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Carotid Endarterectomy: A Little More Light at the End of the Tunnel

  • Michael D. Walker
    Correspondence
    Address reprint requests to Dr. M. D. Walker, Division of Stroke and Trauma, NINDS, Federal Building, Room 8A-08, National Institutes of Health, Bethesda, MD 20892
    Affiliations
    Director, Division of Stroke and Trauma National Institute of Neurological Disorders and Stroke Bethesda, Maryland
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      The report by the Mayo Asymptomatic Carotid Endarterectomy Study Group in this issue of the Mayo Clinic Proceedings (pages 513 to 518) gives pause for thought about several important issues related to the perception of the risks and benefits from carotid endarterectomy and the definitional problems related to stroke research. Although the article concludes that the investigators were unable to answer the null hypothesis proposed about stroke and transient ischemic attack (statistical inference), the reader is left with the perception that medical treatment with aspirin is safer than the combination of being assessed for and actually undergoing a carotid endarterectomy. Several other investigators who also addressed these issues have provided comparative data from large numbers of patients in different settings.
      • Towne JB
      • Weiss DG
      • Hobson II, RW
      First phase report of cooperative Veterans Administration asymptomatic carotid stenosis study—operative morbidity and mortality.
      • Mayberg MR, Wilson SE, Yatsu F, Weiss DG, Messina L, Hershey LA, Colling C, Eskridge J, Deykin D, Winn HR (for the Veterans Affairs Cooperative Studies Program 309 Trialist Group)
      Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis.
      • European Carotid Surgery Trialists' Collaborative Group
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      • CASANOVA Study Group
      Carotid surgery versus medical therapy in asymptomatic carotid stenosis.
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      • Fode NC
      • Sundt Jr, TM
      • Robertson JT
      • Peerless SJ
      • Shields CB
      Multicenter retrospective review of results and complications of carotid endarterectomy in 1981.
      • Healy DA
      • Clowes AW
      • Zierler RE
      • Nicholls SC
      • Bergelin RO
      • Primozich JF
      • Strandness Jr, DE
      Immediate and long-term results of carotid endarterectomy.
      The composition of patients at secondary and tertiary referral centers such as the Mayo Clinic often differs considerably from that seen in many general practices. Frequently, patients who have a greater number of risk factors, more complicated disorders, or a higher probability of unsuccessful surgical results than other patients are referred to institutions that have a reputation for the successful management of complex cases. Nevertheless, the results reported herein, and the results of several recent and ongoing studies of carotid endarterectomy, focus our attention on issues relevant to the perioperative period, the relative importance of major stroke, minor stroke, and transient ischemic attack, and causality.

      Perioperative Morbidity and Mortality.

