Low Risk for Events from Asymptomatic Carotid Stenosis With Intensive Medical Therapy

Susan Jeffrey

September 29, 2008

September 29, 2008 (Vienna, Austria) — New data from 1 center's series of patients with asymptomatic carotid stenosis (ACS) have shown that institution of intensive medical therapy in 2003 was associated with reduced plaque progression, fewer microemboli, and events to levels below the threshold of risk associated with carotid stenting or surgery.

Researchers at Robarts Research Institute, in London, Ontario, while studying the higher stroke risk associated with microemboli on Doppler ultrasound from carotid plaque, found that microemboli and cardiovascular events declined significantly with more intensive risk-factor management in patients with ACS.

Dr. J. David Spence

"What this means is that for patients with asymptomatic carotid stenosis, the treatment of choice is intensive medical therapy, not stenting or endarterectomy," lead author J. David Spence, MD, told attendees here. "Less than 5% of asymptomatic patients can possibly benefit from stenting or endarterectomy with risks of 4% or 5%." Those who can benefit can be identified by the presence of microemboli, he said.

In the United States, between half and two-thirds of stenting and endarterectomy procedures are for asymptomatic vs symptomatic patients, he told Medscape Neurology & Neurosurgery. "What we're showing is it's unwarranted in 95% of them."

Treatment of asymptomatic stenosis is based largely on results published in 1995 of the Asymptomatic Carotid Atherosclerosis Study (ACAS), which showed that endarterectomy reduced the aggregate risk of surgery and ipsilateral stroke from about 11.0% to 5.1% in these patients, he said (Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995;273:1421-1428).

"But in those days, people weren't using high-dose statins routinely in patients with asymptomatic stenosis," Dr. Spence said. "So we shouldn't be using data that old to justify doing procedures now."

Dr. Spence presented their findings here at the 6th World Stroke Congress.

Treating Arteries

The work he is presenting here has "2 beginnings," Dr. Spence said. In the first, he and colleagues began studying carotid total plaque area in 1990, largely for research purposes, and found that those patients in the top quartile for carotid plaque area had a 3.4-times higher risk for stroke or death after adjustment for a wide variety of risk factors. In addition, 50% of these patients had progression of plaque, and those patients were at higher risk for events.

"What this meant was that we were failing in half our patients, just treating according to traditional treatment of risk factors, so we changed the paradigm in our clinic from treating risk factors to treating arteries," he said. That is, regardless of the risk factors, they intensify therapy in the setting of high plaque burden, with the goal of plaque regression. This change occurred in 2003.

They were also studying microemboli on transcranial Doppler (TCD) in patients with asymptomatic carotid stenosis and in 2005 reported that TCD "perfectly defined the patients at risk," he said. The 90% of patients who had no microemboli had a 1% risk for stroke with tight confidence limits (1.01 – 1.36), and the 10% with microemboli had a 15.6% risk for stroke. "This meant the patients without microemboli cannot benefit from revascularization, because their risk is lower than the risk of surgery or stents," Dr. Spence noted.

He and colleagues obtained grant funding to studythe biology associated with plaque with and without microemboli, but 2 years into the study had to report to their funders, the Heart & Stroke Foundation of Ontario, that the microemboli were disappearing. They hypothesized that the decline might be related to the institution of more intensive medical therapy, and in the current study examined secular trends in microemboli and cardiovascular events in their population.

The Decline of Microemboli — and Events

Of 468 patients with asymptomatic carotid stenosis followed at their institution, 199 were studied prior to the shift in practice in 2003, and 169 after. All had baseline microembolus detection by international consensus criteria. The last patients entered were studied for at least a year, Dr. Spence noted, and the database was closed July 1, 2008.

"What we found was that microemboli were present before 2003 in 12.6% of patients, but since 2003, it's only 3.7%, so microemboli had been declining," he said. The annual rate of plaque progression was significant before 2003 and very low after 2003 and the institution of intensive medical therapy.

They also studied 4328 patients from their prevention clinics who had had plaque measurements between 1997 and 2007 to establish the rate of plaque progression. They report that plaque rises steeply with age, particularly after menopause. With an aging population and more patients referred because of stroke and less because of hypertension, he said, "you would expect the rate of plaque progression would be going up and then remain high."

They found the rate did rise, until 2003, when it stopped progressing and they began to see regression on average. The proportion of patients showing regression almost doubled, from 25% to 50%, after the move to intensive therapy. The decline was mirrored by a decline in cholesterol, triglycerides, and low-density lipoprotein and an increase in high-density lipoprotein over the same period, suggesting the changes were due to the intensive medical therapy, he said.

The larger population showed a similar trend in microemboli, showing a 14% risk for stroke in the first year when microemboli were present, and 1.2% without. "Almost all the events occur in the first year of follow-up," he said.

Prior to 2003, the 1-year risk of stroke in patients with asymptomatic stenosis was 4%, he noted, which has declined to 0.8% in the latter period, again with almost no risk seen in year 2. Similarly, myocardial infarction (MI) declined from 6.5% before intensive therapy was introduced to 0% afterward.

Decline in Events Associated with Asymptomatic Carotid Stenosis With and Without Intensive Medical Therapy

Event No Microemboli (%) Microemboli (%) P Before 2003 (%) After 2003 (%) P
Stroke in year 1 1.2 14.3 < .0001 4 0.8 .02
MI in year 1 2.4 8.6 .07 6.5 0 .0001
Death in year 1 2.9 12.1 .027 5.1 2 .12

Dr. Spence noted that in his view, intima-media thickness (IMT), used as an end point now in some trials, cannot provide the basis for this kind of monitoring.

"IMT change annually is around 0.015 mm, and the resolution of carotid ultrasound is 0.3 mm, so the rate of change in an individual cannot be measured from year to year," he said. "On the other hand, the average rate of change of plaque area is 11 mm2 per year, which can readily be measured with a resolution of 0.3 mm.

"So our mantra is trying to treat arteries without measuring plaque is like trying to treat hypertension without measuring blood pressure," he concluded.

The SPACE 2 trial, just getting under way in Europe, will provide some insight into this issue, as it is comparing carotid endarterectomy with carotid stenting in patients with asymptomatic carotid stenosis, but unlike other trials comparing these modalities in asymptomatic patients, it includes an intensive-medical-therapy group.

The study was funded by the Heart & Stroke Foundation of Ontario, the National Institutes of Health, and the Canadian Institutes of Health Research (CIHR-IRSC).

6th World Stroke Congress, Vienna, Austria: Abstract FC01-02. Presented September 25, 2008.

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