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New Data on When to Refer Asymptomatic Carotid Stenosis Patients for Revascularization

Robinson, Richard

doi: 10.1097/01.NT.0000405137.44037.65
DR. SEEMANT CHATURVEDI: “In the last ten to twelve years, medical therapy has improved a lot, especially with the more widespread use of cholesterol-lowering medications. This has reduced the risk of stroke for patients with carotid stenosis” and no symptoms. “Therefore, there is less to be gained from doing the surgery.”

DR. SEEMANT CHATURVEDI: “In the last ten to twelve years, medical therapy has improved a lot, especially with the more widespread use of cholesterol-lowering medications. This has reduced the risk of stroke for patients with carotid stenosis” and no symptoms. “Therefore, there is less to be gained from doing the surgery.”

“Because it's there” was George Mallory's reason for climbing Mount Everest. It also seems to be the main rationale for revascularization in many patients with asymptomatic carotid stenosis (ACS), according to experts who have studied outcomes for ACS patients.

But which asymptomatic patients should be referred for endarterectomy or stenting? Two new studies in the Aug. 17 online edition of Neurology assess the value of two different ultrasound techniques for determining the patients most at risk, and conclude that up to 10 percent of ACS patients are good candidates for revascularization.

When carotid narrowing is found in a patient who has had a stroke, however, early intervention may save lives. [For more detail about the study protocols and findings, see “Study Data: Approaches to Identifying Risk Factors for Stroke in ACS Patients.”]

“Most neurologists think there are too many revascularization procedures,” said Seemant Chaturvedi, MD, professor of neurology and director of the Stroke Program at Wayne State University School of Medicine in Detroit. Dr. Chaturvedi, who was not involved in any of the current studies, chaired the AAN committee that released guidelines on carotid endarterectomy in 2005.

“In the last ten to twelve years, medical therapy has improved a lot, especially with the more widespread use of cholesterol-lowering medications. This has reduced the risk of stroke for patients with carotid stenosis” and no symptoms, he said. “Therefore, there is less to be gained from doing the surgery.”

While the relative value of intervention “still needs to be definitively assessed” with clinical trials, he continued, “with the improvements in medical therapy, neurologists have felt decreasing enthusiasm to refer those patients for surgery.”

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With aggressive therapy, the risk of intervention in asymptomatic patients is, on average, greater than the risk of not intervening, said David Spence, MD, who is professor of neurology and clinical pharmacology at the University of Western Ontario, and director of the Stroke Prevention and Atherosclerosis Research Centre at the Robarts Research Institute in London, Ontario.

In a 2010 paper in the Archives of Neurology, Dr. Spence and colleagues reported that intensive medical therapy instituted after 2003 in their institution reduced both the frequency of microemboli on TCD and the risk for stroke, myocardial infarction, and death, compared with the period before 2003.

“There are ways to identify patients who could benefit,” Dr. Spence said. The standard approach — to assess increased risk for stroke in ACS and identify patients who could benefit from intervention — has been to use transcranial Doppler ultrasound (TCD) to detect microemboli. The procedure takes time, both for the recording, typically one to two hours, and for the evaluation of the recording by the physician. Microemboli are typically detected in about 5 percent of ACS patients, he said.

Dr. Spence was the lead author on one of the new studies, examining the potential of three-dimensional ultrasound to detect ulceration in the carotid wall. Ulceration detected by angiography was shown in the NASCET (The North American Symptomatic Carotid Endarterectomy Trial) to be associated with greater risk of stroke, he pointed out, adding that 3D ultrasound is a more reliable and sensitive tool for detecting ulceration, Dr. Spence said.

In the current Neurology study, Dr. Spence and colleagues reported that adding 3D ultrasound to microemboli detection doubled the number of patients who were identified as candidates for revascularization to 10 percent of the sample. While some patients had both ulcers and microemboli, the two groups remained largely separate.

“We showed that if there were three or more ulcers, regardless of the side, that was equivalent to two or more emboli,” increasing the three-year stroke risk to 20 percent, versus 1.7 percent without either indicator.

“Nobody should operate on an ACS patient without doing one or both of these procedures,” he said.

Dr. Spence noted that while 3D ultrasound is still not routinely available, all the major manufacturers now offer it, and as imaging centers replace their equipment, it will become more commonplace. There are other techniques for identifying vulnerable plaques coming down the pike as well, he said, including MRI and PET. “My estimate is that adding up everything you can do to identify vulnerable patients, it is never going to be above 15 percent.”



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An alternative and simpler ultrasound method for catching more ACS patients at risk may be assessment of the echolucency of plaques, according to Raffi Topakian, MD, a clinician and researcher in the department of neurology at the Academic Teaching Hospital Wagner-Jauregg in Linz, Austria. His work was part of the larger Asymptomatic Carotid Emboli trial published in the July 2010 Lancet Neurology, which quantified the risk of stroke in ACS patients.

