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Carotid Surgery May Be Unnecessary for Asymptomatic Stenosis Patients

Article In Brief

New findings suggest asymptomatic patients may not need to undergo early carotid endarterectomy given advances in medical management of carotid artery stenosis.

Advances in medical management of carotid artery stenosis have improved to the point that asymptomatic patients may not need to undergo early carotid endarterectomy (CEA), according to a novel study that used veterans' health and mortality data to configure a simulated randomized clinical trial.

In several different analyses of five-year mortality data among older, asymptomatic veterans who underwent either CEA or initial medical therapy, the researchers found that any differences in survival rates since 2004 were too small for statistical significance when non-stroke deaths were included.

Newer high-potency statins and better antiplatelet regimens over the past two decades, coupled with large gains in controlling blood pressure and diabetes, have significantly reduced the risk of fatal and nonfatal strokes in asymptomatic patients treated medically, researchers reported in the September issue of JAMA Neurology.

There is an ongoing debate regarding the management of asymptomatic carotid stenosis and several large clinical trials underway to address the question. Current national guidelines recommend that asymptomatic patients who have more than 70 percent narrowing of the carotid artery, and those who have more than 50 percent stenosis along with symptoms, be evaluated for surgery.

However, the investigators noted that the most recent of three major randomized clinical trials (RCTs) that established the clinical benefit of CEA over medical therapy in asymptomatic patients was conducted 25 years ago.

“Clinical trials dating back to the mid-80s may not extend to real-world practice today if deaths from all factors are considered,” said lead author Salomeh Keyhani, MD, MPH, a professor at the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center.

Two major trials—The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis 2 (CREST-2) and the Asymptomatic Carotid Surgery Trial-2 (ACST-2)—are currently underway comparing CEA against medical therapy, but it may be several years before results are available.

Study Methodology, Findings

In the new study, Dr. Keyhani and her colleagues first analyzed five-year stroke and other mortality data in several major databases maintained by the Department of Veterans Affairs of patients who underwent carotid imaging between January 2005 and December 2009. Among 5,221 patients, 2,712 received CEA and 2,479 were treated medically within one year of carotid imaging.

In this part of the study, they found the absolute reduction in risk of fatal and nonfatal strokes associated with early CEA was less than half that reported in trials from 20 years ago, and was no longer statistically significant when non-stroke deaths were included.

The rate of stroke or death from perioperative complications within 30 days was 2.5 percent in the CEA cohort. The 5-year risk of fatal and nonfatal strokes was 5.6 percent in CEA patients compared to 7.8 percent in the medical therapy group. However, when competing death risks were included, the difference was -0.8 percent and not statistically significant.

“Given the upfront perioperative risks associated with CEA, initial medical therapy may be an equally acceptable treatment strategy for the management of patients with asymptomatic carotid stenosis,” said Dr. Keyhani.

The investigators next used inclusion and exclusion criteria from the 2004 Asymptomatic Carotid Surgery Trial (ACST) to simulate a trial using data from 2,678 CEA patients and 2,479 medical treatment patients. They found the fatal and nonfatal stroke risk difference at five years was 5.5 percent in the CEA group compared with 7.6 percent in the medical treatment cohort. But again, when competing causes of death were included, the risk difference was -0.9, again too low for statistical significance.

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“Given the upfront perioperative risks associated with CEA, initial medical therapy may be an equally acceptable treatment strategy for the management of patients with asymptomatic carotid stenosis.”—DR. SALOMEH KEYHANI

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“In my many years of experience in designing, conducting, and reviewing clinical trials, I would say these findings add support and justification for [our] clinical trial. If I did not know CREST-2 was in progress, I would call for one, and I would call for it to be conducted in a more representative sample population of hospitals that perform CEAs across the U.S.”—DR. VIRGINIA J. HOWARD

This corresponds to an annual net stroke reduction benefit of only 0.46 percent per year, or a number-to-treat of 43 at five years, the researchers said. In other words, 43 patients would need to be revascularized within one year to prevent a single fatal or nonfatal stroke within five years. In the ACST trial, the number-to-treat at five years was 18.

“If the decrease in the stroke rate among patients with carotid artery stenosis is associated with improvements in primary stroke prevention, revascularization may no longer be the preferred treatment strategy,” Dr. Keyhani told Neurology Today.