      A time frame characteristically analyzed in surgical studies is the 30-day perioperative morbidity and mortality interval (PO30). Traditionally, all events during the PO30 interval have been assigned to “surgical misadventure” or the cost of subjecting a patient to an operative workup, anesthesia, the formal operation, and postanesthetic recovery. The PO30 interval is an arbitrary variable that generally fits within the context of events that occur within a month after an operation and that physicians believe should be attributed to the surgical procedure. Some investigators restrict the perioperative events to those that occur during the hospitalization for the operation, but the PO30 interval is consistent, convenient, and generally accepted. In trials, a period comparable to the PO30 is frequently defined for the nonsurgical group for purposes of comparison.
      In a major effort to provide an estimate of the PO30 morbidity and mortality, Fode and colleagues
      • Fode NC
      • Sundt Jr, TM
      • Robertson JT
      • Peerless SJ
      • Shields CB
      Multicenter retrospective review of results and complications of carotid endarterectomy in 1981.
      obtained data related to 3,328 patients who underwent carotid endarterectomy at 46 medical centers and estimated the PO30 death rate as 1.98%, stroke rate as 4.20%, and total surgically assignable PO30 events as approximately 6%. Symptomatic patients are widely believed to be at greater risk than asymptomatic patients, and the Committee on Health Care Issues of the American Neurological Association
      • Committee on Health Care Issues, American Neurological Association
      Does carotid endarterectomy decrease stroke and death in patients with transient ischemic attacks?.
      recommended that the PO30 stroke-related morbidity and mortality rate for asymptomatic patients should not exceed 3% and for symptomatic patients should not exceed 6%. For the past several years, new data have been emerging from several controlled clinical trials and from large sequential case series, which allow a closer approximation than previously of the current PO30 morbidity and mortality for carotid endarterectomy. For the purposes of this discussion, the PO30 morbidity and mortality is defined as including all deaths from any cause (stroke leading to death is counted as a death) and any stroke. Transient ischemic attacks, because of their variability, have not been counted.
      In Table 1 are data aggregated from several recent studies that included large numbers of patients and thus provide the opportunity to examine the PO30 in asymptomatic patients
      • Towne JB
      • Weiss DG
      • Hobson II, RW
      First phase report of cooperative Veterans Administration asymptomatic carotid stenosis study—operative morbidity and mortality.
      • CASANOVA Study Group
      Carotid surgery versus medical therapy in asymptomatic carotid stenosis.
      • Healy DA
      • Clowes AW
      • Zierler RE
      • Nicholls SC
      • Bergelin RO
      • Primozich JF
      • Strandness Jr, DE
      Immediate and long-term results of carotid endarterectomy.
      • Moore WS
      • Vescera CL
      • Robertson JT
      • Baker WH
      • Howard VJ
      • Toole JF
      Selection process for surgeons in the Asymptomatic Carotid Atherosclerosis Study.
      • Freischlag JA
      • Hannah D
      • Moore WS
      Improved prognosis for asymptomatic carotid stenosis with prophylactic carotid endarterectomy.
      and also in symptomatic patients.
      • Mayberg MR, Wilson SE, Yatsu F, Weiss DG, Messina L, Hershey LA, Colling C, Eskridge J, Deykin D, Winn HR (for the Veterans Affairs Cooperative Studies Program 309 Trialist Group)
      Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis.
      • European Carotid Surgery Trialists' Collaborative Group
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      • Healy DA
      • Clowes AW
      • Zierler RE
      • Nicholls SC
      • Bergelin RO
      • Primozich JF
      • Strandness Jr, DE
      Immediate and long-term results of carotid endarterectomy.
      • Moore WS
      • Vescera CL
      • Robertson JT
      • Baker WH
      • Howard VJ
      • Toole JF
      Selection process for surgeons in the Asymptomatic Carotid Atherosclerosis Study.
      • North American Symptomatic Carotid Endarterectomy Trial (NASCET) Steering Committee
      North American Symptomatic Carotid Endarterectomy Trial: methods, patient characteristics, and progress.
      • Sundt Jr, TM
      • Whisnant JP
      • Houser OW
      • Fode NC
      Prospective study of the effectiveness and durability of carotid endarterectomy.
      In addition, for the first time, some data are available for comparable symptomatic patients who are fully acceptable for surgical treatment but who have not undergone carotid endarterectomy (Table 2).
      • Mayberg MR, Wilson SE, Yatsu F, Weiss DG, Messina L, Hershey LA, Colling C, Eskridge J, Deykin D, Winn HR (for the Veterans Affairs Cooperative Studies Program 309 Trialist Group)
      Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis.
      • European Carotid Surgery Trialists' Collaborative Group
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      The PO30 death rate is similar for asymptomatic (0.88%) and symptomatic (0.86%) patients, whereas the PO30 stroke rates are 1.28% for asymptomatic patients and 2.52% for symptomatic patients (P<0.001). More important are the early estimates for the PO30 morbidity and mortality for symptomatic patients who have not received surgical treatment. The similarity of these patients with the surgically treated patients is provided by virtue of randomization. In these nonsurgical patients, the death rate in the PO30 window equivalent is 0.22%, and the stroke rate in the PO30 window equivalent is a remarkable 2.1%. In a sense, the data for the PO30 window equivalent for such nonsurgical patients correspond to the natural history of patients who undergo a workup and are considered for surgical intervention, but without the direct contribution of carotid endarterectomy.
