One of the challenges in stroke prevention has been how to manage patients with significantly narrowed carotid arteries who have not had a recent stroke or transient ischemic attack. Whether, when and how to intervene in these patients has been a subject of debate for a long time. Their risk is lower but not negligible, and the large number of such patients means that even small improvements in prevention strategies can have a big impact.
The CREST-2 trial—published in The New England Journal of Medicine—is a new study that could change how asymptomatic patients at serious risk for stroke are treated and, hopefully, help them avoid having a stroke at all. The study focused on people with severe blockages in their carotid arteries. With about 800,000 strokes in the U.S. every year, these blockages account for over 130,000 of them.
“Research conducted decades ago determined that a combination of revascularization procedures, medications and lifestyle changes was beneficial,” said study coauthor Herbert Aronow, MD, MPH, an interventional cardiologist and medical director of Heart and Vascular Services at Henry Ford Health. “However, this research was conducted in an era when medical therapy was not as advanced as it is today, with far fewer medications available to reduce stroke risk.”
“With more effective medical therapies available now, we questioned whether conclusions drawn decades ago are still valid today,” said Dr. Aronow. “Specifically, is it still appropriate to subject asymptomatic patients to an invasive procedure for a carotid artery blockage?”
Given that millions of people are unaware of their risk level, and that all too often the first warning sign can be a life-threatening stroke, the study’s finding that a minimally invasive procedure can correct the blockage and avoid stroke could improve outlooks and outcomes for many people.
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Answering a long-standing question
The study involved more than 1,200 patients in 155 health centers in five countries. Participants were followed for four years, and plans are to monitor them out to 10 years. This is important given the relatively low annual event rates in asymptomatic patients and the subsequent need for extended observation.
CREST-2 included two separate randomized trials comparing medication and lifestyle changes alone versus combined with carotid revascularization. The first employed carotid endarterectomy, the long-time standard practice for repairing a narrowed carotid artery. The second utilized carotid stenting, which uses a catheter to place a small wire mesh tube inside the artery to prop it open. Results of both trials were then compared with treatment by medication and lifestyle changes alone.
“Long ago, carotid endarterectomy became the gold standard,” Dr. Aronow explained. “When carotid stenting emerged a couple of decades ago, it was compared to endarterectomy and found to be equivalent for most patients. However, it had never been tested directly against medical therapy and lifestyle change alone.”
In the trial, patients who underwent stenting, combined with medication and lifestyle changes, were subsequently at less risk of stroke than those treated with noninvasive management alone. The risk of stroke in the stenting cohort was reduced by about half over four years, the first direct, randomized evidence of stenting’s additional benefits above and beyond medical therapy.
On the surgical side, outcomes were directionally similar but did not reach statistical significance at four years. Longer follow-up is expected to provide more information as additional events occur.
Challenging expectations
The findings indicate several key takeaways when it comes to preventing stroke.
Carotid artery disease is one of the few cardiovascular conditions in which treating patients without symptoms may be appropriate. This is uncommon in cardiovascular disease, as most asymptomatic conditions are managed conservatively. CREST-2 reinforces that carotid artery disease represents a distinct exception in carefully selected patients. Also, it highlights that multiple treatment options can be safe and more effective than medical management alone.
“However,” Dr. Aronow cautioned, “these procedures do not replace medical therapy but complement ongoing management of risk factors.”
The release of the CREST-2 results has sparked lively discussion within the clinical community. Many were surprised by the findings, having expected that advances in medical therapy alone would eliminate the need for procedural intervention.
“We sometimes struggle as a community to take a fresh, objective look at new data. Some clinicians have been inclined to overinterpret the results as favoring one procedural approach over another, while others have focused on perceived limitations of the study design,” Dr. Aronow said. “But the trial was not designed to compare carotid stenting directly with surgery.
“Rather, it addressed a more fundamental question: Does intervening on asymptomatic carotid stenosis still provide benefits in the era of modern medical therapy?” he added.
What this means for asymptomatic patients
The results of the study show that even with today’s advanced medications and strategies for controlling risk factors, procedural intervention can significantly reduce the risk of stroke in many asymptomatic patients. This challenges the assumption that medical management by itself would be sufficient for all such patients.
“Carotid stenosis should not be viewed as an isolated condition,” said Dr. Aronow. “It is one manifestation of atherosclerotic cardiovascular disease, a systemic process involving plaque buildup throughout the arterial system.”
When carotid disease is identified, similar pathology is often present in coronary arteries or peripheral circulation, even if it has not yet produced symptoms elsewhere. While certain risk factors cannot be mitigated, such as age, others like blood pressure, cholesterol, smoking and diabetes can be modified. Given that about half of adults in the U.S. have high blood pressure, and most do not have it controlled according to current guidelines, primary care can play a key role in identifying and lowering those risks.
Atherosclerosis often begins decades before it becomes clinically apparent, with autopsy studies revealing early plaque formation in even young adults. This underscores the importance of addressing modifiable risk factors early, well before carotid disease or neurologic symptoms develop.
Prevention starts with medical management
Risk factor modification was a central component of the trial. While lifestyle modification proved critically important, the study showed that it is often insufficient on its own for high-risk patients. Medications are still necessary to achieve guideline-recommended targets, particularly for cholesterol management, because lifestyle changes alone cannot adequately reduce levels that are significantly above target.
Carotid stenting as an option adds to the importance of discussing all available courses of treatment with patients. Even though all options are safe and effective, they may not align with individual patients’ preferences. Some may want to avoid invasive procedures, while others may be uncomfortable with long-term medication use, and these preferences should be respected and considered when planning for care.
“Shared decision-making needs to be part of everything we do,” Dr. Aronow said. “Our responsibility is to work with patients to help them achieve their health goals in ways that are meaningful to them.”
