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Natural history of asymptomatic ulcerative plaques of the carotid bifurcation
Natural History of Asymptomatic Ulcerative Plaques of the Carotid Bifurcation
Timothy R.S. Harward, MD, La Jolla, California John M. Kroener, MD, La Jolla, California lngmar G. Wickbom, MD, La Jolla, California Eugene F. Bernstein, MD, PhD, La Jolla, California
Asymptomatic atherosclerotic disease of the carotid
bifurcation became a controversial problem in clinical management when the initial reports of Thompson et al [l-3] indicated that patients with asymptomatic carotid bruits were at high risk for subsequent stroke. Further information has clarified the situation to some degree in that patients with hemodynamically significant asymptomatic &noses clearly fall into a high-risk group and, in many centers, are considered candidates for elective prophylactic surgery [4-91. However, the significance of asymptomatic nonstenotic ulcerative carotid artery lesions remains to be clarified. The absence of reliable data regarding the natural history of angiographically demonstrated asymptomatic carotid ulcers has resulted in a controversy regarding their appropriate management. In 1978, Moore et al [IO] reported that patients with asymptomatic ulcerative lesions of the carotid artery faced an 87 percent chance of cumulative stroke 7 years after diagnosis. Consequently, they suggested that these patients should be advised to undergo prophylactic carotid endarterectomy. In contrast, Kroener et al [II], following a similar population with 91 carotid ulcers in 79 patients, identified a single stroke in the appropriate cerebral distribution, with a 1 percent cumulative stroke rate after 7 years of life table analysis. On the basis of these data, they concluded that prophylactic carotid surgery in patients with asymptomatic, shallow ulFrom the Departments of Surgery and Radiology, University of California, San Diego, School of Medicine, and Scripps Clinic and Research Foundation, La Jolla, California. Requests for reprints should be addressed to Eugene F. Bernstein. MD, Division of Vascular and Thoracic Surgery, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, California 92037. Presented at the 1 lth Annual Ming of the Society for Clinical Vascular Surgery, Palm Springs, California, March 23-27. 1963.
20%
cerative plaques was not justified. Recently, the question was again brought to light by Dixon et al [12], who described a larger group of patients, combining the University of California, San Francisco series of Moore et al [IO] with additional patients from UCLA. In this combined series, the stroke rate for large and complicated ulcers was quite high, averaging 21 percent for type B ulcers and 19 percent for type C ulcers. The purpose of this presentation is to provide additional follow-up data for the series of patients originally reported by Kroener et al [I 1] by documenting the subsequent course of those patients originally seen at the University of California, San Diego Medical Center, and the Veterans Administration Hospital in La Jolla, California. Material and Methods The angiographic files of the University of California, San Diego Medical Center, and the Veterans Administration Hospital in La Jolla were reviewed for data on all patients who underwent carotid angiography for any indication between January 1972 and June 1979. The charts of those patients for whom the original angiographic report described carotid artery ulceration were reviewed; those patients who underwent operative treatment of the lesion at the time of the angiogram were excluded. Coexisting risk factors and available follow-up data were tabulated. All the angiograms were reexamined by a single experienced cerebrovascular angiographer (IGW), both to confirm the diagnosis of carotid ulceration and to categorize the ulcers according to the type A, B, and C classification first introduced by Gomensoro et al [13] and further refined by Moore et al [IO]. An effort was then made to obtain follow-up information by direct mail, telephone, hospital visits, or contacts with the referring physician or next of kin. If death had occurred, physicians, friends, or relatives were contacted to determine the cause of death and any history of antecedent cerebral symptoms. Descriptions of all cerebrovascular events were documented. The State
The Amertcan Journal of Surgery
Asymptomatic
TABLE
I
Life Table Analysis
of the Development
Ulcerative
Plaques
of Symptoms in Patients With Ulcerative Carotid Artery Plaques Years of Follow-Up
Carotid arteries at risk at start of interval (n) Lost owing to death or end of follow-up (n) Carotid arteries at risk during interval (n) Strokes during interval (n) Appropriate strokes during interval (n) Appropriate TlAs during interval (n) Appropriate stroke rate (%) Interval Cumulative Appropriate symptom rate (%) Interval Cumulative
o-o.5
0.5-l
l-2
2-3
3-4
4-5
5-6
6-7
7-a
90 4 87.5 1 1 1
86 1 85.5 0 0 0
85 5 82.5 2 0 1
80 16 72 1 0 1
64 19 54.5 2 0 2
45 14 38 0 0 0
31 7 27.5 0 0 0
24 18 14.5 1 1 1
6 3 4.5 0 0 0
1.1 1.1
0 1.1
0 1.1
0 1.1
0 1.1
0 1.1
0 1.1
6.9 8
0 8
2.3 2.3
0 2.3
1.2 3.5
1.4 4.8
3.7 8.3
0 8.3
0 8.3
13.8 10.9
0 20.9
TlAs = transient ischemic attacks.
