Randomized clinical trials: W h a t can w e expect? R o b e r t W. H o b s o n , II, M D , Newark, N.J.
The randomized clinical trial (RCT) is a form of clinical analysis that has been used by increasing numbers of medical and surgical investigators during the latter half of this century, Although some surgeons have expressed concerns about the design and rationale of RCTs, the clinical credibility assigned to this clinical investigative method demands that we become more familiar with its format and application to the evaluation of important clinical ~aestions affecting our practices. My interest and use of this clinical investigative technique were initiated through participation in the Planning Committee (Table I) of the Veterans Administration Cooperative Clinical Trial on the Role of Carotid Endarterectomy in Asymptomatic Carotid Stenosis. ~ I am indebted to r_his group for my knowledge of this methodology, which I gained as we worked our way toward the design of a clinical trial that has now completed acquisition of some 450 patients among 10 medical centers. I will confine my remarks to the use of RCTs in this context, however, suggesting the value and importance of such clinical protocol designs in answering other important questions in our specialty. As emphasized by Barnes 2 in his special article last year on investigative clinical trials, clinicians have ~ed both observational and experimental studies as methods of clinical investigation (Table II). Many of us have presented papers at this Society's annual meetings using the methods listed under the observational studies section of Table II. Valuable data have been deldved from cross-sectional studies including case reports and retrospective analyses. Epidemiologic studies have provided information on the incidence of vascular disease in our society and prospective analyses of specific cohorts of patients have defined natural history and suggested improved From the Section of Vascular Surgery, Universityof Medicine and Dentistry of New Jersey, Newark. Presented at the Critical Issues Forum of the Societyfor Vascular Surgery, Los Angeles, Calif., June 3, i990. Reprint requests: Robert W. Hobson, II, MD, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Ave., MSB G-532, Newark, NJ 07103-2757. 24/9/28009
methods of management. However, it is the prospective R C T that studies the efficacy of a particular medical management or surgical procedure. It is characterized by a randomized and unbiased assignment of clinically comparable patients to various treatment categories. Although the methodology does not ensure that this assignment will necessarily be uniform as regards the incidence of clinical variables, it does ensure that the assignment is unbiased. If the principal investigators have selected an appropriate sample size, the clinical risk factors are generally distributed uniformly between the various treatment groups. These studies therefore are "hypothesis testing" as opposed to "hypothesis seeking," and their results characterize the efficacy of one treatment modality in comparison to another alternative. 2 The R C T has been used as a mechanism for clinical investigation by members of this Society in significantly increasing numbers during the 1980s as compared with 1970s. 2 Consistent with this identifiable trend, three important studies that use this methodology are on the Society's 1990 program. Although the results of RCTs inevitably will have greater impact and influence on our clinical practices as compared with observational studies, application of the R C T will continue to be appropriate in only selected instances at individual centers or as part of multicentered trials. In addition, it may be too obvious to emphasize, but for the purposes of this report it should be stated that observational studies will continue to constitute important contributions to our practices and will provide meaningful data in our assessment of surgical management of vascular disease. However, as clinicians continue to use the R C T model more frequently, we should be encouraged to participate as a reflection of our commitment to the performance of excellence in our specialty. Some clinicians have been reluctant to participate because of perceived flaws in the design methodology or perhaps because of concerns over continued justification of a given surgical therapy, However, regardless o f the outcome as far as supporting or refuting a surgical approach to therapy, we need to consider our participation and involvement in these 539
Journal of VASCULAR SURGERY
540 Hobson
Table I. Planning committee: Efficacy of Carotid Endarterectomy For Asymptomatic Carotid Stenosis, VA Clinical Trial (1979-1983) Robert W. Hobson, II, MD (Chairman), University of Medicine and Dentistry of New Jersey, Newark, N.J. and VAMC, East Orange, N.J.; William S. Fields, MD (Consultant Neurologist) University of Texas Health Science Center, Texas; Andrew Gage, MD, University of Buffalo and VAMC, Buffalo, N.Y.; Jerry Goldstone, MD University of California and VAMC, San Francisco, Calif.; Wesley M. Moore, MD, University of California and VAMC, Los Angeles, Calif.; Creighton B. Wright, Universiry of Iowa and VAMC, Iowa City, Iowa (Currently at Cincinnati, Ohio); David G. Weiss, PhD (Biostatistician), Cooperative Studies Program Coordinating Center, Perry Point, Md.
