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  • Opinions: Asymptomatic Carotid Stenosis: Surgery’s the Answer, but That’s Not the Question

    Authors

    James L. Frey, MD

    Division of Neurology, Barrow Neurological Institute, Mercy Healthcare Arizona

    Key Words : opinions

    Two important studies have addressed the value of surgery for stroke prevention in patients with asymptomatic carotid stenosis. The first, the Veterans Affairs trial,8 studied 444 men with stenoses greater than 50%. The results suggested a possible benefit from surgery, but perioperative stroke and death, combined with the small number of patients in the study, precluded statistical support for carotid endarterectomy for stroke alone as an end point.

    The second major trial, the Asymptomatic Carotid Atherosclerosis Study (ACAS),3 evaluated 1,662 patients, both men and women, with stenoses greater than 60%. The recently published results of this trial indicate that carotid endarterectomy confers a statistically significant 53% 5-year relative risk reduction for ipsilateral stroke and any perioperative stroke or death. Strictly interpreted, these results justify surgery with two important qualifications. First, patients must have a reasonable 5-year survival to achieve benefit from surgery. Second, angiography and surgery must be performed with less than a 2.3% risk of stroke or death. Although the answer to the ACAS primary end-point question is statistically clear, the data harbor other important facts relevant to clinical decision-making.

    First, although surgery confers a 53% relative risk reduction after 5 years, the annual event rate for patients treated medically is only 2.2% (surgery reduces this risk to 1%). From this perspective, a 2.3% risk of stroke or death from the combination of angiography and surgery may be less readily acceptable. Furthermore, the level of expertise in the ACAS centers was high, and angiography and surgery cannot be recommended in any center where the combined risk exceeds 2.3% or where a patient’s survivability is much less than 5 years.

    Second, although the primary question of ACAS was answered in favor of surgery, five of the six remaining questions were not. Surgery did not reduce the risk of (1) a major ipsilateral stroke or any perioperative major stroke or death, (2) any stroke or any perioperative death, (3) any major stroke or perioperative death, (4) any stroke or death, or (5) any major stroke or death.

    Third, the relative risk reduction with surgery for men was 66%, which was statistically significant. For women, however, it was 17%, which was not statistically significant. The data suggest that perioperative complications may be at least one reason that surgery failed to benefit women (3.6% for women and 1.7% for men), but the fewer numbers of women in the ACAS preclude conclusions about other factors such as age, degree of stenosis, and other risk factors.

    Fourth, anticlotting therapy for medical management in the ACAS was limited to 325 mg of aspirin daily. Although this regimen seemed reasonable when the ACAS began, it may not be the best medical management today. Recent data suggest that higher doses of aspirin may work better than the ACAS dosage.1,7 Ticlopidine® reduces stroke better than even high-dose aspirin.6 The combination of warfarin and aspirin is also thought to be a potentially more effective anticlotting regimen for stroke prevention.5,11,16,17 Although these data are not from studies of primary prevention for asymptomatic carotid stenosis, they suggest the possibility that other anticlotting regimens may be more effective than 325 mg of aspirin daily. This likelihood diminishes the significance of the surgical benefit found in ACAS.

    Fifth, the cost-effectiveness of endarterectomy for asymptomatic carotid stenosis remains to be established. In the ACAS, approximately 800 endarterectomies prevented 50 strokes. The 90-day cost of stroke has been estimated at $15,000.10 Excluding the value of economic loss from stroke, which is hard to know, the medical savings from the prevention of 50 strokes would be $750,000. On a simple equivalency basis, if 800 endarterectomies (and angiograms) were performed for $750,000, then each pair of procedures would cost less than $1,000. Because the actual cost of these procedures is many times higher than this in most centers, the cost-effectiveness of surgery for asymptomatic carotid stenosis is open to legitimate question.

    Even though the ACAS has provided an answer to the question about surgery for asymptomatic carotid stenosis, the above facts compel us to address one other question: “Who with asymptomatic carotid stenosis is really at risk of stroke?” If an answer to this question can be found, a more clearly favorable benefit from surgery may be obtainable relative to risk and cost.

    Although the North American Symptomatic Carotid Endarterectomy Trial12 and the European Carotid Surgery Trial2 demonstrated that ipsilateral stroke risk correlates with degree of stenosis, ulceration, and contralateral occlusion in symptomatic patients, the ACAS data cannot answer these questions because the event rates are relatively small in the asymptomatic group. The European Trial for Asymptomatic Carotid Stenosis15 intends to study this question with attention to plaque morphology, stenosis progression, blood-flow characteristics, and systemic risk factors. Results of this trial are unlikely to be available for 5 to 10 years, and there is no guarantee that the study will produce an answer to the question.