Office of Vital Statistics was contacted regarding death certificates and all autopsy protocols were reviewed. Patients in whom a transient ischemic attack or stroke was identified were classified as symptomatic and continued to be part of the survival analysis. All results were summarized by life table analysis. Using the effective number of patients at risk during each yearly interval, the cumulative stroke rate, cerebrovascular symptom rate (stroke and transient ischemic attack), and survival rates were calculated. These data were then compared with the data previously obtained by Kroener et al [I I], as well as with survival data for an age- and sex-matched general population. Differences between the groups were analyzed for statistical significance by comparing the standard of the mean for each interval using a one-tailed Student’s t test that examined each yearly interval separately. Results Seventy-nine patients with 91 angiographically documented asymptomatic carotid ulcerative plaques were identified. Of this group, 78 patients (98.7 percent) were traced, with a mean follow-up period of 54 months (range 2 to 111 months). In these patients, the initial indication for angiographic study was a transient ischemic attack in the contralateral hemisphere (43 patients), transient ischemic attacks of the posterior circulation (13 patients), an asymptomatic bruit (18 patients), and head trauma or contusion (4 patients). Of the 90 ulcerating lesions followed, 64 were categorized as type A or shallow, smooth single ulcers. Twenty-six were categorized as type B on the basis of a large, obvious excavation. There were no patients in this series with multicavernous, complex type C ulcers. In Table I, data concerning the incidence of transient ischemic attacks and strokes during the period of the follow-up are tabulated. Seven strokes were documented during the study period, but only two of these were anatomically appropriate to the ulcerative lesion under observation. Neither of the two appropriate strokes were fatal. One of them occurred during the first month of follow-up, as previously
Volume 146, August 1983
reported by Kroener et al [I 11. The second occurred during the 84th month of follow-up in a patient who had had a lateralizing transient ischemic attack but refused elective carotid endarterectomy. This patient was therefore continued in the follow-up study group. Transient ischemic attacks were identified in seven subjects, six of whom were in the appropriate anatomic distribution for their ulcerative lesion. Both of the strokes observed during the course of this study were in patients with lesions originally classified as type A ulcers, and live of the six transient ischemic episodes that developed were referrable to lesions originally classified as type A. The cumulative stroke rate from 6 months to 7 years was 1.1 percent by life table analysis (Table I). In the seventh year, because of the second stroke (which followed a prior transient ischemic attack), the cumulative stroke rate increased to 8 percent. The cumulative symptom rate, which includes both transient ischemic attacks and strokes, gradually increased over the period of follow-up to 20.9 percent at 7 years. These data are depicted in Figure 1, in which both the cumulative stroke-free and symptom-free rates are plotted. There were no significant changes in our data and those initially presented by Kroener et al [11] in 1980, which were based on a much shorter period of follow-up. Comparisons between the type A and type B ulcer subgroups also revealed no statistically significant difference. In addition, comparisons of subgroups based on age, sex, and the presence of diabetes or hypertension demonstrated no significant differences regarding either the development of stroke or transient ischemic attack. Data concerning survival are summarized in Table II and Figure 2. Of the 78 patients followed, 29 died. Only one death was secondary to a stroke, and it was in a cerebral distribution inappropriate to the ulcerating plaque. Twelve deaths were secondary to cardiac disease, 10 to neoplastic disease, and 6 to miscellaneous causes. There was no significant difference in survival between those patients with type
209
Harward et al
STROKE-FREE RATE 1998 STROKE-FREE RRTE 1992 SYMPTOM-FREE RATE 1966 SYMPTOM-FREE RATE 1962
F&Wt?7.SbVk8-fI%?and~free
rates In
LENGTH
OF FOLLOW-UP
(MONTHS)
A and those with type B carotid ulcers. The overall survival rate was 61 percent at 5 years and 49 percent at 7 years. When the life table analysis survival curve was compared with the expected survival of the normal population, the difference was statistically significant after the second year (p <0.025) and increased over time (p
TABLE II
nized pathogenic precursor of transient ischemic attacks and stroke. Concern regarding the course of patients with asymptomatic carotid disease was based on the initial experience of Thompson et al [I-3], in which patients were identified because of the presence of a carotid bruit but were not necessarily subjected to angiography. In the experience of Thompson et al [3], the nonoperated asymptomatic patients with carotid bruits had a 17.4 percent incidence of stroke in comparison to a 4.6 percent incidence in those patients who had elective operations. Cooperman et al [16] and Dorazio et al [I 71 each examined other patients with asymptomatic carotid bruits and demonstrated a 15 and 19 percent incidence of stroke, respectively, in unoperated patients over a 7 year follow-up period. These investigators recommended prophylactic carotid endarterectomy for such patients, reasoning that a 2 to 3 percent morbidity and
Life Table Analysis of Survival in Patients With Asymptomatic Carotid Artery Ulceration Patient Data
o-o.5
At risk at beginning of the year (n) Lost owing to length of follow-up (n) At risk for death during interval (n) Dying during interval (n) Interval mortality rate (%) Interval survival rate I % 1 Cumulative survivalir&e’( % )
76 0 76 2 2.6 97.4 97.4
210
patknfs wffh asyn~ptomatk carotM ukers. Data plotted in life table lash/on demonstrate no signffkant change In results with the passage of thne (from 7980 to 1982).