Table II. Types of clinical studies ~ Observational studies Epidemiologic studies Cross-sectional studies Retrospective studies (case control) Prospective studies (cohort) Experimental studies Prospective studies (clinical trials) Uncontrolled studies Controlled studies Nonrandomized Randomized *From: Barnes RW. J VAse Sung 1989;9:609-18.
Modified from Hobson RW. Stroke 1986;17:534-9.
studies, if for no other reason, to avoid being dictated to by other groups, as occurred to the neurosurgical community in the clinical trial regarding efficacy of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. 3 ETHICAL C O N S I D E R A T I O N S Ethical questions concerning participation in RCTs has been discussed in the scientific literature. As reviewed by Levine, 4 Fried, 5 and Freedman, 6 each clinical trial must be based on an ethical presumption that an honest hypothesis can be formulated. If, for example, a surgeon knows that carotid endarterectomy for a given clinical indication is superior to medical management alone, ethics require that he provide his patient with the superior treatment. However, if the clinicians agrees that uncertainty exists regarding the indications for one form of management or the other, a state defined as "equipoise''s'6 exists. Obviously, the clinician must agree that a genuine equipoise exists between the treatment alternatives, if a prospective randomized trial involving separate treatments is to be successful. As outlined by Freedman, 6 some of the problems regarding equipoise relate to its conceptual definition. Shaw and Chalmers r have reported that a clinician who "knows or has a good reason to believe" that one of the treatments is superior may not participate ethically. Furthermore, if the investigator is willing to accept an uncertainty regarding efficacy of treatment modalities, early clinical results from the trial (originally based on genuine equipoise) may unbalance the equipoise and necessitate dismantling of the clinical trial. In an effort to resolve this dilemma for participating clinicians, Freedman 6 has defined "clinical equipoise" as being related to a lack of consensus between expert clinical groups on the
merits of one treatment versus another. In other words, the lack of consensus on the management of asymptomatic and symptomatic carotid stenosis is recognized within the medical community. Cons~"~ quenfly, it becomes clinically ethical to consider participation in such a protocol, even though the individual clinician's body of knowledge suggests a preference for one of the two treatment arms. Principal investigators must simply recognize that qualified and competent colleagues in other specialties wotfld favor the opposite approach. They must also be convinced that the design of the trial will in fact answer a question and address the state of equipoise, so that at the end of the clinical trial the equipoise will be disturbed in favor of one treatment or another. Freedman 6 acknowledges that "clinical equipoise" may be weaker than a position of "theoretical equipoise," which extracts from the investigator the position of nonparticipation if one treatment modality or another is favored. However, the ethics of clinical equipoise seems clear and should b' carefully considered by members of this Society, before declining participation in RCTs because of ethical considerations. As an example, many of us considered that a state of "clinical equipoise" existed in the performance of carotid endarterectomy for asymptomatic carotid stenosis. Conversely, all of us did not agree that clinical equipoise was balanced regarding the efficacy of carotid endarterectomy in the treatment of patients with symptomatic carotid occlusive disease. Consequently, many of us have declined participation in the RCTs regarding the treatment of symptomatic patients. Nevertheless, knowledge of the methodology of RCTs coupled with an appreciation of concepts such as "clinical equipoise" should allow an increasing number of us to understand and perhaps participate in RCTs, as a method of clinical investigation for selected questions in vascular surgery.
