VOLUME 67

Results of a Randomized Controlled Trial of CarotidEndarterectomy for Asymptomatic Carotid Stenosis

MAYO ASYMPTOMATIC CAROTID ENDARTERECTOMY STUDY GROUP*

JUNE 1992

We undertook a randomized controlled trial designed to compare the effects of carotid endarterectomywith medical treatment using low-dose aspirin in patients with asymptomatic carotid stenosis. During30 months of recruitment, 71 randomized and 87 eligible nonrandomized patients participated in afollow-up protocol. The total ipsilateral perioperative stroke and death rate was 0% among random­izedpatients and 3% among nonrandomized patients, and the major stroke and death rate was 0% forboth groups. Too few cerebral ischemic events occurred to judge the comparative effectiveness ofcarotid endarterectomy versus low-dose aspirin for asymptomatic carotid stenosis. The trial wasterminated early because of a significantly higher number of myocardial infarctions and transientcerebral ischemic events in the surgical group than in the medical group. Most of the events were nottemporally related to the surgical procedure, but there was evidence that these events could haverelated to the absence of aspirin use in the surgical group. These observations reinforce the appropri­ateness of the use of aspirin throughout the perioperative period and beyond (unless contraindicationsexist) in patients with asymptomatic carotid stenosis who undergo carotid endarterectomy.

During the first 35 years after the introduction of carotidendarterectomy in the mid-1950s, only one randomized con­trolled trial was reported that assessed the effectiveness ofthis procedure in asymptomatic patients. I That study in­cluded 29 randomized patients, 14 of whom received aspirinand 15 of whom underwent carotid endarterectomy. Al­though the investigators found no benefit from carotid endar­terectomy, the sample size was small, the follow-up intervalwas brief (32 months), and the unfavorable outcomes in thesurgical group consisted of three myocardial events and oneasymptomatic recurrent carotid stenosis. No strokes oc­curred in either group. Five patients in the group given

*The members of the group are listedin the Appendix, page518.

Address reprint requests to Dr. D. O. Wiebers, Department ofNeurology, MayoClinic, Rochester, MN55905.

aspirin had a transient ischemic attack in comparison withnone in the endarterectomy group.

On the basis of that study, no conclusion could be reachedabout the benefit of carotid endarterectomy in patients withasymptomatic carotid stenosis. No information was avail­able about the use of aspirin in the endarterectomy group.Although several large favorable surgical series have beenpublished in the literature.' none has included a randomizedcontrol group for comparison of outcome.

Continuing controversy about the efficacy of this opera­tion led to the initiation of four randomized trials for patientswith asymptomatic carotid stenosis, three of which havebeen undertaken in North America'? and one in Europe."Recently, the results of the European study, based on 410patients with asymptomatic 50 to 90% carotid stenosis, werereported.' Although the authors concluded that carotid end­arterectomy was not indicated for this group of patients, the

Mayo Clin Proc 67:513-518,1992 513

514 ENDARTERECTOMY FOR ASYMPTOMATIC CAROTID STENOSIS Mayo Clin Proc, June 1992, Vol 67

study did not address the most compelling subgroup of pa­tients with high-grade (more than 90%) asymptomatic ca­rotid stenosis. Furthermore, patients in the nonsurgical armof the study routinely underwent carotid endarterectomy iffollow-up studies indicated progression of the carotid steno­sis to more than 90%.

METHODSThe methods used in this trial have been described in detailin a previous publication.' Only the key features are men­tioned here.

Eligibility ofPatients. Inclusion Criteria-For partici­pation in this trial, all patients fulfilled the following criteria:(1) absence of a history of symptoms of cerebral or retinalischemic disease, (2) presence or absence of localized ca­rotid bruits, and (3) evidence of pressure-significant lesionsin one or both internal carotid systems on ocular pneumo­plethysmography and carotid stenosis (50% or more linearstenosis or 75% cross-sectional area stenosis) but not occlu­sion on duplex ultrasound scans or intravenous digital sub­traction angiograms.