0.5-l 76 0 76 1 1.3 96.7 96.1
l-2 75 0 75 4 5.3 94.7 91.0
Years of Follow-Up 2-3 3-4 4-5 71 7 67.5 7 10.4 69.6 61.6
57 9 52.5 6 11.4 66.6 72.3
42 6 39 6 15.4 64.6 61.1
5-6
6-7
7-6
30 6 26 0 0 100 61.1
22 13 15.5 3 19.4 60.6 49.3
6 3 4.5 0 0 100 49.3
The American Journal of Surgery
Asymptomatic
BE
-
70
-
60
-
20
-
Ulcerative Plaques
RsYw=TanRnc ULCERS PRllENTs
LCEI -
Figure 2. Survival rates in patients with asymptomafic carotid ulcers. Comparison between normal, ageadjusied population curve and the lite tab/e curve demonstrafes a stafisfica/ly aignfficanf increased mortalMy in the stu* population affer 2 years. This dltierence increases with time.
30
-
tla
-
I0
-
0 0
6
I2
mortality rate associated with such surgery was less than the stroke rate associated with nonoperative ‘observation. On the other hand, a number of reports in the literature have advocated conservative therapy for patients with asymptomatic stenotic lesions [18-241, particularly when they have been associated with a successful contralateral carotid endarterectomy [ZO-241. Humphries et al [20] followed a large group of such patients with asymptomatic but hemodynamically significant stenoses in whom a 0.5 percent incidence of stroke without prior warning from transient ischemic attacks was documented. Johnson et al [21] and Levin et al [22,23] also followed similar groups of patients and observed very low stroke rates without warnings from transient ischemic attacks. Finally, Javid et al [24] followed a group of patients in whom the late stroke rate was 4 percent, but the late mortality rate due to cardiac disease was 30 percent. All of these investigators recommended conservative therapy for asymptomatic stenotic lesions because of a relatively low stroke rate which was not preceded by a warning transient ischemic attack, and the high attrition rate due to other cardiovascular lesions in these patients. None of these reports specifically identified asymptomatic ulcerating lesions, and all were based on the angiographic demonstration of hemodynamically significant stenoses. In the most recent report of Dixon et al [12], 136 patients with asymptomatic carotid ulcerative lesions were followed. Seventeen frank strokes were recorded within the first 2 years of follow-up without preceding transient ischemic attacks. In their study, the incidence of stroke was clearly related to the angiographic classification of the ulcer. With type A ulcers the stroke incidence was 0.9 percent per year,
Volume 146, August 1983
16 2’i LENGTH
30
OF
36
42
‘4s
FCILLOW-UP
S-i
60
66
72
76
1 8’-1
CMONTH53
whereas for type B and C lesions it was 4.5 and 7.5 percent per year, respectively. The eventual incidence of stroke was 3 percent for type A lesions, 21 percent for type B lesions, and 19 percent for type C lesions. Dixon et al [12] concluded that both type B and C lesions represent significant threats of future strokes and should be treated by prophylactic carotid endarterectomy. In both the report of Dixon et al [12] and our study, patients with type A ulcerative lesions had a low likelihood of future stroke. In our study there were no patients with type C lesions. Thus, the two studies differ only in their findings regarding type B lesions. In our study none of the 24 patients with type B lesions suffered a stroke, whereas in the report of Dixon et al [12], there were 10 strokes in 54 patients with type B lesions. An analysis of the age, sex, and associated risk factors in the two reports demonstrated no significant difference between the two study groups. However, the initial indications for angiographic study in the report of Dixon et al [12] are not specified, and it is possible that those patients had a generally more advanced disease process than the patients in the present report. In his study of the natural history of carotid artery bifurcation lesions, Javid et al [25] reported a steady increase in size in 62 percent of the carotid atheromonas studied, and an increase of greater than 25 percent per year in a third of the lesions. Since the anatomy of the carotid bifurcation at the time of the stroke event is not known from the study of Dixon et al [12], it is possible that some of those lesions had changed their character dramatically between the time of the original angiographic diagnosis and their neurologic event. The recent work of Lusby et al [26] sheds new light on the pathogenesis of this disease by documenting
211
Harward et al
the frequency with which a neurologic event is associated with the occurrence of subendothelial hemorrhage, and the onset of an ulcerated mound in the carotid artery plaque. Thus, patients in either of these studies treated with anticoagulation or with antiplatelet adhesive agents are at greater risk for the development of a subendothelial hemorrhagic expansion of their carotid lesions. Data regarding the use of such drugs or their correlation with symptom development are not available for either series. The possibility of one series containing a disproportionate number of tandem lesions or diffuse intracerebral disease also may help explain the differences in outcome that have been observed. For these reasons, future studies of this problem should clearly document the initial indication for angiography, the complete cerebrovascular anatomy, and any nonsurgical therapy.