Volume 13 Number 4 April 1991
CAROTID OCCLUSIVE DISEASE: D E F I N I N G THE I N D I C A T I O N S F O R CAROTID ENDARTERECTOMY As I outlined, my major involvement has been in the use of the randomized clinical trial model for the investigation of carotid occlusive disease. In an effort to maximize our sample size and to provide a uniform follow-up, a multicentered trial within 10 Veterans Administration hospitals was planned and ultimately approved for initiation of patient randomization in April 1983. Acquisition of some 450 patients to the study was completed in the fall of 1987, and the results of this trial including a mean clinical follow-up of 60 months for the medical and surgical treatment arms is anticipated next year. The Planning Committee perceived that genuine "clinical equipoise" existed in the management of patients with asymptomatic arotid stenosis and justified the performance of this study on the basis of the following important prior and continuing recommendations: "The diversity of reported experience is clear evidence that the question of prophylactic endarterectomy in asymptomatic patients is not answered... We believe that a properly supervised, probably multicentered, randomized prospective study should be undertaken."s "An adequate answer to the question posed in the title of this review (The asymptomatic carotid bruit: Operate or not?) will be forthcoming only when the natural history of asymptomatic carotid artery stenosis is studied and the opportunity provided for evaluating the results of prophylactic operation in alterating this natural history. "9 "A prospective randomized trial comparing the follow-up data on patients undergoing prophylactic endarterectomy with data on those not receiving operation is clearly needed to resolve this question. ''1° '~The results of a surgical versus medical randomized clinical trial, however large and difficult to carry out, should provide the welcome opportunity to sail with the tide or the firm anchor to ride it out. "11 "Justification of prophylactic surgery ultimately requires a randomized trial since a single study purporting to show benefit is obfuscated by non-random selection bias...,,12 This study was also based on the realization that prior attempts at randomized prospective trials on the efficacy of carotid endarterectomy were less than successful in providing conclusive results and recommendations. A major concern about these prior analyses has been the reported high complication rates of operation. The trial reported by Shaw et al) s is frequently commented on by our colleagues in medical specialties. Reported in 1984, the trial was
Randomized clinical trials: W h a t can we expect?
541
initiated in 1965 but was abandoned before its objectives were achieved because of a high complication rate in the surgical group (n = 20, mortality rate, 15% and stroke within 30 days after operation, 25%). Furthermore, the follow-up of this group over subsequent years involved such a small sample size that the lack of a statistically significant result in favor of one treatment or another is not surprising. Survival, which we would not expect to be affected by performance of carotid endarterectomy, was predictably unchanged. However, the reduction in transient ischemic attack (TIA) rate was significant, and when coupled with stroke provided a significant result although these investigators were primarily interested in demonstrating whether or not a reduction in stroke rate alone was detectable. Fields and The Joint Study group ~4 also reported on the randomization of 316 patients who had experienced TEA and had been randomized to carotid endarterectomy or medical management. Unfortunately, significant differences were not demonstrable between the groups based on an analysis of subsequent stroke and/or death. With regard to natural history, Chambers and Norris ~s demonstrated significant differences for patients with high-grade carotid stenosis in terms of combined TIA and stroke rates, particularly in men with associated cardiac disease. Inexplicably, these investigators recommended against operation even though natural history suggested its choice, presumably because of an 11% perioperative complication rate at their institution for carotid endarterectomy. Similarly, prospective studies conducted by Roederer et a1.16 demonstrated that the higher grade stenoses (= 80%) as defined by duplex imaging were associated with a significantly higher TEA and stroke rates, suggesting appropriate use of operation when perioperative complications are acceptably low. Defining the indications for operation by use of the R C T methodology is particularly important at a time when the federal government, third party payers, and clinicians in other specialties are questioning the propriety of our current practice and selection of patients for operation) 6 Clinical outcome analysis was one of the early reasons for the establishment of the American College of Surgeons. Consequently, surgeons can take special pride in the fact that the current Veterans Administration (VA) clinical trial on asymptomatic carotid stenosis was the first to be initiated in this country and was the result of concerns among surgical investigators regarding the efficacy of and indications for carotid endarterectomy.
