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Critique of the extracranial-intracranial bypass study
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Surg Neurol 1986;26:218-21
Critique of the Extracranial-Intracranial Bypass Study James I. Ausman, M.D., Ph.D. and Fernando G. Diaz, M.D., Ph.D. Department of Neurological Surgery, Henry Ford Hospital, Detroit, Michigan
Ausman J1, Diaz FG. Critique of the extracranial-intracranial bypass study. Surg Neurol 1986;26:218-21.
The potential benefit of extracranial-intracranial anastomosis was evaluated by a multicenter international co-
operative study headed by the group in London, Ontario, Canada. The final conclusion of the study was that the extracranial-intracranial anastomosis did not provide any benefit over the treatment with aspirin. Several objections and shortcomings have been identified in this study. In our evaluation it cannot be concluded that EC-IC bypass surgery is not effective in reducing stroke in all patient populations. KEY WORDS: Extracranial-intracranial anastomosis; Cerebral revascularization; Cerebral bypass; Superficial temporal artery-middle cerebral artery anastomosis
In 1967 the first superficial temporal artery to middle cerebral artery bypass (STA-MCA) procedure was performed on people [7,32]. The theoretical basis for this operation was to provide extra blood flow to the brain in those patients who were suffering from symptoms related to decreased blood flow from stenosis or occlusion of specific arteries to the brain. This is also known by different names as a cerebral revascularization procedure, a STA-MCA bypass procedure, and an extracranial-intracranial (EC-IC) bypass operation. In 1977, because of the increasing frequency with which this procedure was performed, the National Institute of Neurologic Diseases and Stroke (NINCDS) became interested in performing a randomized trial to test the value of the procedure. At that time several investigators reported that it had benefited patients who were having the warning symptoms of a stroke [4,11,13,14,15,17,25,28,33] and had also diminished the stroke recurrence rate in those patients who had already had a stroke [4,7,11,13,14,25,33]. Because of their experience with multicenter trials, the group in London, Ontario, Canada led by Dr. H e n r y
Address reprint requests to: James 1. Ausman, M.D., Ph.D., Department of Neurological Surgery, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, Michigan 48202.
© 1986 by Elsevier Science Publishing Co., Inc.
Barnett was chosen to develop, direct, and lead this study. Funds were provided for this project. In order to accumulate the number of patients that would be required to do this study, 71 centers around the world were enlisted and over 1400 patients were entered into the study [9]. The hypothesis of the study was to determine whether EC-IC bypass surgery was better than the best medical care in reducing the risk of stroke or stroke-related death in a specifically chosen population of patients evaluated and analyzed according to the methods of the study [19]. The results of the EC-IC Bypass Study were presented at the International Congress of Neurosurgery in T o r o n t o in July 1985, and were published in the N o v e m b e r 7, 1985 issue o f the New EnglandJournal of Medicine [9]. The following conclusions have been drawn by the trial investigators and others: Bypass surgery is no more effective than the best medical care in reducing stroke or stroke-related death; bypass surgery is of no value for revascularization of the brain in patients with atherosclerosis; bypass surgery was shown to be of no value in any of the subgroups of patients entered into the study; and the postoperative angiogram showing "luxuriant perfusion" by the bypass did not prevent future strokes [9,20]. Others have used the trial results to conclude that all funding for this procedure should be terminated [8,23], that it would be irresponsible to operate on any patients without a new randomized trial [8], and it therefore would be malpractice to perform the operation. In contrast, observations by scientists around the world for the past 18 years have demonstrated that after superficial temporal to middle cerebral artery bypass surgery, there is an increasing diameter of the superficial temporal artery [16,27,28,35]; there is increasing filling of the intracranial vessels with time in the same patient [16]; retinal artery perfusion pressure and ischemic retinopathy are improved after bypass surgery to the affected side [28]; cerebral blood flow is improved ipsilateral to the bypass or in both hemispheres by xenon blood flow techniques [2,14,18,24], xenon computed tomography (CT) techniques [34], and PET scanning detection methods [3,18,24]; cerebral oxygenation is improved [3,24] and metabolism is improved; and a reduction of oxygen extraction can occur [24]. Addi0090-3019/86/$3.50
Bypass Study Critique
tional observations indicate that large volumes of flow can occur through the STA [26] and that infarcted brain cannot be revascularized [1]. Also the same operation (STA-MCA anastomosis to cortical vessel) has been utilized for 18 years to increase cerebral perfusion, while evidence exists that with a modification in the operation, increased perfusion or filling will occur with higher volume flows when the anastomosis is made to more proximal vessels [6,19]. The stroke rate after EC-IC bypass surgery in populations selected by investigators with a large experience was 0 - 2 . 