Exclusion Criteria-For this study, the following fac­tors were exclusion criteria: (1) age younger than 18 years orolder than 79 years; (2) women of childbearing age; (3) anycontraindication to the use of aspirin; (4) a prior allergicreaction to contrast dye; (5) unstable angina or myocardialinfarction within the preceding 6 months; (6) potentialsources of cardiac embolus, such as atrial fibrillation, atrialflutter, complete heart block, and severe valvular disease(including prosthetic cardiac valves); (7) moderate to severecongestive heart failure; (8) severe obstructive pulmonarydisease; (9) cancer other than of the skin or another illnesslikely to be terminal within 3 years; (10) dementia or psychi­atric illness that precluded informed consent; (11) other non­atherosclerotic reasons for carotid stenosis, such as carotiddissection or fibromuscular disease; (12) hematologic orsystemic diseases that might be associated with episodes offocal cerebral ischemia (for example, active polycythemia orarteritis); (13) renal failure (serum creatinine concentrationof more than 2 mg/dl); and (14) uncontrolled hypertension ordiabetes.

Baseline Studies.-At the time of entry into the study, allpatients underwent a general physical examination and aneurologic examination as well as noninvasive cerebrovas­cular studies; in addition, historical information about riskfactors for stroke was elicited. Baseline laboratory studiesincluded a coagulation profile, hematology and chemistrystudies, serum lipid determinations, and, in some cases,computed tomography or magnetic resonance imaging of thehead.

Enrollment ofPatients.-Eligible patients were random­ized by a dynamic randomization scheme' after informed

consent was obtained. The five balancing factors used in thescheme were age, sex, history of hypertension, history ofcoronary artery disease, and history of cigarette smokingwithin 1 year of entry into the trial.

Treatment.-Patients were randomized to either themedical or the surgical treatment group. Patients in thesurgical arm of the study were scheduled for carotid arteri­ography and endarterectomy. Patients randomized to thesurgical arm of the study could undergo either unilateral orbilateral carotid endarterectomy, depending on the discretionof the surgeon. Concomitant bilateral carotid endarterec­tomy or concomitant carotid endarterectomy and coronaryartery bypass grafting, however, precluded participation inthe trial. Use of aspirin was discouraged in the surgicaltreatment arm to avoid a potential confounding variableintroduced by an interaction between aspirin and surgerythat could mask the true effect of surgery (for example, ifaspirin had a detrimental effect on surgically treated pa­tients). Such a design also increased the likelihood of show­ing a difference between the two groups. Use of aspirin wasallowed in patients who had it prescribed for other indica­tions such as known cardiac disease. Patients randomized tothe medical arm of the study were treated with aspirin (80mg/day orally for the duration of the study) and, when fea­sible, were discouraged from taking extra doses of aspirinand other antiplatelet agents including nonsteroidal anti­inflammatory drugs. Patients in both arms of the studyreceived treatment, as indicated, for other cerebrovascularrisk factors, including hypertension, hyperlipidemia, anddiabetes.

Follow-Up.-Patients in both treatment groups wereasked to return for two follow-up visits-at 6 months and 2years after entering the study. An additional telephone inter­view was conducted approximately 30 days after initiation oftreatment. The rest of the follow-up was accomplished bycompletion of questionnaires at 12 months, 18 months, andevery 6 months after the 2-year follow-up visit.

Ascertainment of Endpoints.-Primary endpoints forthis study were the occurrence of transient ischemic attack,ischemic or hemorrhagic stroke in any vascular distribution,and death. Secondary endpoints were the occurrence ofmyocardial infarction or the performance of coronary arterybypass grafting for symptomatic coronary artery disease.Focal cerebral ischemic events were evaluated to determinethe location, vascular distribution, severity, duration, andtype.