542
Hobson
WHAT CAN WE EXPECT? Defining the indications for carotid endarterectomy will be the object of clinical investigation during the 1990s. The prospective randomized trials will be of greatest influence because of their rigorous clinical design. Currently, four major trials are underway in North America. The prospective trial on carotid endarterectomy for asymptomatic carotid stenosis as undertaken by the VA group has been reviewed. In addition, the National Institutes of Health has initiated a prospective randomized trial on efficacy of carotid endarterectomy in asymptomatic carotid stenosis under the direction of its principal investigator, Dr, James Toole. 18Although the study's protocol is quite similar to the VA clinical trial, its design provides for a larger sample size and will include both male and female patients, which adds additional significance beyond that anticipated from the VA trial. Both studies will analyze differences in the incidence of TIA and stroke in the two populations. In addition, two important studies are underway in patients with symptomatic carotid occlusive disease, TIA or stroke with minimal deficit. The first study to be initiated is currently under the direction of Barnett et al. 19 as sponsored by the National Institutes of Health, the North American Symptomatic Carotid Endarterectomy Trial (NASCET). The most recent study to be initiated is the Veterans Administration Trial on Symptomatic Carotid Occlusive under the direction of Wilson, Mayberg, and Yatsu. 2° Both studies will evaluate patients with high-grade stenosis and TIA or stroke with minimal deficit who will be randomized to medical management versus carotid endarterectomy. In addition, the NASCET trial will randomize similar patients with lesser stenoses to the two treatment modalities. The difficulty in discussing any of these four trials involves the absence of reported clinical outcome data. Necessarily, the RCT methodology does not allow preliminary reports that then might or might not interfere with clinical follow-up. Consequently, it can be anticipated that these investigators will continue to accm-nulate data until a clinical follow-up of 4 to 5 years has been achieved, or until a statistically significant outcome becomes apparent. Results from the VA Asymptomatic Trial will be available next year, and other results will follow during the subsequent 2 to 5 years. In the final analysis, these results should help us answer the question presented by Warlow, 21 as well as identify subsets of patients who will benefit significantly from operation. In the meantime, our practice should be guided by recent assessments from knowledgeable
Journal of VASCULAR SURGERY
clinicians in vascular surgery, neurosurgery and neurology.2224 Performance of clinical audits on the morbidity and mortality rates of carotid endarterectomy in individual hospitals becomes an important and required surgical obligation. 26 Until data are available from randomized trials, operation can be recommended only by individual surgeons or groups able to accomplish the procedure within prescribed limits for perioperative complications. ='23 Conversely, we recommend against premature changes in the indications for performance of carotid endarterectomy, as has been suggested by recent clinical analyses. It should be recognized that the reported reduction in the number of carotid endarterectomies performed in this country is based on no prospective clinical data and may in fact be limiting application of operation to an important subset of patients, lr Rather than being intimidated to reduce our practic~ of carotid endarterectomy, we should remain firm in our positions regarding the indications for operation provided the procedure can be offered to our patients with low surgical morbidity and mortality rates based on current clinical audits within our hospitals. This current approach seems both ethical and clinically responsible. As the clinical trials are completed during the next 5 years, I am reassured that many members of the Society for Vascular Surgery are participants in these RCTs designed to evaluate the efficacy of carotid endarterectomy. REFERENCES 1. Hobson RW. Role of carotid endarterectomy in asymptomatic carotid stenosis: a Veterans Administration cooperative study. Stroke 1986;17:534-9. 2. Barnes RW. Understanding investigative clinical trials. J VAS~ SURG 1989;9:609-18. 3. Failure ofextracranial-intracranialarterial bypass to reduce the risk ofischemic stroke: the EC/IC bypass study group. N Engl J Med 1985;313:1191-200. 4. Levine RJ. Ethics and regulation of clinical research, 2nd ed. Baltimore: Urban and Schwarzenberg, 1986, 5. Fried C. Medical experimentation: personal integrity and social policy. Amsterdam: North-Holland Publishing, 1974. 6. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141-5. 7. Shaw LW, Chalmers TC. Ethics in cooperative clinical trials. Ann NY Acad Sci 1970;169:487-95. 8. Humphries AW, Young JR, SantiUi PH, Beven EG, deWolfe BG. Asymptomatic significant internal carotid artery stenosis: a review of 182 instances. Surgery 1976;80:695-8. 9. Fields WS. The asymptomatic carotid bruit: operate or not? Stroke 1978;9:264-71. 10. Moore WS, Boren C, Malone JM, Goldstone J. Asymptomatic carotid stenosis: immediate and long-term results after prophylactic endarterectomy. Am J Surg 1979;138:228-33. 11. Mohr JP. Asymptomatic carotid arterydisease. Stroke 1982; 13:431-3.
Volume 13 Number 4 April 1991
12. Yatsu FM, Hart RG. Asymptomatic carotid bnlit and stenosis: reappraisal. Stroke 1983;14:301-4. 13. Shaw DA, Venables GS, Carffidge NEF, Bates D, Dickinson PH. Carotid endarterectomy in patients with transient cerebral ischaemia. [1Neurol Sci 1984;64:45-53. 14. Fields WS, Maslenikov V, Meyer IS, Hass WK, Remington RD, MacdoJnald M. Joint study of extracranial arterial occlusion, V. Progress report of prognosis following surgery or nonsurgical treatment for transient cerebral ischemic attacks and cervical carotid artery lesions. JAMA 1970;211: 1993-2003. 15. Chambers BR, Norris JW. The case against surgery for asymptomatic carotid stenosis. Stroke 1984;15:964-7. 16_ Roederer GO, Langlois YE, Jager KA, et al. The natural history of carotid arterial disease in asymptomatic patients with cervical bruit. Stroke 1984;15:605-13. 17. Pokras R, Dyken ML. Dramatic changes in the performance of endarterecr,omy for disease of the extracranial arteries of the head. Stroke 1988;19:1289-90. 18. ACASS (Asymptomatic Carotid Artery Stenosis Study): a prospective multicenter review of morbidity/mortality in carotid endarterectomies [Abstract]. Stroke 1986;17:146.