5 % per year [5,12,30,31], much less than reported for the EC-IC trial. These observations are disregarded as "anecdotal" and of no value because of the results of the randomized trial [9]. The real question is why the results of the trial differed from those observations of many investigators around the world. Observations of other scientists cannot be disregarded as meaningless; science would require us to explain the reason for the difference between what has been observed in one set of scientific experiences compared to another. There are a number of criticisms of the trial that may help to explain these differences. First, the study was designed to evaluate the surgical procedure in patients who had a presumed blood flow deficit to a portion of the brain that was to be treated by a surgical procedure to improve that deficit. Blood flow technology was not widely available at the beginning of the trial. Entry into the study was determined by detection of a lesion that the participating neurosurgeon thought would "benefit from bypass surgery." There was an outside review of the angiographic data, but the reviewer only verified that the angiogram was readable and that the lesion occurred in the correct region [10]. No criteria for the degree of stenosis was made, although it is well established that greater than 80% stenosis of the cross-sectional vessel lumen is required for reduction of flow. Also, only bilateral carotid angiography was required for the study. Vertebral angiography, which is important in evaluating the total cerebral circulation and understanding the collateral circulation to the brain, was not routinely performed. This would be the same as asking cardiologists and cardiovascular surgeons to evaluate myocardial ischemia by injecting only one coronary vessel. For full evaluation of individuals with cerebral vascular ischemia by today's standards, selective four-vessel angiography is required. In addition, in reports about the trial there was no mention of whether subtraction angiography was required to estimate the actual appearance of the lesion so that a more precise determination of the degree of stenosis could be made. Even without blood flow, four-vessel angiograms, or CT scan results, it can be estimated that at least 37% of patients enrolled in the trial may not have had a blood
Surg Neurol 1986;26:218-21
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flow deficit to the brain and would have no need for the surgery [9]. These were patients with internal carotid artery occlusion who were entered into the study with no further ischemic symptoms since their initial ischemic event. In fact, some centers participating in the trial refused to randomize this type of patient to surgery. For the remaining 21% of the patients with internal carotid artery occlusion and with symptoms, the severity and number of symptoms are not described. Most neurosurgeons accomplished in this therapy today would not treat patients with bypass surgery if the patients had no further symptoms or if they had minimal symptoms. The proponents of the study will argue that it was based on the methods of selection that have been used by neurosurgeons who have published articles on the procedure claiming its benefit [9]. This statement is true but relates to publication of work done over the last 10 years [4,7,11,13,15,17,25,28,33]. It does not reflect the changing practice of those experienced in the procedure who no longer follow the indications upon which this study was initially based, or upon which the initial experience in the literature was reported, because of a better understanding of the problem of stroke and of those patients who could benefit from this procedure. If, in fact, the number of patients selected for the study who would have benefitted from this surgery was small, as is suspected, and the larger remaining number did not have a perfusion deficit as a cause of their problem, the group that would benefit would have been masked by the poor performance of those in the study who were included but did not need the surgery. This group that did not need surgery could have had a comparably worse outcome than their medical counterparts because of the added risk of surgery and postoperative angiography. Thus, according to today's standards, in our opinion, the primary methods of selection of patients for the trial were suboptimal. At the present time the criteria for selection of these patients have matured; now those patients are selected who are clinically unstable and failures of medical therapy with continuing evidence of cerebral ischemia without any systemic cause, with evidence of impaired collateral circulation to the brain by four-vessel cerebral angiography (the study required only two major vessels to be studied), and with confirmatory cerebral blood flow testing, if available. The second major objection is that although those in the study claimed that there was no detectable surgical benefit with a power of 0.98, this high power was achieved by combining smaller groups of patients with different angiographic lesions and possibly different outcomes. In the methodology paper describing the design of the study, five subgroups were identified: internal carotid occlusion, internal carotid siphon stenosis, middle cerebral artery stenosis (MCS), middle cerebral artery occlusion