    Existing data suggest that disease progression and stroke may be predictable in patients with asymptomatic carotid stenosis. Grotta et al.4 followed 38 patients with asymptomatic carotid stenosis with serial ultrasound examinations and found that the eight patients whose stenosis progressed had higher levels of low-density lipoprotein and fibrinogen and a higher incidence of coronary artery disease than patients whose disease did not progress. Roederer et al.14 studied 167 patients with asymptomatic carotid stenosis with serial ultrasound and found that symptoms developed in 10 patients, 8 of whom had demonstrable disease progression. Greater than 80% stenosis or progression to greater than 80% stenosis correlated with either occlusion or symptoms.

    Especially intriguing is the prospect of predicting stroke based on blood flow data. Powers,13 Yonas et al.,18 and Kleiser and Widderstudied a total of 209 patients with carotid stenosis or occlusion using positron emission tomography, xenon scanning, and transcranial Doppler flow technology. Analysis of their pooled data discloses a 28% 2-year incidence of stroke ipsilateral to the carotid lesion in patients with significantly impaired blood flow in the hemisphere distal to the stenosis. By comparison, the incidence of stroke was 4% in patients with adequate blood flow.

    As yet, a reliable approach to predicting stroke risk in patients with asymptomatic carotid stenosis does not exist. Available information suggests that certain parameters may be relevant, but none of these has been studied prospectively in large enough numbers to be relied upon. Flow data may be the parameter whose predictive value could be investigated, at least preliminarily, by a study of angiograms from patients in the ACAS and the Veterans Affairs trial. Collateral flow in patients who suffered strokes could be compared with collateral flow in patients who did not.

    In conclusion, although surgery effectively prevents ipsilateral stroke in patients with asymptomatic carotid stenosis, the stroke risk in this population is small; the absolute risk reduction with surgery is small; surgery does not prevent stroke and death overall; 325 mg of aspirin daily may no longer be the best option for medical management; and the cost of surgery relative to the cost of stroke for the population at risk is large. For these reasons it is appropriate for us to address the question: “Who, exactly, is at risk?” This question may prove to be more challenging than the original one.

    Reprinted from Annals of Neurology 39(3):405-406, 1996 by permission of Little, Brown and Company (Inc.).

    References

    1. Bornstein NM, Karepov VG, Aronovich BD, et al: Failure of aspirin treatment after stroke. Stroke 25:275-277, 1994
    2. European Carotid Surgery Trialists’ Collaborative Group: Interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet 337:1235-1243, 1991
    3. Executive Committee for ACAS Study: Endarterectomy for asymptomatic carotid artery stenosis. JAMA 273:1421-1428, 1995
    4. Grotta JC, Yatsu FM, Pettigrew LC, et al: Prediction of carotid stenosis progression by lipid and hematologic measurements.Neurology 39:1325-1331, 1989
    5. Hart RG, Sherman DG, Halperin JL: Stroke Prevention in Atrial Fibrillation (SPAF) III Study. University of Texas Health Science Center at San Antonio. Sponsored by National Institute of Neurological Disorders and Stroke, National Institutes of Health, May 1993 to June 1998. Stroke 26:352, 1995
    6. Hass WK, Easton JD, Adams HP, Jr., et al: A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 321:501-507, 1989
    7. Helgason CM, Tortorice KL, Winkler SR, et al: Aspirin response and failure in cerebral infarction. Stroke 24:345-350, 1993
    8. Hobson RW, II., Weiss DG, Fields WS, et al and Veterans Affairs Cooperative Study Group: Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. N Engl J Med 328:221-227, 1993
    9. Kleiser B, Widder B: Course of carotid artery occlusions with impaired cerebrovascular reactivity. Stroke 23:171-174, 1992
    10. Matchar D: Cost of stroke. Stroke Clinical Updates 5:9, 1994
    11. Miller A, Lees RS: Simultaneous therapy with antiplatelet and anticoagulant drugs in symptomatic cardiovascular disease. Stroke 16:668-675, 1985
    12. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 325:445-453, 1991
    13. Powers WJ: Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol 29:231-240, 1991
    14. Roederer GO, Langlois YE, Jager KA, et al: The natural history of carotid arterial disease in asymptomatic patients with cervical bruits. Stroke 15:605-613, 1984
    15. Thomas DJ: The European Trial on Asymptomatic Carotid Stenosis (platform presentation). 20th Joint International Conference on Stroke and Cerebral Circulation, Charleston SC, 1995
    16. Tilley BC: Atrial fibrillation, aspirin, and anticoagulant therapy (AFASAK 2). Stroke 26:352, 1995
    17. Turpie AG, Gent M, Laupacis A, et al: A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 329:524-529, 1993
    18. Yonas H, Smith HA, Durham SR, et al: Increased stroke risk predicted by compromised cerebral blood flow reactivity. J Neurosurg 79:483-489, 1993

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