6.
7.
8.
9.
10.
11.
12.
Summary In 79 patients with 91 asymptomatic ulcerating lesions of the carotid bifurcation who were followed an average of 54 months, there were two strokes, one of which was preceded by a warning transient ischemic attack. These data suggest that asymptomatic type A and type B carotid ulcerating lesions do not carry a significant early risk of stroke and do not warrant prophylactic carotid endarterectomy. However, the effect of antiplatelet drugs and anticoagulation in enhancing the development of subintimal hemorrhagic lesions remains uncertain. Further data with serial follow-up, preferably by noninvasive means, will be necessary to define the evolution of asymptomatic ulcerating carotid plaques and eventually permit identification of those lesions that have significant stroke potential.
13.
14. 15. 16. 17. 18.
19. 20.
21.
References 1. Thompson JE, Kartchner MM, Austin DJ, Wheeler CG, Patman RD. Carotid endarterectomy for cerebrovascular insufficiency (stroke): followup of 359 cases. Ann Surg 1966; 163:751-63. 2. Thompson JE, Patman RD. Endarterectomy for asymptomatic carotid bruits. Surg Digest 1972;7:9-14. 3. Thompson JE, Patman RD, Talkington CM. Asymptomatic carotid bruit: long-term outcome of patients having endarterectomy compared with unoperated controls. Ann Surg 1978;188:308-16. 4. Blaisdell FW, Glickman M, Trunkey DD. Ulcerated atheroma of the carotid artery. Arch Surg 1974;108:491-6. 5. Moore WS, Boren C, Malone JM, Goldstone J. Asymptomatic carotid stenosis-immediate and long-term results after
212
22.
23.
24.
25. 26.
prophylactic endarterectomy. Am J Surg 1979; 138:22833. Jarrett F, McHush W. Transient ischemic atacks, asymptomatic bruits, and carotid endarterectomy. JAMA 1978;239: 2027-8. DeWeese JA, Rob CG, Satran R, et al. Endarterectomy for atherosclerotic lesions of the carotid artery. J Cardiovasc Surg 1971;23:299-308. Busuttil RW, Baker JD, Davidson RK, Machleder HI. Carotid artery stenosis-hemodynamic significance and clinical course. JAMA 1981;245:1438-41. Podore PC, DeWeese JA, May AG, Rob CG. Asymptomatic contralateral carotid artery stenosis: a five-year follow-up study following carotid endarterectomy. Surgery 1980;80: 748-52. Moore WS, Clark B, Malone JM, et al. Natural history of nonstenotic, asymptomatic ulcerative lesions of the carotid artery. Arch Surg 1978:113:1352-Q. Kroener JM, Dorn PL, Shoor PM, Wickbom IG, Bernstein EF. Prognosis of asymptomatic ulcerated carotid lesions. Arch Surg 1980;115:1387-92. Dixon S, Pais 0. Raviola C, et al. Natural history of nonstenotic, asymptomatic ulcerative lesions of the carotid artery: a further analysis. Arch Sura 1982:117:1493-8. Gomensoro JB. MaslenikovV, DeBoni JA, et al. Ulcerated atheromatous plaques of the carotid artery bifurcation. Stroke 1973;4:912-6. Fisher CM, Pritchard JE, Mathews WH. Artheriosclerosis of the carotid arteries. Circulation 1952;6:457-65. Julian OC, Dye WS, Javid H, Hunter JA. Ulcerative lesions of the carotid artery bifurcation. Arch Surg 1963;86:803-9. Cooperman M. Martin EW, Evans WE. Significance of asymptomatic carotid bruits. Arch Surg 1978; 113: 1339-40. Dorazio RA, Ezzet F, Nesbitt NJ. Long-term follow-up of asymptomatic carotid bruits. Am J Surg 1980;140:212-3. Brewster DC, Schlaen HH, Raines JK, Abbott WM, Darling C. Rational management of