Echolucency, he explained, was due to a high proportion of lipid in the plaque, and corresponded to a decreased plaque stability. In contrast, echogenic plaques are fibrous and calcified, and are more stable. His study showed that plaque echolucency was associated with a more than six-fold increased risk of ipsilateral stroke, and that, when combined with microemboli detection, about 8 percent of ACS patients qualified as high-risk for future stroke. When neither microemboli nor plaque echolucency were present, risk was less than 1.0 percent.

“The plaque morphology assessment is really very simple,” Dr. Topakian said. “It is just a visual scale, and every clinician trained in ultrasound imaging can do that.”

While he said that the utility of echolucency to assess risk still needs to be confirmed by other studies, “the main message is that we probably have two ultrasound measures which can be very useful in distinguishing patients at very high risk of stroke with ACS.”



Dr. Chaturvedi suggested caution in interpreting the results of this study, since it conflicts with results from the recent ACST trial, which was larger and found echolucency not to be a useful predictor. Evaluating ulcers using 3D ultrasound can be valuable, he said, “but the question is whether that finding is valuable on top of other predictors we already know about,” including the effects of sex and age.

Nonetheless, he said, methods to refine the patient selection process are welcome, given the large number of unnecessary surgeries performed. Dr. Chaturvedi noted that previous studies have shown that in Canada, approximately 30 percent of all endarterectomy procedures are performed in asymptomatic patients, while in the United States, the figure is up to 90 percent. “So there is a huge disparity in the practice patterns in the two countries.” Dr. Spence, not one to mince words, called that disparity “a national disgrace.” All agreed that reducing the rate of revascularization in asymptomatic patients, while identifying those most at risk, was a top priority.

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Plaque Echolucency as a Risk Factor in ACS (Raffi Topakian, MD, et al)

  • As a pre-specified subanalysis of the Asymptomatic Carotid Emboli (ACES) study, researchers performed transcranial Doppler and duplex ultrasound on 435 patients with ACS (≥70 percent narrowing), who were followed for two years.
  • Echolucent plaques were found in 164 patients. Those patients were 6.4 times as likely to have a stroke during follow-up versus those with no echolucency. Patients with both echolucency and microemboli were 10.6 times as likely to have a stroke versus those with neither.

Ulceration on 3D Ultrasound as a Risk Factor in ACS (David Spence, MD, et al)

  • Three-dimensional ultrasound and transcranial Doppler ultrasound were performed on 253 patients with ACS (>60 percent narrowing), who were followed for three years.
  • Eleven patients had 3 or more ulcers, and 11 had microemboli, with only one patient having both. Eighteen percent of patients who had 3 or more ulcers had a stroke or died during follow-up, versus 2 percent of those with no ulcers (p=0.03). Microembolus detection was associated with a 20 percent risk of stroke or death during follow-up, versus 2 percent for those with no microemboli (p=0.003).
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Athird article in the same issue of Neurology finds that the highest risk of stroke recurrence occurs within the first 72 hours, suggesting that such patients may benefit from intervention much sooner than current guidelines recommend.

In patients with symptomatic carotid stenosis (greater or equal to 50 percent), current guidelines recommend revascularization within two weeks of the onset of symptoms. Nonetheless, surgery is frequently delayed, and stroke recurrence is common, according to Michael Marnane, MD, a stroke research fellow at the Mater Misericordiae University Hospital in Dublin, Ireland.

In a population-based prospective cohort study, Dr. Marnane and colleagues examined the risk of a second stroke in patients with carotid narrowing. A second stroke occurred within 72 hours in 5.6 percent of those with stenosis, versus only 0.4 percent of those without. Those figures rose to 5.6 percent and 0.7 percent respectively by 7 days, and 8.3 percent and 1.8 percent by 14 days.

“The risk of recurrent stroke is very much front-loaded,” Dr. Marnane said. “Patients who are going to have one tend to have it very, very early.”

Such patients may be appropriate for early endarterectomy, said Seemant Chaturvedi, MD, professor of neurology and director of the Stroke Program at Wayne State University School of Medicine in Detroit, who was not involved with the study. “Patients must be stable and sufficiently recovered from stroke, but in general the trend should be to operate sooner rather than later.”

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Madani A, Beletsky V, Spence JD, et al. High risk asymptomatic carotid stenosis: Ulceration on 3D ultrasound versus TCD microemboli. Neurology 2011; E-pub 2011 Aug 17.
    Topakian R, King A, Markus HS, et al, for the ACES Investigators. Ultrasonic plaque echolucency and emboli signals predict stroke in asymptomatic carotid stenosis. Neurology 201; E-pub 2011 Aug 17.
      Marnane M, Chroinin N, Kelly PJ, et al. Stroke recurrence within the time-window recommended for carotid endarterectomy. Neurology 2011; E-pub 201 Aug 17.
        Spence JD, Coates V, Hegele RA, et al. Effects of intensive medical therapy on microemboli and cardiovascular risk in asymptomatic carotid stenosis. Arch Neurol 2010;67(2):180–186.
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              ©2011 American Academy of Neurology