Article In Brief
In February, the US Preventive Services Task Force affirmed its 2014 recommendation that the screening of the general population for asymptomatic carotid artery stenosis should not be performed. The guidance demonstrates the need for trials that answer questions about the benefits of such screening, experts say.
There has been such a dearth of new evidence over the past several years relevant to the screening of the general population for asymptomatic carotid artery stenosis that experts say it was no surprise that in February the US Preventive Services Task Force (USPSTF) reaffirmed its 2014 recommendation that the screening should not be performed.
But they also told Neurology Today that the unchanged recommendation, the first update since 2014, underscores the need for trials that answer questions about the usefulness of such screening.
Since the USPSTF recommendation in 2014 that the general population should not be screened, investigators found only two “limited, prematurely terminated” trials that compared the effectiveness of carotid revascularization plus best medical therapy with best medical therapy alone.
The SPACE-2 trial, with 316 patients enrolled, reported no significant difference in the composite outcome of stroke or death at 30 days or ipsilateral ischemic stroke at one year after carotid endarterectomy or carotid artery stenting compared with best medical therapy. A smaller trial, called AMTEC, with 55 patients, reported a statistically significantly lower composite risk of non-fatal ipsilateral stroke or death among the carotid endarterectomy group at a median of 3.3 years.
Data from the two trials, along with two national data sets and three surgical registries, produced estimates that the procedural harms of post-operative, 30-day rates of stroke or death varied from 1.4 percent to 3.5 percent for carotid endarterectomy and from 2.6 percent to 5.1 percent for carotid artery stenting.
“There was no direct evidence examining the benefits or harms of screening,” wrote Janelle Guirguis-Blake, MD, of the family medicine department at the University of Washington, in a research letter in the February 2 issue of JAMA. “The [two] new trials added little to the evidence base on effectiveness of revascularization compared with best medical therapy.”
Other Ongoing Trials
In an accompanying editorial, Larry B. Goldstein, MD, FAAN, chair of neurology at the University of Kentucky, agreed with the guidance against population screening but said additional data from contemporary trials evaluating revascularization procedures compared to modern medical therapy would be helpful.
“Observational studies suggest that the frequency of stroke with medical therapy without endarterectomy among patients with an asymptomatic 70 percent to 99 percent stenosis of the extracranial internal carotid artery may be a fraction of the rates reported in the cited older trials,” Dr. Goldstein told Neurology Today. “Declining event rates with medical therapy as suggested by observational studies could obviate the small absolute benefits of interventional approaches for patients with an asymptomatic extracranial carotid artery stenosis.”
New trials should provide some of this data, he said. CREST-2 involves two multicenter randomized trials—one comparing intensive medical therapy alone with carotid endarterectomy plus intensive medical therapy, and another comparing intensive medical therapy alone with carotid artery angioplasty/stenting plus intensive medical therapy.
In the randomized, phase 3, ASCT-2, researchers are comparing carotid endarterectomy with carotid artery stenting for primary stroke prevention in people with asymptomatic extracranial internal carotid artery stenosis. And in ESCT-2, which was suspended after 429 of a planned 2,000 people were enrolled, best medical therapy alone was compared with best medical therapy plus urgent revascularization in patients with greater than 50 percent carotid artery stenosis, whether symptomatic or asymptomatic and who were estimated to be low to intermediate risk.
“The trials in progress offer to address the issue regarding the efficacy of revascularization strategies added to current best medical therapy once an asymptomatic stenosis is identified,” Dr. Goldstein said.
He said “the magnitude of the benefit, if any, would further inform assessments of the utility of a population screening program,” but wouldn't fully resolve the issue given the low population of the condition, combined with the false positive and false negative rates associated with screening.
In another editorial, Kristen Bibbins-Domingo, PhD, MD, MAS, professor and chair of epidemiology and biostatistics at the University of California, San Francisco (UCSF), and Rebecca Smith-Bindman, MD, professor of radiology at UCSF, said that a trial that randomized people to be screened or not, and then follows them for three, five or even 10 years, is needed to get to the heart of the question on general population asymptomatic carotid artery screening.
“What continues to be striking is the overall absence of direct evidence that screening itself is actually beneficial,” they wrote. “Without a true randomized clinical trial to directly answer the question, there is a lack of consensus and clarity on the role of carotid ultrasonographic screening for prevention of stroke in individuals who are asymptomatic in clinical practice.”