“The decreased stroke risk, the persistent up-front perioperative risks, and the small difference in stroke risk between the two treatment strategies, suggest that patients treated with CEA would now require a longer time to accrue enough stroke reduction benefit to justify the up-front risks of the surgical procedure.”

Expert Commentary

“I think this is a very provocative, well-designed trial,” commented Pierre Fayad, MD, FAAN, professor and chief of the vascular neurology and stroke division at the University of Nebraska Medical Center in Omaha. “The researchers used thoughtful and rigorous data manipulation to retrospectively construct a sample randomized clinical trial with a prospective design.”

While the study provides some interesting data, he said he was not surprised by the results. “The problem is that we are not yet that good at selecting patients for surgery and don't have the tools to better determine who should get surgery or not,” he told Neurology Today.

With growing evidence that the benefits of CEA may not be that much higher, he said there is pressure to do less surgery in asymptomatic patients. Pointing to CREST-2 and the ACST-2, he said better data supporting intensive medical therapy should be forthcoming.

In a Neurology article published last July, CREST-2 researchers described difficulties with conducting a clinical trial during the COVID-19 pandemic, but said they owe a moral responsibility to patients already enrolled in the study, and have continued recruitment.

Virginia J. Howard, PhD, Distinguished Professor of Epidemiology at the University of Alabama at Birmingham, and one of the principal investigators in that study, said the new data affirms that the current state of knowledge “is at the right place and sets the stage” for the CREST-2 trial.

“In my many years of experience in designing, conducting, and reviewing clinical trials, I would say these findings add support and justification for [our] clinical trial. If I did not know CREST-2 was in progress, I would call for one, and I would call for it to be conducted in a more representative sample population of hospitals that perform CEAs across the U.S.”

Dr. Howard noted that CREST-2 is actually two trials: One study is randomizing patients to CEA plus intensive medical management (IMM) versus IMM alone. The other trial randomizes patients to carotid artery stenting (CAS) plus IMM versus IMM alone. Patients in all arms of the trial receive protocol-driven intensive medical management.

“CREST was designed to address whether CEA or CAS plus IMM is superior in preventing stroke beyond IMM alone.”

Dr. Howard corrected the authors' description of CREST-2.

“Because the paper focused only on CEA and not CAS, they did not accurately describe the treatment arms in the CREST-2 trial. Both arms include medical therapy, but it is not ‘initial’ medical therapy but intensive medical management up to 48 months,” she told Neurology Today.

“This was a fairly sophisticated analysis of the clinical effectiveness of the two treatments—very well done,” said Larry B. Goldstein, MD, FAAN, professor and chair of neurology and co-director of the Kentucky Neuroscience Institute at the University of Kentucky, Lexington.

He said the findings are consistent with other studies since the mid-1990s. “The point is that the absolute reduction in the risk of fatal and nonfatal strokes associated with early carotid endarterectomy treatment was less than half the reduction in trials initiated more than two decades ago.

“Any intervention is a snapshot of treatment at any time. The question here is whether or not data on interventions are still valid now that two decades have passed. This study suggests just how much things have changed.”

Disclosures

Dr. Keyhani reported no disclosures. Drs. Goldstein and Howard had no relevant disclosures.

Link Up for More Information

• Keyhani K, Cheng EM, Hoggatt KJ, et al. Comparative effectiveness of carotid endarterectomy vs Initial Medical Therapy in patients with asymptomatic carotid stenosis https://jamanetwork.com/journals/jamaneurology/fullarticle/2766571. JAMA Neurol 2020;77:1110–1121.
• Halliday A, Mansfield A, Marro J, et al; MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)16146-1/fulltext. Lancet 2004;363(9420):1491–1502.
• Howard V, Meschia JF, Brajesh L, et al. Carotid revascularization and medical management for asymptomatic carotid stenosis: Protocol of the CREST-2 clinical trials https://journals.sagepub.com/doi/abs/10.1177/1747493017706238. Int J Stroke 2017;12(7):770–778.
• Meschia JF, Brajesh L, Howard G, et al. Carotid revascularization and medical management for asymptomatic carotid stenosis: CREST-2 update https://n.neurology.org/content/94/15_Supplement/1540. Neurology 2020;94 (15 Supplement).