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(MCO), and tandem lesions. The tandem lesion group represented 1 7 % - 1 9 % of those entered while those with pure MCS and M C O represented 4 % o f the total in each medical and surgical subgroup [10]. In the final paper, those with tandem lesions are merged into the MCS and MCO groups, which have increased to 1 3 % - 1 4 % and to 1 1 % - 1 2 % , respectively [9]. The principal investigators in the study maintain that they have carried out these analyses and searched the data for subgroups in which there was a demonstrably positive effect, but could find none. This result is possible if one searched a large group that contained only a relatively small number of patients who might benefit from the procedure. The trial was not designed with sufficient power in these subgroups to do such testing. For example, using the subgroups as described in the methodology paper [10], with the exception o f isolated ICA occlusion, the probability of reaching a false negative conclusion, that surgery is no better than medical therapy, would range from 0.53 to 0.82 (i.e., power would be 0.47-0.18) because o f the small numbers of patients in these subgroups. As a third objection, it is believed that some of the 71 centers did not contribute all of their eligible patients. Evidence from 2 of 71 centers involved in the study indicate that over 90 patients in those two centers were not included in the study and underwent surgery. The bypass results paper reports only a total of 52 patients from all centers who were operated on outside of the study [9]. An evaluation is now underway to determine if these 90 patients were all eligible for the study and to determine if eligible patients were not randomized at the other 69 centers involved. If this should prove to be a widespread practice, then determining the EC-IC trial's population of inference will be difficult. If those most in need o f surgery were not randomized, then trial results would apply to a more selective subset of patients. (Results of a recent survey of participating centers in the study by two independent sources indicate that over 1000 bypass operations were performed outside the study in N o r t h America at these centers.) The evaluation o f the patient for stroke in the study was based on clinical examination and, "where available," CT scan [9]. The CT scans were not routinely required. T o evaluate a patient in 1986 for cerebral infarction, clinical examination alone is not accurate [21,22,29]. The addition of CT scanning would make the distinction between hemorrhage and infarction, and would also help determine the location of the lesion. Cerebral angiography would determine if the bypass is patent and functioning; emboli might be detected as the cause of the stroke, or other processes may be revealed that had contributed to the infarction. Claims were also made in the study that angiography
Ausman and Diaz
performed after the surgery, even if the filling was luxuriant, did not relate to the successful outcome o f the patient nor did it relate to the prevention of future infarction [9]. Unfortunately, the study was never designed to relate angiographic filling to clinical outcome. T o do this correctly, the angiogram would have to be performed at the time of final clinical assessment, and this was not done in the trial. Furthermore, the assumption was made that a single postoperative angiogram was a reflection of the intracranial filling that was present throughout the patients clinical course. There is ample evidence, through experience with this procedure, that the angiographic filling increases with time [16]. In the trial, only one postoperative angiogram was performed, and could have been taken at any time in the postoperative course. Thus, no conclusions can be drawn regarding the relationship between angiographic filling in the patients in this study and their clinical outcome. The Extracranial-Intracranial Bypass Study, as all studies, must withstand the objective evaluation and criticism of scientists in order to be accepted. As o f this time, there has not been sufficient discussion o f this report and the questions raised in it have not been appropriately answered to satisfy the physicians skilled in its use, i.e., that the procedure is of no value. At the present time it cannot be concluded that EC-IC bypass surgery is not effective in reducing stroke or strokerelated death in all patient populations for the reasons given above. Also, because this trial only involved patients with ischemia to the anterior circulation, no conclusions can be drawn regarding bypass surgery to the vertebral-basilar circulation. Statements indicating that bypass surgery should not be performed for cerebral ischemia, that the procedure should not be paid for by insurance companies, and that it would be malpractice to continue to perform this procedure, are generalizations beyond the data provided by the study. Such statements are only counterproductive in an area in which further investigation must be stimulated and in which an atmosphere of scientific investigation needs to be promoted.
References 1. Ausman JI. Bypass procedures for cerebrovascular disease. In: Moossy J, Reinmuth O, eds. Twelfth research conference on cerebral vascular disease. New York: Raven Press, 1981:255-9. 2. Austin G, LaffinD, Hayward. Microcerebralanastomosis for the prevention of stroke. In: Handa W, ed. Microneurosurgery.Tokyo: Igaku-Shoin, 1975:47-67. 3. BaronJC, Bousser MG, Rey A, Guillard A, Comar O, Castaigne P. Reversal of focal "misery-perfusion syndrome" by extra-intracranial arterial bypassin hemodynamiccerebral ischemia. Stroke 1981;12:454-9.
Bypass Study Critique