the asymptomatic carotid bruit. Arch Surg 1978;113:927-30. Fields WS. The asymptomatic carotid bruit-operate or not. Stroke 1978;9:269-7 1. Humphries AW, Young JR, Santini PH. Beven EG, DeWolfe VG. Unoperated, asymptomatic significant internal carotid artery stenosis: a review of 182 instances. Surgery 1976;80: 695-8. Johnson N, Burnham SJ, Flanigan DP, et al. Carotid endarterectomy: a followup study ofthe contralateral nonoperated carotid artery. Ann Sura 1978;188:748-52. Levin SM, Sondheimer ?K. Stenosis of the contralateral asymptomatic carotid artery-to operate or not? Vast Surg 1973;7:3-13. Levin SM, Sondheimer FK, Levin JM. The contralateral diseased but asymptomatic carotid artery: to operate or not? An update. Am J Surg 1980;140:203-5. Javid H, Ostermiller WE, Hangesh JW, et al. Carotid endarterectomy for asymptomatic patients. Arch Surg 1971;102: 389-91. Javid H, Ostermiller WE, Hengesh JW, et al. Natural history of carotid bifurcation atheroma. Surgery 1970;67:80-6. Lusby RJ, Ferrell LD, Ehrenfeld WK. Stoney RJ, Wylie EJ. Carotid plaque hemorrhage: its role in production of cerebral ischemia. Arch Surg 1982; 117: 1479-88.
The Amertcan Journal of Surgery
Timothy R.S. Harward, MD, La Jolla, California John M. Kroener, MD, La Jolla, California lngmar G. Wickbom, MD, La Jolla, California Eugene F. Bernstein, MD, PhD, La Jolla, California
Asymptomatic atherosclerotic disease of the carotid
bifurcation became a controversial problem in clinical management when the initial reports of Thompson et al [l-3] indicated that patients with asymptomatic carotid bruits were at high risk for subsequent stroke. Further information has clarified the situation to some degree in that patients with hemodynamically significant asymptomatic &noses clearly fall into a high-risk group and, in many centers, are considered candidates for elective prophylactic surgery [4-91. However, the significance of asymptomatic nonstenotic ulcerative carotid artery lesions remains to be clarified. The absence of reliable data regarding the natural history of angiographically demonstrated asymptomatic carotid ulcers has resulted in a controversy regarding their appropriate management. In 1978, Moore et al [IO] reported that patients with asymptomatic ulcerative lesions of the carotid artery faced an 87 percent chance of cumulative stroke 7 years after diagnosis. Consequently, they suggested that these patients should be advised to undergo prophylactic carotid endarterectomy. In contrast, Kroener et al [II], following a similar population with 91 carotid ulcers in 79 patients, identified a single stroke in the appropriate cerebral distribution, with a 1 percent cumulative stroke rate after 7 years of life table analysis. On the basis of these data, they concluded that prophylactic carotid surgery in patients with asymptomatic, shallow ulFrom the Departments of Surgery and Radiology, University of California, San Diego, School of Medicine, and Scripps Clinic and Research Foundation, La Jolla, California. Requests for reprints should be addressed to Eugene F. Bernstein. MD, Division of Vascular and Thoracic Surgery, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, California 92037. Presented at the 1 lth Annual Ming of the Society for Clinical Vascular Surgery, Palm Springs, California, March 23-27. 1963.