Randomized clinical trials: W h a t can we expect?
543
19. Barnett HJM. Carotid endarterectomy: three critical evaluations. North American symptomatic carotid endarterectomy study group. Stroke 1987;18:987-9. 20. Wilson SE, Mayberg MR, Yatsu FM. Defining the indication for carotid endarterectomy. Surgery 1989;104:932-3. 21. Warlow C. Carotid endarterectomy: does it work? Stroke 1984;15:1068-75. 22. Callow AD, Caplan LR, CorreU JW, et al. Carotid endarterectomy: what is its current status? Am J Med 1988;85: 835-8. 23. Beebe HG, Clagett GP, DeWeese JA, et al. Assessing risk associated with carotid endarterectomy. (Special report: AHA stroke council carotid endarterectomy risk). Stroke 1989;20: 314-5. 24. Interim assessment: carotid endarterectomy (Report of the American Academy of Neurology, Therapeutics and Technology Assessment Subcommittee). Neurology 1990;40: 682-3. 25. Thompson JE. Don't throw out the baby with the bath water. J VASC SURG 1986;4:543-6. 26. Hobson RW, Towne J. Carotid endarterectomy for asymptomatic carotid stenosis. Stroke 1989;20:575-6.
The randomized clinical trial (RCT) is a form of clinical analysis that has been used by increasing numbers of medical and surgical investigators during the latter half of this century, Although some surgeons have expressed concerns about the design and rationale of RCTs, the clinical credibility assigned to this clinical investigative method demands that we become more familiar with its format and application to the evaluation of important clinical ~aestions affecting our practices. My interest and use of this clinical investigative technique were initiated through participation in the Planning Committee (Table I) of the Veterans Administration Cooperative Clinical Trial on the Role of Carotid Endarterectomy in Asymptomatic Carotid Stenosis. ~ I am indebted to r_his group for my knowledge of this methodology, which I gained as we worked our way toward the design of a clinical trial that has now completed acquisition of some 450 patients among 10 medical centers. I will confine my remarks to the use of RCTs in this context, however, suggesting the value and importance of such clinical protocol designs in answering other important questions in our specialty. As emphasized by Barnes 2 in his special article last year on investigative clinical trials, clinicians have ~ed both observational and experimental studies as methods of clinical investigation (Table II). Many of us have presented papers at this Society's annual meetings using the methods listed under the observational studies section of Table II. Valuable data have been deldved from cross-sectional studies including case reports and retrospective analyses. Epidemiologic studies have provided information on the incidence of vascular disease in our society and prospective analyses of specific cohorts of patients have defined natural history and suggested improved From the Section of Vascular Surgery, Universityof Medicine and Dentistry of New Jersey, Newark. Presented at the Critical Issues Forum of the Societyfor Vascular Surgery, Los Angeles, Calif., June 3, i990. Reprint requests: Robert W. Hobson, II, MD, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Ave., MSB G-532, Newark, NJ 07103-2757. 24/9/28009
methods of management. However, it is the prospective R C T that studies the efficacy of a particular medical management or surgical procedure. It is characterized by a randomized and unbiased assignment of clinically comparable patients to various treatment categories. Although the methodology does not ensure that this assignment will necessarily be uniform as regards the incidence of clinical variables, it does ensure that the assignment is unbiased. If the principal investigators have selected an appropriate sample size, the clinical risk factors are generally distributed uniformly between the various treatment groups. These studies therefore are "hypothesis testing" as opposed to "hypothesis seeking," and their results characterize the efficacy of one treatment modality in comparison to another alternative. 2 The R C T has been used as a mechanism for clinical investigation by members of this Society in significantly increasing numbers during the 1980s as compared with 1970s. 2 Consistent with this identifiable trend, three important studies that use this methodology are on the Society's 1990 program. Although the results of RCTs inevitably will have greater impact and influence on our clinical practices as compared with observational studies, application of the R C T will continue to be appropriate in only selected instances at individual centers or as part of multicentered trials. In addition, it may be too obvious to emphasize, but for the purposes of this report it should be stated that observational studies will continue to constitute important contributions to our practices and will provide meaningful data in our assessment of surgical management of vascular disease. However, as clinicians continue to use the R C T model more frequently, we should be encouraged to participate as a reflection of our commitment to the performance of excellence in our specialty. Some clinicians have been reluctant to participate because of perceived flaws in the design methodology or perhaps because of concerns over continued justification of a given surgical therapy, However, regardless o f the outcome as far as supporting or refuting a surgical approach to therapy, we need to consider our participation and involvement in these 539