4. Chater N. Patient selection and results of extra to intracranial anastomoses in selected cases of cerebrovascular disease. Clin Neurosurg 1976;23:287-309. 5. Chater N. Neurosurgical extracranial-intracranial bypass for stroke with 400 cases. Neurol Res 1983;5:1-9. 6. Diaz FG, Umansky F, Mehta B, Montoya S, Dujovny M, Ausman JI, Cabezudo J. Cerebral revascularization to a main limb of the middle cerebral artery in the Sylvian fissure: an alternative approach to conventional anastomosis. J Neurosurg 1985 ;63:21-9. 7. Donaghy P. Evaluation of extracranial-intracranial blood flow diversion. In: Austin GM, ed. Microneurosurgical anastomoses for cerebral ischemia. Springfield, Ill: CC Thomas, 1976:256-74. 8. Anonymous. Extracranial to intracranial bypass and the prevention of stroke [editorial]. Lancet 1985:1401-2. 9. The EC-IC Bypass Study Group. Failure of extracranialintracranial arterial bypass to reduce the risk of ischemic stroke. N Engl J Med 1985;313:1191-200. 10. The EC-IC Bypass Study Group. The international cooperative study of extracranial-intracranial arterial anastomosis (EC-IC bypass study): methodology and entry characteristics. Stroke 1985;16:397-405. 11. Gratzl O, Schmiedek P, Spetzler R, Steinhoff H, Marguth F. Clinical experience with extra-intracranial arterial anastomosis in 65 cases. J Neurosurg 1976;44:313-24. 12. Gratzl O, Schmiedek P. STA-MCA bypass: results 10 years postoperatively. Neurol Res 1983;5:11-8. 13. Guegan R, Deruty R, Reg A, Lagarrique J. EICA in transient ischemic attacks and neurological deficits. Acta Neurochir 1979; 28(Suppl):304-5. 14. Heilbrun MP, Reichman OH, Anderson RE, Roberts TS. Regional cerebral blood flow studies following superficial temporal-middle cerebral artery anastomosis. J Neurosurg 1975 ;43: 706-16. 15. Holbach KH, Wassmann H. Advantages of using hyperbaric oxygenation in combination with extra-intracranial arterial bypass (EIAB) in the treatment of completed stroke. Acta Neurochir 1979;28(Suppl):309. 16. Latchaw RE, Ausman Jl, Lee MC. Superficial temporal-middle cerebral artery bypass: a detailed analysis of multiple pre- and postoperative angiograms in 40 consecutive patients. J Neurosurg 1979;51:455-65. 17. Lee MC, Ausman JI, Geiger JD, Latchaw RE, Klassen AC, Chou SN, Resch JA. Superficial temporal to middle cerebral artery anastomosis: clinical outcome in patients with ischemia or infarction in internal carotid artery distribution. Arch Neurol 1979;36:1-4. 18. Little JR, Yamamoto YL, Feindel W, Meyer E, Hodge CP. Cerebral blood flow in superficial temporal artery to middle cerebral artery anastomosis. In: Peerless SJ, McCormick CW, eds. Microsurgery for cerebral ischemia. New York: Springer-Verlag, 1980:59-66. 19. Little JR, Furlan AJ, Bryerton B. Short vein grafts for cerebral revascularization. J Neurosurg 1983;59:384-8. 20. McDowell F, Flamm ES. EC-IC bypass study. Stroke 1986;17:1-2. 21. Norris JW, Hachinski VC. Misdiagnosis of stroke. Lancet 1982:328-31. 22. Panzer RJ, Feibel JH, Barker WH, Griner PF. Predicting the likelihood of hemorrhage in patients with stroke. Arch Intern Med 1985;145:1800-3. 23. Plum F" Extracranial-intracranial arterial bypass and cerebral-vascular disease. N Engl J Med 1985;313:1221-3.
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24. Powers WJ, Wayne Martin WR, Herscovitch P, Raichle M, Grubb R Jr. Extracranial-intracranial bypass surgery: hemodynamic and metabolic effects. Neurology 1984;34:1168-74. 25. Reichman OH. Neurosurgical microsurgical anastomosis for cerebral ischemia: five years' experience. In: Scheinberg P, ed. Cerebrovascular disease. 10th Princeton Conference. New York: Raven Press, 1974:311-30. 26. Reichman OH. Estimation of flow through STA-bypass graft. In: FeinJM, Reichman OH, eds. Microvascular anastomoses for cerebral ischemia. New York: Springer-Verlag, 1978:220-40. 27. Samson DS, Boone S. Extracranial-intracranial (EC-IC) arterial bypass: past performance and current concepts. Neurosurgery 1978;3:79-86. 28. Sundt TM, Siekert RG, Sharbrough RW, Houser OW. Bypass surgery for vascular disease of the carotid system. Mayo Clinic Proc 1976;50:677-92. 29. Von Arbin M, Britton M, de Faire V, Helmers C, Miah K, Murray V. Accuracy of bedside diagnosis of stroke. Stroke 1981;12:288-93. 30. Weinstein PR, Rodriguez y Baena R, Chater NL. Results of extracranial-intracranial arterial bypass for intracranial internal carotid artery stenosis: review of 105 cases. Neurosurgery 1984;15:787-94. 31. Whisnant JP, Sundt RM Jr, Fode NC. Long-term mortality and stroke morbidity after superficial temporal artery-middle cerebral artery bypass operation. Mayo Clin Proc 1985;60:241-6. 32. Yasargil MG. In: Yasargil MG, ed. Microsurgery applied to neurosurgery. Stuttgart: Georg Thieme, 1969:105-15. 33. Yasargil MG, Yonekawa Y. Results of microsurgical extra-intracranial arterial bypass in the treatment of cerebral ischemia. Neurosurgery 1977;1:22-4. 34. Yonas H, Cur D, Good BC, Latchaw RE, Wolfson SKJr, Good WF, Maitz GG, Colsher JH, Barnes JE, Colliander KG. Stable xenon CT blood flow mapping for evaluation of patients with extracranial-intracranial bypass surgery. J Neurosurg 1985;62: 324-333. 35. Yonekawa Y, Yasargil MG. Extra-intracranial arterial anastomosis: clinical and technical aspects. Results. In: Advances and technical standards in neurosurgery. 1976;3:47-78. E d i t o r ' s N o t e : This excellent critique was requestedbecause of the authors'preliminary draft which came to the attention of one of the members of the editorial board of SURGICAL NEUROLOGY. On their own initiative, the authors have shortened, modified, and further improved their original contribution. The present critique presents a reasoned and wellorganized commentary on the article by the EC-IC Bypass Study Group, "The International Study of Extracraniallntracranial Arterial Bypass Surgery" (Stroke 1985; 16:3 79-405). Any decision about a surgical procedure for a patient should be predicated on sound scientific data and decided upon by the combinedjudgment of the informed patient and the surgeon. We consider this paper by Dr. Ausman and Dr. Diaz to be an important documentfor neurosurgeons wishing to be informed on the EC-IC bypass debate and to discover the true facts of the matter. E B E N A L E X A N D E R , JR., M.D., Editor
Surg Neurol 1986;26:218-21
Critique of the Extracranial-Intracranial Bypass Study James I. Ausman, M.D., Ph.D. and Fernando G. Diaz, M.D., Ph.D. Department of Neurological Surgery, Henry Ford Hospital, Detroit, Michigan
Ausman J1, Diaz FG. Critique of the extracranial-intracranial bypass study. Surg Neurol 1986;26:218-21.