20%
cerative plaques was not justified. Recently, the question was again brought to light by Dixon et al [12], who described a larger group of patients, combining the University of California, San Francisco series of Moore et al [IO] with additional patients from UCLA. In this combined series, the stroke rate for large and complicated ulcers was quite high, averaging 21 percent for type B ulcers and 19 percent for type C ulcers. The purpose of this presentation is to provide additional follow-up data for the series of patients originally reported by Kroener et al [I 1] by documenting the subsequent course of those patients originally seen at the University of California, San Diego Medical Center, and the Veterans Administration Hospital in La Jolla, California. Material and Methods The angiographic files of the University of California, San Diego Medical Center, and the Veterans Administration Hospital in La Jolla were reviewed for data on all patients who underwent carotid angiography for any indication between January 1972 and June 1979. The charts of those patients for whom the original angiographic report described carotid artery ulceration were reviewed; those patients who underwent operative treatment of the lesion at the time of the angiogram were excluded. Coexisting risk factors and available follow-up data were tabulated. All the angiograms were reexamined by a single experienced cerebrovascular angiographer (IGW), both to confirm the diagnosis of carotid ulceration and to categorize the ulcers according to the type A, B, and C classification first introduced by Gomensoro et al [13] and further refined by Moore et al [IO]. An effort was then made to obtain follow-up information by direct mail, telephone, hospital visits, or contacts with the referring physician or next of kin. If death had occurred, physicians, friends, or relatives were contacted to determine the cause of death and any history of antecedent cerebral symptoms. Descriptions of all cerebrovascular events were documented. The State
The Amertcan Journal of Surgery
Asymptomatic
TABLE
I
Life Table Analysis
of the Development
Ulcerative
Plaques
of Symptoms in Patients With Ulcerative Carotid Artery Plaques Years of Follow-Up
Carotid arteries at risk at start of interval (n) Lost owing to death or end of follow-up (n) Carotid arteries at risk during interval (n) Strokes during interval (n) Appropriate strokes during interval (n) Appropriate TlAs during interval (n) Appropriate stroke rate (%) Interval Cumulative Appropriate symptom rate (%) Interval Cumulative
o-o.5
0.5-l
l-2
2-3
3-4
4-5
5-6
6-7
7-a
90 4 87.5 1 1 1
86 1 85.5 0 0 0
85 5 82.5 2 0 1
80 16 72 1 0 1
64 19 54.5 2 0 2
45 14 38 0 0 0
31 7 27.5 0 0 0
24 18 14.5 1 1 1
6 3 4.5 0 0 0
1.1 1.1
0 1.1
0 1.1
0 1.1
0 1.1
0 1.1
0 1.1
6.9 8
0 8
2.3 2.3
0 2.3
1.2 3.5
1.4 4.8
3.7 8.3
0 8.3
0 8.3
13.8 10.9
0 20.9
TlAs = transient ischemic attacks.
Office of Vital Statistics was contacted regarding death certificates and all autopsy protocols were reviewed. Patients in whom a transient ischemic attack or stroke was identified were classified as symptomatic and continued to be part of the survival analysis. All results were summarized by life table analysis. Using the effective number of patients at risk during each yearly interval, the cumulative stroke rate, cerebrovascular symptom rate (stroke and transient ischemic attack), and survival rates were calculated. These data were then compared with the data previously obtained by Kroener et al [I I], as well as with survival data for an age- and sex-matched general population. Differences between the groups were analyzed for statistical significance by comparing the standard of the mean for each interval using a one-tailed Student’s t test that examined each yearly interval separately. Results Seventy-nine patients with 91 angiographically documented asymptomatic carotid ulcerative plaques were identified. Of this group, 78 patients (98.7 percent) were traced, with a mean follow-up period of 54 months (range 2 to 111 months). In these patients, the initial indication for angiographic study was a transient ischemic attack in the contralateral hemisphere (43 patients), transient ischemic attacks of the posterior circulation (13 patients), an asymptomatic bruit (18 patients), and head trauma or contusion (4 patients). Of the 90 ulcerating lesions followed, 64 were categorized as type A or shallow, smooth single ulcers. Twenty-six were categorized as type B on the basis of a large, obvious excavation. There were no patients in this series with multicavernous, complex type C ulcers. In Table I, data concerning the incidence of transient ischemic attacks and strokes during the period of the follow-up are tabulated. Seven strokes were documented during the study period, but only two of these were anatomically appropriate to the ulcerative lesion under observation. Neither of the two appropriate strokes were fatal. One of them occurred during the first month of follow-up, as previously