Journal of VASCULAR SURGERY
540 Hobson
Table I. Planning committee: Efficacy of Carotid Endarterectomy For Asymptomatic Carotid Stenosis, VA Clinical Trial (1979-1983) Robert W. Hobson, II, MD (Chairman), University of Medicine and Dentistry of New Jersey, Newark, N.J. and VAMC, East Orange, N.J.; William S. Fields, MD (Consultant Neurologist) University of Texas Health Science Center, Texas; Andrew Gage, MD, University of Buffalo and VAMC, Buffalo, N.Y.; Jerry Goldstone, MD University of California and VAMC, San Francisco, Calif.; Wesley M. Moore, MD, University of California and VAMC, Los Angeles, Calif.; Creighton B. Wright, Universiry of Iowa and VAMC, Iowa City, Iowa (Currently at Cincinnati, Ohio); David G. Weiss, PhD (Biostatistician), Cooperative Studies Program Coordinating Center, Perry Point, Md.
Table II. Types of clinical studies ~ Observational studies Epidemiologic studies Cross-sectional studies Retrospective studies (case control) Prospective studies (cohort) Experimental studies Prospective studies (clinical trials) Uncontrolled studies Controlled studies Nonrandomized Randomized *From: Barnes RW. J VAse Sung 1989;9:609-18.
Modified from Hobson RW. Stroke 1986;17:534-9.
studies, if for no other reason, to avoid being dictated to by other groups, as occurred to the neurosurgical community in the clinical trial regarding efficacy of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. 3 ETHICAL C O N S I D E R A T I O N S Ethical questions concerning participation in RCTs has been discussed in the scientific literature. As reviewed by Levine, 4 Fried, 5 and Freedman, 6 each clinical trial must be based on an ethical presumption that an honest hypothesis can be formulated. If, for example, a surgeon knows that carotid endarterectomy for a given clinical indication is superior to medical management alone, ethics require that he provide his patient with the superior treatment. However, if the clinicians agrees that uncertainty exists regarding the indications for one form of management or the other, a state defined as "equipoise''s'6 exists. Obviously, the clinician must agree that a genuine equipoise exists between the treatment alternatives, if a prospective randomized trial involving separate treatments is to be successful. As outlined by Freedman, 6 some of the problems regarding equipoise relate to its conceptual definition. Shaw and Chalmers r have reported that a clinician who "knows or has a good reason to believe" that one of the treatments is superior may not participate ethically. Furthermore, if the investigator is willing to accept an uncertainty regarding efficacy of treatment modalities, early clinical results from the trial (originally based on genuine equipoise) may unbalance the equipoise and necessitate dismantling of the clinical trial. In an effort to resolve this dilemma for participating clinicians, Freedman 6 has defined "clinical equipoise" as being related to a lack of consensus between expert clinical groups on the
merits of one treatment versus another. In other words, the lack of consensus on the management of asymptomatic and symptomatic carotid stenosis is recognized within the medical community. Cons~"~ quenfly, it becomes clinically ethical to consider participation in such a protocol, even though the individual clinician's body of knowledge suggests a preference for one of the two treatment arms. Principal investigators must simply recognize that qualified and competent colleagues in other specialties wotfld favor the opposite approach. They must also be convinced that the design of the trial will in fact answer a question and address the state of equipoise, so that at the end of the clinical trial the equipoise will be disturbed in favor of one treatment or another. Freedman 6 acknowledges that "clinical equipoise" may be weaker than a position of "theoretical equipoise," which extracts from the investigator the position of nonparticipation if one treatment modality or another is favored. However, the ethics of clinical equipoise seems clear and should b' carefully considered by members of this Society, before declining participation in RCTs because of ethical considerations. As an example, many of us considered that a state of "clinical equipoise" existed in the performance of carotid endarterectomy for asymptomatic carotid stenosis. Conversely, all of us did not agree that clinical equipoise was balanced regarding the efficacy of carotid endarterectomy in the treatment of patients with symptomatic carotid occlusive disease. Consequently, many of us have declined participation in the RCTs regarding the treatment of symptomatic patients. Nevertheless, knowledge of the methodology of RCTs coupled with an appreciation of concepts such as "clinical equipoise" should allow an increasing number of us to understand and perhaps participate in RCTs, as a method of clinical investigation for selected questions in vascular surgery.