The potential benefit of extracranial-intracranial anastomosis was evaluated by a multicenter international co-
operative study headed by the group in London, Ontario, Canada. The final conclusion of the study was that the extracranial-intracranial anastomosis did not provide any benefit over the treatment with aspirin. Several objections and shortcomings have been identified in this study. In our evaluation it cannot be concluded that EC-IC bypass surgery is not effective in reducing stroke in all patient populations. KEY WORDS: Extracranial-intracranial anastomosis; Cerebral revascularization; Cerebral bypass; Superficial temporal artery-middle cerebral artery anastomosis
In 1967 the first superficial temporal artery to middle cerebral artery bypass (STA-MCA) procedure was performed on people [7,32]. The theoretical basis for this operation was to provide extra blood flow to the brain in those patients who were suffering from symptoms related to decreased blood flow from stenosis or occlusion of specific arteries to the brain. This is also known by different names as a cerebral revascularization procedure, a STA-MCA bypass procedure, and an extracranial-intracranial (EC-IC) bypass operation. In 1977, because of the increasing frequency with which this procedure was performed, the National Institute of Neurologic Diseases and Stroke (NINCDS) became interested in performing a randomized trial to test the value of the procedure. At that time several investigators reported that it had benefited patients who were having the warning symptoms of a stroke [4,11,13,14,15,17,25,28,33] and had also diminished the stroke recurrence rate in those patients who had already had a stroke [4,7,11,13,14,25,33]. Because of their experience with multicenter trials, the group in London, Ontario, Canada led by Dr. H e n r y
Address reprint requests to: James 1. Ausman, M.D., Ph.D., Department of Neurological Surgery, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, Michigan 48202.
© 1986 by Elsevier Science Publishing Co., Inc.
Barnett was chosen to develop, direct, and lead this study. Funds were provided for this project. In order to accumulate the number of patients that would be required to do this study, 71 centers around the world were enlisted and over 1400 patients were entered into the study [9]. The hypothesis of the study was to determine whether EC-IC bypass surgery was better than the best medical care in reducing the risk of stroke or stroke-related death in a specifically chosen population of patients evaluated and analyzed according to the methods of the study [19]. The results of the EC-IC Bypass Study were presented at the International Congress of Neurosurgery in T o r o n t o in July 1985, and were published in the N o v e m b e r 7, 1985 issue o f the New EnglandJournal of Medicine [9]. The following conclusions have been drawn by the trial investigators and others: Bypass surgery is no more effective than the best medical care in reducing stroke or stroke-related death; bypass surgery is of no value for revascularization of the brain in patients with atherosclerosis; bypass surgery was shown to be of no value in any of the subgroups of patients entered into the study; and the postoperative angiogram showing "luxuriant perfusion" by the bypass did not prevent future strokes [9,20]. Others have used the trial results to conclude that all funding for this procedure should be terminated [8,23], that it would be irresponsible to operate on any patients without a new randomized trial [8], and it therefore would be malpractice to perform the operation. In contrast, observations by scientists around the world for the past 18 years have demonstrated that after superficial temporal to middle cerebral artery bypass surgery, there is an increasing diameter of the superficial temporal artery [16,27,28,35]; there is increasing filling of the intracranial vessels with time in the same patient [16]; retinal artery perfusion pressure and ischemic retinopathy are improved after bypass surgery to the affected side [28]; cerebral blood flow is improved ipsilateral to the bypass or in both hemispheres by xenon blood flow techniques [2,14,18,24], xenon computed tomography (CT) techniques [34], and PET scanning detection methods [3,18,24]; cerebral oxygenation is improved [3,24] and metabolism is improved; and a reduction of oxygen extraction can occur [24]. Addi0090-3019/86/$3.50
Bypass Study Critique
tional observations indicate that large volumes of flow can occur through the STA [26] and that infarcted brain cannot be revascularized [1]. Also the same operation (STA-MCA anastomosis to cortical vessel) has been utilized for 18 years to increase cerebral perfusion, while evidence exists that with a modification in the operation, increased perfusion or filling will occur with higher volume flows when the anastomosis is made to more proximal vessels [6,19]. The stroke rate after EC-IC bypass surgery in populations selected by investigators with a large experience was 0 - 2 . 