Volume 146, August 1983
reported by Kroener et al [I 11. The second occurred during the 84th month of follow-up in a patient who had had a lateralizing transient ischemic attack but refused elective carotid endarterectomy. This patient was therefore continued in the follow-up study group. Transient ischemic attacks were identified in seven subjects, six of whom were in the appropriate anatomic distribution for their ulcerative lesion. Both of the strokes observed during the course of this study were in patients with lesions originally classified as type A ulcers, and live of the six transient ischemic episodes that developed were referrable to lesions originally classified as type A. The cumulative stroke rate from 6 months to 7 years was 1.1 percent by life table analysis (Table I). In the seventh year, because of the second stroke (which followed a prior transient ischemic attack), the cumulative stroke rate increased to 8 percent. The cumulative symptom rate, which includes both transient ischemic attacks and strokes, gradually increased over the period of follow-up to 20.9 percent at 7 years. These data are depicted in Figure 1, in which both the cumulative stroke-free and symptom-free rates are plotted. There were no significant changes in our data and those initially presented by Kroener et al [11] in 1980, which were based on a much shorter period of follow-up. Comparisons between the type A and type B ulcer subgroups also revealed no statistically significant difference. In addition, comparisons of subgroups based on age, sex, and the presence of diabetes or hypertension demonstrated no significant differences regarding either the development of stroke or transient ischemic attack. Data concerning survival are summarized in Table II and Figure 2. Of the 78 patients followed, 29 died. Only one death was secondary to a stroke, and it was in a cerebral distribution inappropriate to the ulcerating plaque. Twelve deaths were secondary to cardiac disease, 10 to neoplastic disease, and 6 to miscellaneous causes. There was no significant difference in survival between those patients with type
209
Harward et al
STROKE-FREE RATE 1998 STROKE-FREE RRTE 1992 SYMPTOM-FREE RATE 1966 SYMPTOM-FREE RATE 1962
F&Wt?7.SbVk8-fI%?and~free
rates In
LENGTH
OF FOLLOW-UP
(MONTHS)
A and those with type B carotid ulcers. The overall survival rate was 61 percent at 5 years and 49 percent at 7 years. When the life table analysis survival curve was compared with the expected survival of the normal population, the difference was statistically significant after the second year (p <0.025) and increased over time (p
TABLE II
nized pathogenic precursor of transient ischemic attacks and stroke. Concern regarding the course of patients with asymptomatic carotid disease was based on the initial experience of Thompson et al [I-3], in which patients were identified because of the presence of a carotid bruit but were not necessarily subjected to angiography. In the experience of Thompson et al [3], the nonoperated asymptomatic patients with carotid bruits had a 17.4 percent incidence of stroke in comparison to a 4.6 percent incidence in those patients who had elective operations. Cooperman et al [16] and Dorazio et al [I 71 each examined other patients with asymptomatic carotid bruits and demonstrated a 15 and 19 percent incidence of stroke, respectively, in unoperated patients over a 7 year follow-up period. These investigators recommended prophylactic carotid endarterectomy for such patients, reasoning that a 2 to 3 percent morbidity and
Life Table Analysis of Survival in Patients With Asymptomatic Carotid Artery Ulceration Patient Data
o-o.5
At risk at beginning of the year (n) Lost owing to length of follow-up (n) At risk for death during interval (n) Dying during interval (n) Interval mortality rate (%) Interval survival rate I % 1 Cumulative survivalir&e’( % )
76 0 76 2 2.6 97.4 97.4
210
patknfs wffh asyn~ptomatk carotM ukers. Data plotted in life table lash/on demonstrate no signffkant change In results with the passage of thne (from 7980 to 1982).
0.5-l 76 0 76 1 1.3 96.7 96.1
l-2 75 0 75 4 5.3 94.7 91.0
Years of Follow-Up 2-3 3-4 4-5 71 7 67.5 7 10.4 69.6 61.6
57 9 52.5 6 11.4 66.6 72.3
42 6 39 6 15.4 64.6 61.1
5-6
6-7
7-6
30 6 26 0 0 100 61.1
22 13 15.5 3 19.4 60.6 49.3
6 3 4.5 0 0 100 49.3
The American Journal of Surgery
Asymptomatic
BE
-
70
-
60
-
20
-
Ulcerative Plaques
RsYw=TanRnc ULCERS PRllENTs
LCEI -
Figure 2. Survival rates in patients with asymptomafic carotid ulcers. Comparison between normal, ageadjusied population curve and the lite tab/e curve demonstrafes a stafisfica/ly aignfficanf increased mortalMy in the stu* population affer 2 years. This dltierence increases with time.