      Table 1Summary of Data From Published Studies of Asymptomatic and Symptomatic Patients Who Underwent Carotid Endarterectomy
      ACAS = Asymptomatic Carotid Atherosclerosis Study; TIA = transient ischemic attack.
      No. of patientsDeath (%)Stroke (%) (minor + major)Total (%)Degree of stenosis (%)CommentReference
      Asymptomatic patients
      1,511121325AllPrequalification data for ACAS
      • Moore WS
      • Vescera CL
      • Robertson JT
      • Baker WH
      • Howard VJ
      • Toole JF
      Selection process for surgeons in the Asymptomatic Carotid Atherosclerosis Study.
      33441 + 51050-90All surgical patients counted; none >90% stenosis
      • CASANOVA Study Group
      Carotid surgery versus medical therapy in asymptomatic carotid stenosis.
      21140 + 5950-492 TIAs; 8 patients with bilateral operations
      • Towne JB
      • Weiss DG
      • Hobson II, RW
      First phase report of cooperative Veterans Administration asymptomatic carotid stenosis study—operative morbidity and mortality.
      14100 + 22>75
      • Freischlag JA
      • Hannah D
      • Moore WS
      Improved prognosis for asymptomatic carotid stenosis with prophylactic carotid endarterectomy.
      77033All1 TIA
      • Healy DA
      • Clowes AW
      • Zierler RE
      • Nicholls SC
      • Bergelin RO
      • Primozich JF
      • Strandness Jr, DE
      Immediate and long-term results of carotid endarterectomy.
      2,27420 (0.88)
      Numbers in parentheses are 30-day perioperative rates.
      29 (1.28)
      Numbers in parentheses are 30-day perioperative rates.
      49 (2.15)
      Numbers in parentheses are 30-day perioperative rates.
      Symptomatic patients
      4,1303376109AllPrequalification data for ACAS
      • Moore WS
      • Vescera CL
      • Robertson JT
      • Baker WH
      • Howard VJ
      • Toole JF
      Selection process for surgeons in the Asymptomatic Carotid Atherosclerosis Study.
      435417+133470-99455 allocated to surgical treatment; author's estimate
      • European Carotid Surgery Trialists' Collaborative Group
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      328212 + 51970-99
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      ,
      • North American Symptomatic Carotid Endarterectomy Trial (NASCET) Steering Committee
      North American Symptomatic Carotid Endarterectomy Trial: methods, patient characteristics, and progress.
      28225 + 07All5 TIAs; a few asymptomatic patients
      • Sundt Jr, TM
      • Whisnant JP
      • Houser OW
      • Fode NC
      Prospective study of the effectiveness and durability of carotid endarterectomy.
      20635 + 2100-29Author's estimate
      • European Carotid Surgery Trialists' Collaborative Group
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      123134All
      • Healy DA
      • Clowes AW
      • Zierler RE
      • Nicholls SC
      • Bergelin RO
      • Primozich JF
      • Strandness Jr, DE
      Immediate and long-term results of carotid endarterectomy.
      9132 + 1650-99High-risk-factor population
      • Mayberg MR, Wilson SE, Yatsu F, Weiss DG, Messina L, Hershey LA, Colling C, Eskridge J, Deykin D, Winn HR (for the Veterans Affairs Cooperative Studies Program 309 Trialist Group)
      Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis.
      5,59548 (0.86)
      Numbers in parentheses are 30-day perioperative rates.
      141 (2.52)
      Numbers in parentheses are 30-day perioperative rates.
      189 (3.38)
      Numbers in parentheses are 30-day perioperative rates.
      * ACAS = Asymptomatic Carotid Atherosclerosis Study; TIA = transient ischemic attack.
      Numbers in parentheses are 30-day perioperative rates.
      Table 2Summary of Data From Published Studies of Symptomatic Patients Who Qualified for but Did Not Undergo Carotid Endarterectomy
      TIAs = transient ischemic attacks.
      No. of patientsDeathStroke (%) (minor + major)Total (%)Degree of stenosis (%)CommentReference
      33118 + 21170–99
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      32314570–99Estimates
      • European Carotid Surgery Trialists' Collaborative Group
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      1550330–29Estimates
      • European Carotid Surgery Trialists' Collaborative Group
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      9802250–994 crescendo TIAs
      • Mayberg MR, Wilson SE, Yatsu F, Weiss DG, Messina L, Hershey LA, Colling C, Eskridge J, Deykin D, Winn HR (for the Veterans Affairs Cooperative Studies Program 309 Trialist Group)
      Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis.
      9072 (0.22)
      Numbers in parentheses are 30-day perioperative rates.
      19 (2.10)
      Numbers in parentheses are 30-day perioperative rates.
      21 (2.32)
      Numbers in parentheses are 30-day perioperative rates.
      * TIAs = transient ischemic attacks.
      Numbers in parentheses are 30-day perioperative rates.
      The total PO30 morbidity and mortality can be considered in its two components as the natural history during that period plus the contribution of surgical treatment. The contribution of endarterectomy can be calculated as being approximately 1% (3.38% − 2.32% = 1.06%). Although the event rates are relatively low and the precision of the data is questionable, they are derived from well-conducted and carefully controlled multi-institutional studies performed under the watchful eyes of many experts, and they represent the most informative data to date. For symptomatic patients with severe stenosis (70 to 99%), the policy of prolonging the consideration for surgical treatment (doing nothing) or waiting for a month to “allow the patient to stabilize from a stroke” necessitates serious reconsideration.