5 % per year [5,12,30,31], much less than reported for the EC-IC trial. These observations are disregarded as "anecdotal" and of no value because of the results of the randomized trial [9]. The real question is why the results of the trial differed from those observations of many investigators around the world. Observations of other scientists cannot be disregarded as meaningless; science would require us to explain the reason for the difference between what has been observed in one set of scientific experiences compared to another. There are a number of criticisms of the trial that may help to explain these differences. First, the study was designed to evaluate the surgical procedure in patients who had a presumed blood flow deficit to a portion of the brain that was to be treated by a surgical procedure to improve that deficit. Blood flow technology was not widely available at the beginning of the trial. Entry into the study was determined by detection of a lesion that the participating neurosurgeon thought would "benefit from bypass surgery." There was an outside review of the angiographic data, but the reviewer only verified that the angiogram was readable and that the lesion occurred in the correct region [10]. No criteria for the degree of stenosis was made, although it is well established that greater than 80% stenosis of the cross-sectional vessel lumen is required for reduction of flow. Also, only bilateral carotid angiography was required for the study. Vertebral angiography, which is important in evaluating the total cerebral circulation and understanding the collateral circulation to the brain, was not routinely performed. This would be the same as asking cardiologists and cardiovascular surgeons to evaluate myocardial ischemia by injecting only one coronary vessel. For full evaluation of individuals with cerebral vascular ischemia by today's standards, selective four-vessel angiography is required. In addition, in reports about the trial there was no mention of whether subtraction angiography was required to estimate the actual appearance of the lesion so that a more precise determination of the degree of stenosis could be made. Even without blood flow, four-vessel angiograms, or CT scan results, it can be estimated that at least 37% of patients enrolled in the trial may not have had a blood
Surg Neurol 1986;26:218-21
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flow deficit to the brain and would have no need for the surgery [9]. These were patients with internal carotid artery occlusion who were entered into the study with no further ischemic symptoms since their initial ischemic event. In fact, some centers participating in the trial refused to randomize this type of patient to surgery. For the remaining 21% of the patients with internal carotid artery occlusion and with symptoms, the severity and number of symptoms are not described. Most neurosurgeons accomplished in this therapy today would not treat patients with bypass surgery if the patients had no further symptoms or if they had minimal symptoms. The proponents of the study will argue that it was based on the methods of selection that have been used by neurosurgeons who have published articles on the procedure claiming its benefit [9]. This statement is true but relates to publication of work done over the last 10 years [4,7,11,13,15,17,25,28,33]. It does not reflect the changing practice of those experienced in the procedure who no longer follow the indications upon which this study was initially based, or upon which the initial experience in the literature was reported, because of a better understanding of the problem of stroke and of those patients who could benefit from this procedure. If, in fact, the number of patients selected for the study who would have benefitted from this surgery was small, as is suspected, and the larger remaining number did not have a perfusion deficit as a cause of their problem, the group that would benefit would have been masked by the poor performance of those in the study who were included but did not need the surgery. This group that did not need surgery could have had a comparably worse outcome than their medical counterparts because of the added risk of surgery and postoperative angiography. Thus, according to today's standards, in our opinion, the primary methods of selection of patients for the trial were suboptimal. At the present time the criteria for selection of these patients have matured; now those patients are selected who are clinically unstable and failures of medical therapy with continuing evidence of cerebral ischemia without any systemic cause, with evidence of impaired collateral circulation to the brain by four-vessel cerebral angiography (the study required only two major vessels to be studied), and with confirmatory cerebral blood flow testing, if available. The second major objection is that although those in the study claimed that there was no detectable surgical benefit with a power of 0.98, this high power was achieved by combining smaller groups of patients with different angiographic lesions and possibly different outcomes. In the methodology paper describing the design of the study, five subgroups were identified: internal carotid occlusion, internal carotid siphon stenosis, middle cerebral artery stenosis (MCS), middle cerebral artery occlusion
220