30
-
tla
-
I0
-
0 0
6
I2
mortality rate associated with such surgery was less than the stroke rate associated with nonoperative ‘observation. On the other hand, a number of reports in the literature have advocated conservative therapy for patients with asymptomatic stenotic lesions [18-241, particularly when they have been associated with a successful contralateral carotid endarterectomy [ZO-241. Humphries et al [20] followed a large group of such patients with asymptomatic but hemodynamically significant stenoses in whom a 0.5 percent incidence of stroke without prior warning from transient ischemic attacks was documented. Johnson et al [21] and Levin et al [22,23] also followed similar groups of patients and observed very low stroke rates without warnings from transient ischemic attacks. Finally, Javid et al [24] followed a group of patients in whom the late stroke rate was 4 percent, but the late mortality rate due to cardiac disease was 30 percent. All of these investigators recommended conservative therapy for asymptomatic stenotic lesions because of a relatively low stroke rate which was not preceded by a warning transient ischemic attack, and the high attrition rate due to other cardiovascular lesions in these patients. None of these reports specifically identified asymptomatic ulcerating lesions, and all were based on the angiographic demonstration of hemodynamically significant stenoses. In the most recent report of Dixon et al [12], 136 patients with asymptomatic carotid ulcerative lesions were followed. Seventeen frank strokes were recorded within the first 2 years of follow-up without preceding transient ischemic attacks. In their study, the incidence of stroke was clearly related to the angiographic classification of the ulcer. With type A ulcers the stroke incidence was 0.9 percent per year,
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whereas for type B and C lesions it was 4.5 and 7.5 percent per year, respectively. The eventual incidence of stroke was 3 percent for type A lesions, 21 percent for type B lesions, and 19 percent for type C lesions. Dixon et al [12] concluded that both type B and C lesions represent significant threats of future strokes and should be treated by prophylactic carotid endarterectomy. In both the report of Dixon et al [12] and our study, patients with type A ulcerative lesions had a low likelihood of future stroke. In our study there were no patients with type C lesions. Thus, the two studies differ only in their findings regarding type B lesions. In our study none of the 24 patients with type B lesions suffered a stroke, whereas in the report of Dixon et al [12], there were 10 strokes in 54 patients with type B lesions. An analysis of the age, sex, and associated risk factors in the two reports demonstrated no significant difference between the two study groups. However, the initial indications for angiographic study in the report of Dixon et al [12] are not specified, and it is possible that those patients had a generally more advanced disease process than the patients in the present report. In his study of the natural history of carotid artery bifurcation lesions, Javid et al [25] reported a steady increase in size in 62 percent of the carotid atheromonas studied, and an increase of greater than 25 percent per year in a third of the lesions. Since the anatomy of the carotid bifurcation at the time of the stroke event is not known from the study of Dixon et al [12], it is possible that some of those lesions had changed their character dramatically between the time of the original angiographic diagnosis and their neurologic event. The recent work of Lusby et al [26] sheds new light on the pathogenesis of this disease by documenting
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the frequency with which a neurologic event is associated with the occurrence of subendothelial hemorrhage, and the onset of an ulcerated mound in the carotid artery plaque. Thus, patients in either of these studies treated with anticoagulation or with antiplatelet adhesive agents are at greater risk for the development of a subendothelial hemorrhagic expansion of their carotid lesions. Data regarding the use of such drugs or their correlation with symptom development are not available for either series. The possibility of one series containing a disproportionate number of tandem lesions or diffuse intracerebral disease also may help explain the differences in outcome that have been observed. For these reasons, future studies of this problem should clearly document the initial indication for angiography, the complete cerebrovascular anatomy, and any nonsurgical therapy.
6.
7.
8.
9.
10.
11.
12.
Summary In 79 patients with 91 asymptomatic ulcerating lesions of the carotid bifurcation who were followed an average of 54 months, there were two strokes, one of which was preceded by a warning transient ischemic attack. These data suggest that asymptomatic type A and type B carotid ulcerating lesions do not carry a significant early risk of stroke and do not warrant prophylactic carotid endarterectomy. However, the effect of antiplatelet drugs and anticoagulation in enhancing the development of subintimal hemorrhagic lesions remains uncertain. Further data with serial follow-up, preferably by noninvasive means, will be necessary to define the evolution of asymptomatic ulcerating carotid plaques and eventually permit identification of those lesions that have significant stroke potential.
13.
14. 15. 16. 17. 18.
19. 20.
21.
References 1. Thompson JE, Kartchner MM, Austin DJ, Wheeler CG, Patman RD. Carotid endarterectomy for cerebrovascular insufficiency (stroke): followup of 359 cases. Ann Surg 1966; 163:751-63. 2. Thompson JE, Patman RD. Endarterectomy for asymptomatic carotid bruits. Surg Digest 1972;7:9-14. 3. Thompson JE, Patman RD, Talkington CM. Asymptomatic carotid bruit: long-term outcome of patients having endarterectomy compared with unoperated controls. Ann Surg 1978;188:308-16. 4. Blaisdell FW, Glickman M, Trunkey DD. Ulcerated atheroma of the carotid artery. Arch Surg 1974;108:491-6. 5. Moore WS, Boren C, Malone JM, Goldstone J. Asymptomatic carotid stenosis-immediate and long-term results after
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