CREST-2: Testing approaches for stroke prevention
An international clinical trial led by Mayo Clinic will compare the effectiveness of medication and surgical interventions in preventing stroke. Funded by a $39.5 million grant from the National Institute of Neurological Disorders and Stroke, the CREST-2 study builds upon the earlier Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST).
CREST compared treatment with endarterectomy and stenting for patients with symptomatic or asymptomatic carotid artery stenosis. Results of the study, released in 2010, showed the two procedures to have similar overall safety and effectiveness, with stenting favored in patients under age 50 and endarterectomy in those over age 74.
CREST-2 consists of two parallel studies in asymptomatic patients. One compares medical treatment alone versus medical treatment and endarterectomy; the other compares medical treatment alone versus medical treatment and stenting.
"In the current era of medical management, the crucial question is whether it is still productive and appropriate to revascularize the carotid artery, either surgically or with stenting, in asymptomatic patients. Optimal medical management of asymptomatic carotid atherosclerosis might obviate the need for these procedures," says James F. Meschia, M.D., a consultant in the Department of Neurology at Mayo Clinic's campus in Jacksonville, Florida, and co-leader of CREST-2.
Approximately 140,000 carotid revascularizations are performed annually in the United States. Complications include heart attack and stroke, which CREST found to be slightly more common in patients who have surgery and stenting, respectively.
"The risk of complications from surgery and from stenting is very small," says Giuseppe Lanzino, M.D., a consultant in the Department of Neurologic Surgery at Mayo Clinic's campus in Rochester, Minnesota. "However, the information that we have when choosing treatment for patients with asymptomatic carotid stenosis is from studies in the early 1990s. It is very important to do an updated study with modern practices."
CREST-2 is enrolling 2,480 patients at 120 centers in the United States and Canada, and possibly Europe and Australia. Mayo Clinic's campuses in Arizona, Florida and Minnesota are all participating in the seven-year trial.
Patients must have at least 70 percent stenosis and be asymptomatic, defined as having no stroke or stroke-like symptoms ipsilateral to the stenosis within 180 days of randomization in the trial. Modeling clinical practice, referring physicians will recommend appropriate revascularization — surgery or stenting — for each patient, based on clinical, radiologic and angiographic assessment, demographic information, and patient preference. Patients in each group will then be randomized to receive medical management alone or medical management plus revascularization.
"In many cases the patient may be a candidate for either surgery or stenting," Dr. Meschia says. "But just as patients in standard practice can't have both procedures, trial participants will select a procedure after informed consideration and discussion with the physician."
Patients frequently express preferences for one procedure over the other, notes Thomas G. Brott, M.D., a consultant in the Department of Neurology at Mayo Clinic in Jacksonville, who with Dr. Meschia co-leads CREST-2. "Patients in CREST-2 have more input on this decision than study participants ever have experienced previously," he says.
Intensive medical management
Unlike CREST, in which treatment of vascular risks was at the discretion of patients' primary physicians, CREST-2 has a detailed protocol for medical management of all trial participants. "The protocol insists on hitting hard objectives," says Bart M. Demaerschalk, M.D., a consultant in the Department of Neurology at Mayo Clinic's campus in Phoenix/Scottsdale, Arizona. "We're targeting optimal lipid profiles, blood pressure, glycemic control, smoking cessation, ideal body mass index, nutritional and dietary recommendations, and physical activity and exercise."
The trial will cover treatment with anti-platelets such as clopidogrel, several classes of blood pressure medications and statins. The primary outcome measurement will be a composite of all strokes and deaths within 30 days of randomization, and ipsilateral stroke for up to four years afterward. Patient follow-ups will continue until at least two years after the last patient is randomized.
"We expect this intensive medical care aspect of CREST-2 will be beneficial for all patients," Dr. Brott says. "Because of improved medical treatments, asymptomatic carotid artery disease is not nearly as dangerous as it used to be. As a result, we expect very few patients in either study will actually have a stroke."
Another innovative aspect of CREST-2 is cognitive testing, which all participants will undergo at baseline, 1 month, and every 12 months thereafter up to 48 months to determine if cognitive outcomes are different between treatment groups. "Cognitive information has the potential to be a cost-effective and patient-centered way of determining if there's a benefit in preventing not only overt stroke but silent strokes that might manifest as cognitive impairment," Dr. Meschia says.
Mayo Clinic has a distinguished history in the diagnosis and treatment of carotid artery disease. The range of expertise at Mayo Clinic is reflected in the institution's leadership roles in CREST-2.
Robert D. Brown Jr., M.D., M.P.H., a consultant in the Department of Neurology at Mayo Clinic in Rochester, chairs the trial's Endpoint Adjudication Committee. John Huston III, M.D., a consultant in the Department of Radiology at Mayo Clinic in Rochester, directs analysis of CT and MRI imaging. Dr. Demaerschalk chairs the Site Selection and Site Management Committee. Many of the centers participating in CREST-2 also participated in CREST.
"After an extraordinarily successful CREST trial, we have a large, collaborative group of research centers with demonstrated success in researching carotid artery stenosis," Dr. Demaerschalk says. "These teams remain engaged, under the leadership of Dr. Brott and Dr. Meschia and members of the CREST-2 executive team, to rally around carotid artery disease."
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