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(MCO), and tandem lesions. The tandem lesion group represented 1 7 % - 1 9 % of those entered while those with pure MCS and M C O represented 4 % o f the total in each medical and surgical subgroup [10]. In the final paper, those with tandem lesions are merged into the MCS and MCO groups, which have increased to 1 3 % - 1 4 % and to 1 1 % - 1 2 % , respectively [9]. The principal investigators in the study maintain that they have carried out these analyses and searched the data for subgroups in which there was a demonstrably positive effect, but could find none. This result is possible if one searched a large group that contained only a relatively small number of patients who might benefit from the procedure. The trial was not designed with sufficient power in these subgroups to do such testing. For example, using the subgroups as described in the methodology paper [10], with the exception o f isolated ICA occlusion, the probability of reaching a false negative conclusion, that surgery is no better than medical therapy, would range from 0.53 to 0.82 (i.e., power would be 0.47-0.18) because o f the small numbers of patients in these subgroups. As a third objection, it is believed that some of the 71 centers did not contribute all of their eligible patients. Evidence from 2 of 71 centers involved in the study indicate that over 90 patients in those two centers were not included in the study and underwent surgery. The bypass results paper reports only a total of 52 patients from all centers who were operated on outside of the study [9]. An evaluation is now underway to determine if these 90 patients were all eligible for the study and to determine if eligible patients were not randomized at the other 69 centers involved. If this should prove to be a widespread practice, then determining the EC-IC trial's population of inference will be difficult. If those most in need o f surgery were not randomized, then trial results would apply to a more selective subset of patients. (Results of a recent survey of participating centers in the study by two independent sources indicate that over 1000 bypass operations were performed outside the study in N o r t h America at these centers.) The evaluation o f the patient for stroke in the study was based on clinical examination and, "where available," CT scan [9]. The CT scans were not routinely required. T o evaluate a patient in 1986 for cerebral infarction, clinical examination alone is not accurate [21,22,29]. The addition of CT scanning would make the distinction between hemorrhage and infarction, and would also help determine the location of the lesion. Cerebral angiography would determine if the bypass is patent and functioning; emboli might be detected as the cause of the stroke, or other processes may be revealed that had contributed to the infarction. Claims were also made in the study that angiography
Ausman and Diaz
performed after the surgery, even if the filling was luxuriant, did not relate to the successful outcome o f the patient nor did it relate to the prevention of future infarction [9]. Unfortunately, the study was never designed to relate angiographic filling to clinical outcome. T o do this correctly, the angiogram would have to be performed at the time of final clinical assessment, and this was not done in the trial. Furthermore, the assumption was made that a single postoperative angiogram was a reflection of the intracranial filling that was present throughout the patients clinical course. There is ample evidence, through experience with this procedure, that the angiographic filling increases with time [16]. In the trial, only one postoperative angiogram was performed, and could have been taken at any time in the postoperative course. Thus, no conclusions can be drawn regarding the relationship between angiographic filling in the patients in this study and their clinical outcome. The Extracranial-Intracranial Bypass Study, as all studies, must withstand the objective evaluation and criticism of scientists in order to be accepted. As o f this time, there has not been sufficient discussion o f this report and the questions raised in it have not been appropriately answered to satisfy the physicians skilled in its use, i.e., that the procedure is of no value. At the present time it cannot be concluded that EC-IC bypass surgery is not effective in reducing stroke or strokerelated death in all patient populations for the reasons given above. Also, because this trial only involved patients with ischemia to the anterior circulation, no conclusions can be drawn regarding bypass surgery to the vertebral-basilar circulation. Statements indicating that bypass surgery should not be performed for cerebral ischemia, that the procedure should not be paid for by insurance companies, and that it would be malpractice to continue to perform this procedure, are generalizations beyond the data provided by the study. Such statements are only counterproductive in an area in which further investigation must be stimulated and in which an atmosphere of scientific investigation needs to be promoted.
References 1. Ausman JI. Bypass procedures for cerebrovascular disease. In: Moossy J, Reinmuth O, eds. Twelfth research conference on cerebral vascular disease. New York: Raven Press, 1981:255-9. 2. Austin G, LaffinD, Hayward. Microcerebralanastomosis for the prevention of stroke. In: Handa W, ed. Microneurosurgery.Tokyo: Igaku-Shoin, 1975:47-67. 3. BaronJC, Bousser MG, Rey A, Guillard A, Comar O, Castaigne P. Reversal of focal "misery-perfusion syndrome" by extra-intracranial arterial bypassin hemodynamiccerebral ischemia. Stroke 1981;12:454-9.