The occurrence and severity of endpoints were adjudi­cated by two participating neurologists and surgeons whowere not involved in the management of the patient and whowere unaware of the treatment arm~

Statistical Design.-Rates of occurrence of each ofthe aforementioned endpoints were estimated by using the

Mayo Clin Proc, June 1992, Vol 67 ENDARTERECTOMY FOR ASYMPTOMATIC CAROTID STENOSIS 515

Kaplan-Meier product limit method. All analyses werebased on an intent-to-treat premise unless otherwise speci­fied. The primary analysis was performed by using onlyprimary endpoints. Another analysis used a combinationof all primary and secondary endpoints. For comparisonsof treatments for both primary and secondary events, thelog-rank test for duration to occurrence of an event wasused. Baseline characteristics for randomized versus eligi­ble nonrandomized groups and treatment arms withinthose groups were compared with use ofaX2 test for dis­crete variables and rank tests as appropriate for continuousvariables.

Analyses were performed in June 1990 and December1990. The results of these analyses were to be known only tothe Data and Safety Monitoring Committee; after confiden­tial review, they would notify the investigators of any sig­nificant difference between the two treatment arms that per­sisted for at least 6 months.

Nonrandomized Patients.-All patients screened for thetrial who had abnormal findings on ocular pneumopleth­ysmography or either duplex Doppler or digital subtractionangiographic findings of 50% or greater surgically acces­sible linear stenosis of the common carotid or internal ca­rotid arteries were identified and characterized. Patientswho fulfilled all eligibility criteria but did not participate inthe randomization were classified as eligible nonrandomizedpatients. The initial study characteristics of these patientswere recorded exactly as for patients randomized into thetrial; thus, a detailed comparison of eligible patients whowere and who were not randomized was possible. In addi­tion, after informed consent was obtained, these patientsparticipated in a follow-up protocol similar to that for therandomized patients.

RESULTSEarly Termination of the Trial.-The Data and SafetyMonitoring Committee recommended termination of thetrial on Dec. 10, 1990. This decision was based on analysisof primary and secondary endpoints (particularly the latter)that had occurred in patients entered into the trial throughJune 1, 1990.

Patient Population and Characteristics.-During 30months of recruitment, 158 study subjects (71 randomizedand 87 eligible nonrandomized patients) completed the fol­low-up protocol. Among the randomized patients, 36 wereassigned to the surgical arm and 35 to the aspirin arm of thestudy. Among the eligible nonrandomized patients, 32 weretreated surgically and 55 were treated with aspirin.

The baseline characteristics of the randomized and theeligible nonrandomized patients are shown in Table 1. Theprocess of randomization produced balanced treatment armsin regard to the five variables used as well as other baseline

characteristics. The comparability between eligible patientswho were and who were not randomized indicates that nogroup of eligible patients was systematically excluded fromthe trial, although a greater percentage of men (46%) thanwomen (19%) received surgical treatment in the nonran­domized group.

Among screened patients whose noninvasive studies sug­gested surgically accessible asymptomatic pressure-signifi­cant carotid stenosis but who were deemed ineligible toparticipate in the study, the most common reasons for ineli­gibility were as follows: older than 79 years of age (39%),presence of severe coronary artery disease or pulmonarydisease (24%), digital subtraction angiographic or duplexDoppler evidence of carotid occlusion (15%), other severe orterminal illness (8%), prior ipsilateral carotid endarterec­tomy (7%), inability to give informed consent (because ofmental incompetence) (3%), and contraindications to the useof aspirin (3%).

Follow-Up.-Follow-up was completed for all patients toDec. 1, 1990. The mean duration of follow-up was 23.6months. No patients were lost to follow-up or withdrewfrom the study. Two patients randomized to aspirin therapyunderwent carotid endarterectomy before the occurrence ofan outcome event, and nine patients randomized to the surgi­cal arm did not undergo carotid endarterectomy because of adistal ipsilateral carotid system high-grade stenosis (in fourpatients), increase in symptoms of coronary artery diseasethat necessitated attention before endarterectomy (in four),or occurrence of stroke between the time of randomizationand surgical intervention (in one). Within the medical treat­ment arm, all 90 patients (35 randomized and 55 eligiblenonrandomized) took regular doses of aspirin after entry intothe trial.

