that stenting has emerged as an alternate treatment since that time and medical management has improved greatly over the past 25 years,” Dr. Lal explains. “We have many new anti-platelet drugs to prevent clotting and statins — which weren’t available then — that lower cholesterol dramatically. Plus we now have detailed and effective guidelines to manage diabetes and hypertension, so the area of risk factor management now has improved dramatically.

“Trying to follow the recommendations established back then may not be the appropriate way of treating patients in this day and age,” he adds.

As a result of improvements and refinements among all three standard treatments, the stroke rate among patients has been cut in half. But CREST-2 should help physicians be able to make the choice precisely suiting each patient, Dr. Lal says.

“At the end of the day, when someone comes to me and says, ‘You’re a vascular surgeon. Why are you doing this study?’ I can respond, ‘No matter which treatment modality comes out better, it’s a win’,” he says. “Because ultimately, we’re figuring out what’s best for the patient.”

CREST-2 Data Eagerly Anticipated 

While the researchers involved are eager to learn the results of CREST-2, which will unfold over the next five years, many other groups also have an interest in the coming data: NINDS, of course, but also the Food and Drug Administration, Agency for Healthcare Research & Quality (AHRQ) and the Centers for Medicare & Medicaid Services (CMS). Also curious are investigators of the second European Carotid Surgery Trail (ECST-2), who share CREST-2 researchers’ goal of harmonizing the two protocols, if possible.

With between one and three million Americans at any given point suffering from asymptomatic carotid artery stenosis, “This trial will help determine what’s the best way of treating a large proportion of patients in the U.S.,” Dr. Lal says. “Furthermore, it will become the de facto preferred treatment modality across the world. The fact that all of these agencies are tremendously interested is a reflection of how important this question is and the potential impact we can have.”

For more information, contact Vascular Surgery at 410-328-5840.