      Transient Ischemic Attacks.

      In the study reported in this issue of the Mayo Clinic Proceedings, four focal cerebral ischemic events occurred in both the surgical and the nonoperated groups; however, all four events in the nonoperated group were late transient ischemic attacks, whereas three of the four in the surgical group were strokes that occurred during the PO30 interval. Obviously, as a focal ischemic event, stroke is of more serious consequence than transient ischemic attack; however, the gradations of importance of stroke are often categorized as time-dependent. In the clinical trials compiled for this discussion, “major” stroke is categorized variably as a persistent neurologic deficit at 7 days, 3 weeks, 3 months, or 4 months. Transient ischemic attack is sometimes reported, counted for statistical purposes, or ignored. The results of the North American Symptomatic Carotid Endarterectomy Trial have clearly characterized the significance of transient ischemic attacks thought to be of carotid origin.
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      Two-thirds of the patients had entered the study because of transient ischemic attack or equivalent symptoms; half underwent operation and contributed substantially to the 65% decrease in relative risk for ipsilateral strokes noted at 2 years. Although the final analysis has yet to be completed and published, the following are three important preliminary conclusions: (1) patients with transient ischemic attacks may recover quickly and are asymptomatic, but they are at considerably higher risk for stroke than previously believed; (2) carotid endarterectomy for high-grade stenosis in symptomatic patients effectively decreases the possibility of second stroke or first stroke after transient ischemic attack; and (3) in general, prevention of any stroke should provide the best outcome. Transient ischemic attack may no longer be considered a trivial event, and for patients with severe carotid disease, it is a warning sign after which no second chance may be available. Thus, in this issue of the Mayo Clinic Proceedings, the four patients in the group without surgical treatment who have had transient ischemic attacks are now at a relatively higher risk for occurrence of stroke. Such patients should be seriously considered for operation after careful cardiovascular assessment.
      Frequently, transient ischemic attack has been discounted as an endpoint or an indication for surgical intervention because it is “too vague,” “too variable,” and “too unreliable.” Relatively few transient ischemic attacks were heretofore believed to eventuate in strokes. Part of the doubt relates to whether transient ischemic attack is an adequate substitute for stroke as an endpoint, but what would be the conclusions related to the current Mayo study if all the strokes had occurred in the nonsurgical group and all the transient ischemic attacks had occurred in the group that underwent endarterectomy? New data derived from the North American Symptomatic Carotid Endarterectomy Trial
      • Streifler JY
      • Benavente OR
      • Harbison JW
      • Eliasziw M
      • Hachinski VC
      • Barnett HJM
      Prognostic implications of retinal versus hemispheric TIA in patients with high grade carotid stenosis: observations from NASCET (abstract).
      provide further evidence that well-characterized transient ischemic attacks may be almost as good an endpoint as stroke—and obviously preferable from the patient's viewpoint. Of the 68 patients with first-ever transient ischemic attacks, clearly identified and confined to the hemisphere of concern, 42% had a fatal or a nonfatal stroke within 2 years.

      Management Approaches.

      The rapidly expanding field of clinical research on stroke now has provided more precise data from controlled clinical trials about symptomatic patients with carotid disease that replace or validate conventional wisdom.
      • Pokras R
      • Dyken ML
      Dramatic changes in the performance of endarterectomy for diseases of the extracranial arteries of the head.
      The management of asymptomatic patients with severe carotid stenosis is also becoming more clearly defined and will probably depend on an array of prognostic indicators, the sum of which will suggest immediate endarterectomy, versus another array of prognostic indicators that will advocate delay of endarterectomy. It may well be that the prevention of transient ischemic attack provides more symptom-free time for patients than the prevention of another stroke. In the meantime, we must await the results of the Cooperative Veterans Administration Asymptomatic Carotid Stenosis Study and the Asymptomatic Carotid Atherosclerosis Study for more generalizable opinions and a more comprehensive answer.

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