Outcome Events.-Among randomized patients, focalcerebral ischemic events occurred in four patients in theaspirin arm ofthe study (all had transient ischemic attacks)and in four patients in the surgical arm (three had ischemicstrokes and one had a transient ischemic attack). Among thethree ischemic strokes in patients in the surgical arm of thestudy, two occurred after randomization but before the op­eration, and one occurred in the right posterior cerebraldistribution 4 days after left carotid endarterectomy. Al­though no difference was noted in the occurrence of focalcerebral ischemic events (P = 0.974) or cerebral infarction(P = 0.0866) between the two treatment groups, myocardialinfarction occurred in 8 of the 36 patients in the surgical armof the study in comparison with none of the patients whoreceived aspirin (P =0.0037). Three other patients in thesurgical arm and one in the med~ arm of the trial under­went percutaneous transluminal coronary angioplasty or acoronary artery bypass grafting procedure. Analysis of alIprimary and secondary endpoints among randomized pa-

516 ENDARTERECTOMY FOR ASYMPTOMATIC CAROTID STENOSIS Mayo Chn Proc, June 1992, Vol 67

Table 1.-8ummary of Clinical Characteristics of 158 Patients Who Participatedin the Mayo Asymptomatic Carotid Endarterectomy Study,

Stratified by Randomization Status and Treatment*

Randomized Not randomized

Surgical SurgicalAspirin treatment Aspirin treatment

Clinical characteristic (N =35) (N =36) (N =55) (N =32)

Sex (%)Female 40.0 44.4 45.4 18.8Male 60.0 55.6 54.6 81.2

Race (%)White 100.0 97.2 100.0 100.0Other 2.8

Age, yr(%)::;;55 5.7 2.8 7.3 3.156-65 22.9 27.8 29.1 34.4>65 71.4 69.4 63.6 62.5

History of hypertension (%)None 37.1 36.1 20.0 15.6Controlled with treatment 48.6 47.2 60.0 65.6Uncontrolled 14.3 16.7 20.0 18.8

History of coronary artery disease (%)None 60.0 58.3 60.0 56.3Angina OrMI >6 mo 31.4 33.3 32.7 31.2Stable angina ::;;6 mo 8.6 8.3 7.3 12.5

Cigarette smoking (%)tNever 25.7 33.3 27.3 18.8Past smoker 42.9 41.7 50.9 46.9Current smoker 31.4 25.0 21.8 34.4

Intake of alcohol (%)None 40.0 47.2 43.6 21.9Less than 7 ounces/wk'r-" 28.6 19.5 20.0 15.67 ounces or more/wk3•4 •6•7 31.4 33.3 36.4 62.5

Past medical history (%)Congestive heart failure 8.6 0.0 3.6 12.5Intermittent claudication 22.9 22.2 36.4 46.9Cardiac operation 17.1 16.7 14.6 21.9Angina 40.0 38.9 36.4 40.6MI 14.3 19.4 23.6 18.8Hypertension 62.9 63.9 80.0 84.4Hyperlipidemia 65.7 44.4 58.2 59.4Diabetes mellitus 14.3 19.4 21.8 18.8

Medications (%)Antihypertensive 48.6 52.8 60.0 62.5Antilipidemia 11.4 25.0 25.4 21.9Antiangina or antiarrhythmia 22.9 38.9 34.6 34.4

*MI =myocardial infarction.tHabitually smoked 10 cigarettes/day.

tients revealed a significant difference in favor of the aspirintreatment group (P =0.0363).

Of the eight myocardial infarctions, four occurred afterrandomization but before surgical intervention, two occurredon the day of operation, one occurred 7 days postoperatively,and one occurred 5 months after carotid endarterectomy. No

myocardial infarction was fatal; five were subendocardial,two were transmural, and one was indeterminate in nature.