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4. Chater N. Patient selection and results of extra to intracranial anastomoses in selected cases of cerebrovascular disease. Clin Neurosurg 1976;23:287-309. 5. Chater N. Neurosurgical extracranial-intracranial bypass for stroke with 400 cases. Neurol Res 1983;5:1-9. 6. Diaz FG, Umansky F, Mehta B, Montoya S, Dujovny M, Ausman JI, Cabezudo J. Cerebral revascularization to a main limb of the middle cerebral artery in the Sylvian fissure: an alternative approach to conventional anastomosis. J Neurosurg 1985 ;63:21-9. 7. Donaghy P. Evaluation of extracranial-intracranial blood flow diversion. In: Austin GM, ed. Microneurosurgical anastomoses for cerebral ischemia. Springfield, Ill: CC Thomas, 1976:256-74. 8. Anonymous. Extracranial to intracranial bypass and the prevention of stroke [editorial]. Lancet 1985:1401-2. 9. The EC-IC Bypass Study Group. Failure of extracranialintracranial arterial bypass to reduce the risk of ischemic stroke. N Engl J Med 1985;313:1191-200. 10. The EC-IC Bypass Study Group. The international cooperative study of extracranial-intracranial arterial anastomosis (EC-IC bypass study): methodology and entry characteristics. Stroke 1985;16:397-405. 11. Gratzl O, Schmiedek P, Spetzler R, Steinhoff H, Marguth F. Clinical experience with extra-intracranial arterial anastomosis in 65 cases. J Neurosurg 1976;44:313-24. 12. Gratzl O, Schmiedek P. STA-MCA bypass: results 10 years postoperatively. Neurol Res 1983;5:11-8. 13. Guegan R, Deruty R, Reg A, Lagarrique J. EICA in transient ischemic attacks and neurological deficits. Acta Neurochir 1979; 28(Suppl):304-5. 14. Heilbrun MP, Reichman OH, Anderson RE, Roberts TS. Regional cerebral blood flow studies following superficial temporal-middle cerebral artery anastomosis. J Neurosurg 1975 ;43: 706-16. 15. Holbach KH, Wassmann H. Advantages of using hyperbaric oxygenation in combination with extra-intracranial arterial bypass (EIAB) in the treatment of completed stroke. Acta Neurochir 1979;28(Suppl):309. 16. Latchaw RE, Ausman Jl, Lee MC. Superficial temporal-middle cerebral artery bypass: a detailed analysis of multiple pre- and postoperative angiograms in 40 consecutive patients. J Neurosurg 1979;51:455-65. 17. Lee MC, Ausman JI, Geiger JD, Latchaw RE, Klassen AC, Chou SN, Resch JA. Superficial temporal to middle cerebral artery anastomosis: clinical outcome in patients with ischemia or infarction in internal carotid artery distribution. Arch Neurol 1979;36:1-4. 18. Little JR, Yamamoto YL, Feindel W, Meyer E, Hodge CP. Cerebral blood flow in superficial temporal artery to middle cerebral artery anastomosis. In: Peerless SJ, McCormick CW, eds. Microsurgery for cerebral ischemia. New York: Springer-Verlag, 1980:59-66. 19. Little JR, Furlan AJ, Bryerton B. Short vein grafts for cerebral revascularization. J Neurosurg 1983;59:384-8. 20. McDowell F, Flamm ES. EC-IC bypass study. Stroke 1986;17:1-2. 21. Norris JW, Hachinski VC. Misdiagnosis of stroke. Lancet 1982:328-31. 22. Panzer RJ, Feibel JH, Barker WH, Griner PF. Predicting the likelihood of hemorrhage in patients with stroke. Arch Intern Med 1985;145:1800-3. 23. Plum F" Extracranial-intracranial arterial bypass and cerebral-vascular disease. N Engl J Med 1985;313:1221-3.
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24. Powers WJ, Wayne Martin WR, Herscovitch P, Raichle M, Grubb R Jr. Extracranial-intracranial bypass surgery: hemodynamic and metabolic effects. Neurology 1984;34:1168-74. 25. Reichman OH. Neurosurgical microsurgical anastomosis for cerebral ischemia: five years' experience. In: Scheinberg P, ed. Cerebrovascular disease. 10th Princeton Conference. New York: Raven Press, 1974:311-30. 26. Reichman OH. Estimation of flow through STA-bypass graft. In: FeinJM, Reichman OH, eds. Microvascular anastomoses for cerebral ischemia. New York: Springer-Verlag, 1978:220-40. 27. Samson DS, Boone S. Extracranial-intracranial (EC-IC) arterial bypass: past performance and current concepts. Neurosurgery 1978;3:79-86. 28. Sundt TM, Siekert RG, Sharbrough RW, Houser OW. Bypass surgery for vascular disease of the carotid system. Mayo Clinic Proc 1976;50:677-92. 29. Von Arbin M, Britton M, de Faire V, Helmers C, Miah K, Murray V. Accuracy of bedside diagnosis of stroke. Stroke 1981;12:288-93. 30. Weinstein PR, Rodriguez y Baena R, Chater NL. Results of extracranial-intracranial arterial bypass for intracranial internal carotid artery stenosis: review of 105 cases. Neurosurgery 1984;15:787-94. 31. Whisnant JP, Sundt RM Jr, Fode NC. Long-term mortality and stroke morbidity after superficial temporal artery-middle cerebral artery bypass operation. Mayo Clin Proc 1985;60:241-6. 32. Yasargil MG. In: Yasargil MG, ed. Microsurgery applied to neurosurgery. Stuttgart: Georg Thieme, 1969:105-15. 33. Yasargil MG, Yonekawa Y. Results of microsurgical extra-intracranial arterial bypass in the treatment of cerebral ischemia. Neurosurgery 1977;1:22-4. 34. Yonas H, Cur D, Good BC, Latchaw RE, Wolfson SKJr, Good WF, Maitz GG, Colsher JH, Barnes JE, Colliander KG. Stable xenon CT blood flow mapping for evaluation of patients with extracranial-intracranial bypass surgery. J Neurosurg 1985;62: 324-333. 35. Yonekawa Y, Yasargil MG. Extra-intracranial arterial anastomosis: clinical and technical aspects. Results. In: Advances and technical standards in neurosurgery. 1976;3:47-78. E d i t o r ' s N o t e : This excellent critique was requestedbecause of the authors'preliminary draft which came to the attention of one of the members of the editorial board of SURGICAL NEUROLOGY. On their own initiative, the authors have shortened, modified, and further improved their original contribution. The present critique presents a reasoned and wellorganized commentary on the article by the EC-IC Bypass Study Group, "The International Study of Extracraniallntracranial Arterial Bypass Surgery" (Stroke 1985; 16:3 79-405). Any decision about a surgical procedure for a patient should be predicated on sound scientific data and decided upon by the combinedjudgment of the informed patient and the surgeon. We consider this paper by Dr. Ausman and Dr. Diaz to be an important documentfor neurosurgeons wishing to be informed on the EC-IC bypass debate and to discover the true facts of the matter. E B E N A L E X A N D E R , JR., M.D., Editor