About one-third of strokes are ischemic resulting from carotid artery disease, but most do not have a moderate or higher stenosis ahead of time that could have been detected and treated, they wrote. Only 14 percent of strokes result from thromboembolism from a previously asymptomatic internal carotid artery stenosis, they pointed out. And since some of these patients will suffer a warning transient ischemic attack, only around 11 percent of patients whose stroke was destined to be due to thromboembolism from a previous asymptomatic stenosis could possibly be identified and would benefit from screening.
Still, with effective therapies available, they said, “the goal of screening patients to find those with carotid narrowing has strong face validity, even with the need to screen a large number of people to identify those with the potential to benefit.”
In response to a question about the value of the ongoing trials, Dr. Smith-Bindman said that a cohort in CREST-2 identified as “lifelong asymptomatic patients” would have been more interesting for randomization than the mixed group that actually was randomized. She said that in the CREST-2 Registry, a companion study to the randomized trial, 45 percent of patients have symptoms, which “highlights that patients with carotid artery stenosis are a heterogeneous group including individuals with and without symptoms.”
“I think in current practice, once a patient with carotid artery narrowing is identified—whether by screening, whether they are considered at high-risk because of numerous cardiovascular risk factors and were imaged, or whether imaging was obtained as part of a diagnostic evaluation—there is a diagnostic dilemma regarding the best treatment,” Dr. Smith-Bindman said. “The CREST-2 trial will contribute to informed counseling and decision-making for these patients regarding how to manage their identified narrowing. But this will not provide meaningful information regarding whether screening is worthwhile for asymptomatic patients and [whether it] should be expanded.”
James Meschia, MD, FAAN, professor of neurology at Mayo Clinic in Jacksonville, FL, said the USPSTF recommendation is “unsurprising,” but he noted that clinicians need to remember the key phrase in the article headline—“in the general adult population.”
“It does not mean that once detected, high-grade carotid stenosis should be ignored,” he said. “I also agree that there are not great tools for identifying patients who deserve screening due to high prevalence. However, asymptomatic carotid stenosis is detected all the time in clinical practice, often as an incidental finding when evaluating acute stroke patients for reperfusion therapy. Once detected, the extant trial evidence favors revascularization in the hands of highly capable operators.”
Dr. Meschia said he would like to see trials that target individuals with carotid plaque that is found incidentally when evaluating the contralateral artery in patients with acute stroke. He added that he would also like to see trials that compare best medical therapy and revascularization to use the latest tools for stratifying risk of stroke in those with carotid stenoses, such as MRI-detected plaque hemorrhage, or even artificial intelligence tools to draw extra meaning from plaque imaging for identifying high-risk patients.
Nonetheless, trials already planned will be valuable, he said. CREST-2, for which he is an investigator, “will provide guidance on efficacy relevant to modern medical practice. Also, the trial is exploring the possible cognitive effects of revascularization.”
Jennifer J. Majersik, MD, MS, FAAN, director of the Stroke Center and Telestroke Network at the University of Utah, said before recommending screening carotid arteries for asymptomatic patients, she would like to see clear benefits from it. These could arise from tightening of vascular risk factor goals—such as lowering cholesterol levels and blood pressure or increasing exercise goals—by primary care providers, or from direct benefit of carotid endarterectomy or carotid stenting, or from all of those.
She said the stroke community is eagerly awaiting results of the ongoing trials, which will provide “modern-era evidence.”
But she added, “When the results are published, it will be important to remember that these patients are receiving much more intensive medical management than is usual for patients with asymptomatic disease, so there is no real ‘placebo’ arm to these two trials (CREST-2 and ECST-2) and I wouldn't be surprised if event rates in all arms are lower than what is currently seen in our communities. Also, these trials are not designed as pragmatic trials of carotid screening – all patients in the trials have already been screened prior to entry.”
Although they won't provide direct evidence of whether there are benefits to screening, Dr. Majersik said, “they will be able to answer how to manage carotid atherosclerosis once it is detected. Despite these limitations, I expect publication of CREST-2 and ECST-2 will affect the next set of carotid screening recommendations.”
Dr. Meschia had no relevant disclosures. Dr. Goldstein has received a royalty from UpToDate for a chapter on testing for carotid artery stenosis.