Among eligible nonrandomized patients, focal cerebralischemic events occurred in 3 of the 55 patients treated withaspirin (2 had transient ischemic attacks and 1 had an isch­emic stroke) and in 6 of the 32 patients treated surgically (4

Mayo Clin Proc, June 1992, Vol 67 ENDARTERECTOMY FOR ASYMPTOMATIC CAROTID STENOSIS 517

had transient ischemic attacks and 2 had ischemic strokes­all in the distribution of the operated artery within 2 daysafter the surgical procedure, except 1 transient ischemicattack 6 months postoperatively). Myocardial infarctionoccurred in one patient treated with aspirin and one patienttreated surgically. In the former patient, metastatic cancerwas diagnosed 1 year after entry into the study; subse­quently, sudden unexpected death occurred because of apresumed myocardial infarction. The latter patient had anepisode of sudden congestive heart failure thought to berelated to myocardial infarction by the patient's home physi­cians, but this relationship could not be confirmed on exami­nation 1 month later at the Mayo Clinic. Among nonran­domized patients, a marginally significant difference wasnoted for the occurrence of primary endpoints or myocardialinfarction (or both) in favor of treatment with aspirin (P =0.0412).

Overall, among randomized and nonrandomized patients,primary endpoints or myocardial infarction occurred in 8 of90 patients in the medical arm of the study and in 18 of 68patients treated in the surgical arm (P = 0.0023). In 18 of 26patients with primary endpoints or myocardial infarction, thepatient was not taking aspirin at the time of the event, includ­ing 2 of 8 patients in the medical group who had discontin­ued use of aspirin temporarily and 16 of 18 patients in thesurgical group (P = 0.0011). No significant difference wasnoted among either randomized or nonrandomized medicalor surgical patients for the use of warfarin or antiplateletdrugs other than aspirin at the time of the occurrence of aprimary event or myocardial infarction.

Perioperative Morbidity and Mortality.-Among ran­domized patients in the first 30 days after carotid endarterec­tomy, one patient (4%) had a transient ischemic attack (anepisode of right amaurosis fugax 17 days after right carotidendarterectomy) and 1 (4%) had an ischemic stroke (a leftoccipital infarct 4 days after right carotid endarterectomy).Three patients had myocardial infarction, two of which oc­curred on the day of the surgical procedure and one of whichoccurred 7 days postoperatively. The total perioperativestroke rate was 4% among randomized patients and 3%among nonrandomized patients, and the corresponding ipsi­lateral perioperative stroke rates were 0 and 3%, respec­tively. Restricting the analysis to events responsible forpersistent major disability or death yielded a major strokeand death rate of 0%.

Among randomized patients who underwent carotid end­arterectomy, other surgical complications that occurred dur­ing the first 30 days postoperatively included 3 instances ofminor cranial nerve injury (11%), none of which had anylasting effect on functional status. There were no instancesof wound hematoma, wound infection, congestive heart fail­ure, pneumonia, or other medical complications.

DISCUSSIONThis study was designed to compare the effectiveness ofcarotid endarterectomy with medical treatment using aspirinfor prevention of transient ischemic attack and ischemicstroke. in patients with asymptomatic pressure-significantcarotid stenosis. The results of the trial do not permit us toresolve this issue. There were too few observations of ce­rebral ischemic events for us to make a judgment about adifference between the aspirin and the surgical treatmentgroups. The recommendation of the Data and Safety Mon­itoring Committee to terminate the trial was based on thefrequency of a secondary endpoint (myocardial infarction)in the randomized group that was significantly greater inthe surgical than in the medical arm of the trial. Patients inthe surgical arm were discouraged from taking aspirin un­less other indications (for example, cardiac) existed for theuse of aspirin. Furthermore, patients were usually takenoff aspirin therapy before carotid endarterectomy becausethis had been the standard practice of some surgeons inour group to reduce the probability of bleeding at the site ofendarterectomy.

