Clinical Alert: Clinical Advisory on Carotid Endarterectomy for Patients WithAsymptomatic Internal Carotid Artery Stenosis

National Institutes of Neurological Disorders and Stroke (NINDS)
September 28, 1994

SUMMARY:

The investigators of the Asymptomatic Carotid Atherosclerosis Study (ACAS) are reporting the interim results of a randomized controlled clinical trial of carotid endarterectomy in patients who have asymptomatic carotid stenosis of greater than 60 percent reduction in diameter. In addition to aspirin and aggressive management of modifiable risk factors, one-half of the patients were randomly assigned to receive surgery after angiographic confirmation of the lesion. Carotid endarterectomy is beneficial with a statistically significant absolute reduction of 5.8 percent in the risk of the primary end point of stroke within 5 years and a relative risk reduction of 55 percent. As a consequence of the trial reaching statistical significance in favor of endarterectomy, and on the recommendation of the study's data monitoring committee, physicians participating in the study were immediately notified and advised to reevaluate patients who did not receive surgery. It is important to note that the success of the operation is dependent on medical centers and surgeons who have a documented perioperative morbidity and mortality of less than 3 percent, careful selection of patients, and postoperative management of modifiable risk factors.

OBJECTIVE:

The primary question of efficacy addressed by the ACAS trial was: Among patients with severe but asymptomatic carotid artery stenosis, does carotid endarterectomy, despite a perioperative risk of any stroke or death from any cause, reduce the overall 5-year risk of fatal and non-fatal ipsilateral carotid stroke?(1)

STUDY SITES:

The trial was conducted in 39 U.S. and Canadian centers that had been rigorously evaluated for neurological expertise, quality of the ultrasound laboratory assessment, and the quality of surgical management.(2,3) The participating surgeons had met stringent criteria demonstrating a perioperative complication rate less than 3 percent when the indication for operation was asymptomatic carotid stenosis.

PATIENT ELIGIBILITY:

Patients were eligible for randomization if they were 40-79 years of age, had a life expectancy of at least 5 years, gave informed consent and had at least 60 percent carotid stenosis near the bifurcation of the common or internal carotid artery measured in one of the following three ways:

A. Conventional or arterial digital subtraction angiography indicating diameter stenosis of at least 60% using minimal residual lumen (MRL) and the distal lumen (DL) in the equation [1-(MRL/DL)] x 100.

B. Doppler ultrasonography showing a peak systolic frequency or end diastolic frequency greater than the machine-specific cutpoint with predicted false positive rate of 5% determined by correlation of Doppler flow velocities with arteriography in 50 consecutive cases.

C. Doppler ultrasonography showing a peak systolic frequency or end diastolic frequency greater than the machine-specific cutpoint with predicted 10% false positive and OPG-Gee examination pressure reduction of > 5 mm Hg.

Patients were excluded for conditions which were likely to cause mortality or render follow-up difficult within the 5-year period. No patients with symptoms associated with TIA/stroke or previous endarterectomy on the randomized artery were included. Other exclusions were unstable angina pectoris, uncontrolled atrial fibrillation, severe diabetes, uncontrolled hypertension, renal insufficiency, hepatic disease, cancer, and other conditions which would confound evaluation for end points or contraindicate surgical management.

INTERVENTION:

After obtaining informed consent, one-half of the patients were randomly allocated to surgical management. Patients randomized to surgical management who did not have a prerandomization arteriogram, had an arteriogram prior to surgery to verify the degree of stenosis and to ascertain whether there were contraindications to endarterectomy, such as distal arterial disease. All patients were started on 325mg of aspirin daily and aggressive reduction of modifiable risk factors.

MAIN OUTCOME MEASURES:

The primary end point for evaluation was any stroke or death following randomization and within the 30 day perioperative period for patients receiving surgery, a comparable 42 day period from randomization for those not assigned to surgery, and any ipsilateral stroke or stroke death thereafter. All neurological symptoms and/or signs were evaluated by a neurologist. Patients were interviewed about neurologic symptoms and medical status every 3 months, alternating between telephone and in-clinic interviews. During the clinic visit, a neurologist examined the patient and the ACAS surgeon or his designee made a second assessment if symptoms or signs were found. All potential end points were adjudicated by a blinded end point review committee.

MAIN RESULTS:

Between December 1987 and December 1993, 1662 eligible patients were randomized, 828 to receive surgery and 834 to medical management only. Analysis of randomized patients shows a male to female preponderance of 2:1; approximately half were between the ages of 60 and 69 and 37 percent were 70 or older. Ninety-five percent were Caucasian. Recognized risk factors for stroke, such as hypertension (64%), diabetes (23%), prior myocardial infarction (21%), prior contralateral TIA/stroke (25%) and smoking (26%), were balanced between the two groups.

As of July 31, 1994, the median follow-up was 2.7 years and there were 4,465 patient years of observation for endpoints. The aggregate risk of any stroke or death in the perioperative period for the surgery group was 2.3%. Of 424 post-randomization arteriograms, 31 were Doppler false positive (7.4%) and five strokes were precipitated by arteriography (1.2%). Utilizing Kaplan-Meier projections in an intention-to-treat analysis, the aggregate risk over 5 years for the primary outcome was 4.8% for patients who were assigned to receive surgery and 10.6% for patients who were treated medically. The relative risk reduction conferred by surgery was 55 percent (23-73%, 95 percent confidence interval, p=0.004).

Following endarterectomy, men had 69 percent relative risk reduction of primary endpoint, while women had a 16 percent relative risk reduction. Additional analyses and study will be required to explore the reasons for this apparent difference. The ACAS trial group is now completing follow-up, expanding the database, performing additional statistical analyses, and seeking expeditious publication of results.

CONCLUSION:

Carotid endarterectomy, performed in medical centers with documented combined perioperative morbidity and mortality for asymptomatic endarterectomy of less than 3 percent, and on carefully selected patients who continue to have aggressive modifiable risk factor management is beneficial for patients who meet eligibility criteria of asymptomatic carotid stenosis exceeding 60 percent diameter reduction confirmed by arteriography.

References

1. The Asymptomatic Carotid Atherosclerosis Study Group (Toole JF, Howard, VJ, Chambless LE): Study design for randomized prospective trial of carotid endarterectomy for asymptomatic atherosclerosis. Stroke 1989;20:844-849.
2. Howard G, Chambless LE, Baker WH, Ricotta JJ, Jones AM, O'Leary D, Howard VJ, Elliott TJ, Lefkowitz DS, Toole JF: A multicenter validation study of Doppler ultrasound versus angiogram. J Stroke Cerebrovasc Dis 1991;1:166-173.
3. Moore WS, Vescera CL, Robertson JT, Baker H, Howard VJ, Toole JF: Selection process for participating surgeons in the Asymptomatic Carotid Atherosclerosis Study (ACAS). Stroke 1991;22:1353-1357.

Keywords:

Carotid stenosis, endarterectomy, stroke, randomized trial, carotid ultrasonography

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