The majority of patients who had a primary or secondaryendpoint in the surgical arm were not taking aspirin at thetime of the event, including those patients who had compli­cations in the perioperative period. In light of the fact that allrandomized patients who had myocardial infarction wererandomized to surgery with exclusion of aspirin, and giventhe timing ofthe myocardial infarctions relative to surgery, itis not possible to attribute these events to either aspect oftreatment. However, the absence of aspirin use in the surgi­cal group may have been a determinant of primary or sec­ondary endpoint occurrence. These observations reinforcethe appropriateness of the use of aspirin throughout theperioperative period and beyond (unless contraindicationsexist) in patients with asymptomatic carotid stenosis whoundergo carotid endarterectomy.

Although it is conceivable that a rebound effect occurs 3to 7 days after discontinuation of aspirin, producing a hyper­coagulable state and a greater likelihood of myocardial in­farction and focal cerebral ischemic events, the temporal re­lationship of these events to the number of days aspirin hadnot been taken (range, 7 to 337 days) in those patients whohad been on aspirin therapy was not consistent with that.Among the 18 patients who had focal cerebral ischemia ormyocardial infarction in the surgical group, only 7 had previ­ously been taking aspirin, which was discontinued before theoccurrence of the event.

Recruitment for this trial was considerably slower thananticipated largely because we overestimated the numbers ofeligible patients who would be available to participate. Thenumber of asymptomatic patients with abnormal noninva­sive carotid studies screened (40 to 50 per month) was con-

518 ENDARTERECTOMY FORASYMPTOMATIC CAROTID STENOSIS Mayo Clin Proc, June 1992, Vol 67

sistent with our estimates, but we anticipated that 10 to 20 ofthese patients per month would be randomized, whereas only5 to 6 per month qualified and fewer than 3 per month agreedto randomization. We also underestimated the number ofdistal carotid system lesions that would be revealed on ca­rotid arteriography subsequent to randomization. This was a

. factor in reducing compliance in the surgical group.It is important to point out that the two other asymptom­

atic carotid endarterectomy trialsv' still in progress differfrom this trial in that each provides for routine treatment ofpatients in the surgical arm with antiplatelet therapy in theform of aspirin. Results of these studies have not yet beenpublished but should be helpful in answering the centralquestion about the effectiveness of carotid endarterectomyfor prevention of focal cerebral ischemic events among pa­tients with asymptomatic carotid stenosis.

APPENDIXMembers of the Mayo Asymptomatic Carotid Endarterec­tomy Study Group are as follows:

Mayo Clinic Rochester-David O. Wiebers, M.D., JackP. Whisnant, M.D., Irene Meissner, M.D., Burton A. San­dok, M.D. (neurologists); ThoralfM. Sundt, Jr., M.D., DavidG. Piepgras, M.D., W. Richard Marsh, M.D., Michael J.Ebersold, M.D., Fredric B. Meyer, M.D. (neurosurgeons);Peter C. Pairolero, M.D., Kenneth J. Cherry, M.D., John W.Hallett, Jr., M.D., Peter Gloviczki, M.D., Thomas C. Bower,M.D. (vascular surgeons); O. Wayne Houser, M.D., Glenn S.Forbes, M.D. (neuroradiologists); E. Meredith James, M.D.(ultrasound radiologist); James H. Chesebro, M.D. (cardi­ologist); Haruo Okazaki, M.D. (neuropathologist); W. Mi­chael O'Fallon, Ph.D. (biostatistician); and Bonnie A. Bar­nett, R.N. (study coordinator).

Mayo Clinic Jacksonville-Steven D. Stein, M.D. (neu­rologist);Robert E. Wharen, Jr., M.D. (neurosurgeon); andW. Andrew Oldenburg, M.D. (vascular surgeon).

Mayo Clinic Scottsdale-J. Clarke Stevens, M.D. (neu­rologist); H. Gordon Deen, Jr., M.D. (neurosurgeon); andWilliam M. Stone, M.D. (vascular surgeon).

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