Volume 13 Number 4 April 1991
CAROTID OCCLUSIVE DISEASE: D E F I N I N G THE I N D I C A T I O N S F O R CAROTID ENDARTERECTOMY As I outlined, my major involvement has been in the use of the randomized clinical trial model for the investigation of carotid occlusive disease. In an effort to maximize our sample size and to provide a uniform follow-up, a multicentered trial within 10 Veterans Administration hospitals was planned and ultimately approved for initiation of patient randomization in April 1983. Acquisition of some 450 patients to the study was completed in the fall of 1987, and the results of this trial including a mean clinical follow-up of 60 months for the medical and surgical treatment arms is anticipated next year. The Planning Committee perceived that genuine "clinical equipoise" existed in the management of patients with asymptomatic arotid stenosis and justified the performance of this study on the basis of the following important prior and continuing recommendations: "The diversity of reported experience is clear evidence that the question of prophylactic endarterectomy in asymptomatic patients is not answered... We believe that a properly supervised, probably multicentered, randomized prospective study should be undertaken."s "An adequate answer to the question posed in the title of this review (The asymptomatic carotid bruit: Operate or not?) will be forthcoming only when the natural history of asymptomatic carotid artery stenosis is studied and the opportunity provided for evaluating the results of prophylactic operation in alterating this natural history. "9 "A prospective randomized trial comparing the follow-up data on patients undergoing prophylactic endarterectomy with data on those not receiving operation is clearly needed to resolve this question. ''1° '~The results of a surgical versus medical randomized clinical trial, however large and difficult to carry out, should provide the welcome opportunity to sail with the tide or the firm anchor to ride it out. "11 "Justification of prophylactic surgery ultimately requires a randomized trial since a single study purporting to show benefit is obfuscated by non-random selection bias...,,12 This study was also based on the realization that prior attempts at randomized prospective trials on the efficacy of carotid endarterectomy were less than successful in providing conclusive results and recommendations. A major concern about these prior analyses has been the reported high complication rates of operation. The trial reported by Shaw et al) s is frequently commented on by our colleagues in medical specialties. Reported in 1984, the trial was
Randomized clinical trials: W h a t can we expect?
541
initiated in 1965 but was abandoned before its objectives were achieved because of a high complication rate in the surgical group (n = 20, mortality rate, 15% and stroke within 30 days after operation, 25%). Furthermore, the follow-up of this group over subsequent years involved such a small sample size that the lack of a statistically significant result in favor of one treatment or another is not surprising. Survival, which we would not expect to be affected by performance of carotid endarterectomy, was predictably unchanged. However, the reduction in transient ischemic attack (TIA) rate was significant, and when coupled with stroke provided a significant result although these investigators were primarily interested in demonstrating whether or not a reduction in stroke rate alone was detectable. Fields and The Joint Study group ~4 also reported on the randomization of 316 patients who had experienced TEA and had been randomized to carotid endarterectomy or medical management. Unfortunately, significant differences were not demonstrable between the groups based on an analysis of subsequent stroke and/or death. With regard to natural history, Chambers and Norris ~s demonstrated significant differences for patients with high-grade carotid stenosis in terms of combined TIA and stroke rates, particularly in men with associated cardiac disease. Inexplicably, these investigators recommended against operation even though natural history suggested its choice, presumably because of an 11% perioperative complication rate at their institution for carotid endarterectomy. Similarly, prospective studies conducted by Roederer et a1.16 demonstrated that the higher grade stenoses (= 80%) as defined by duplex imaging were associated with a significantly higher TEA and stroke rates, suggesting appropriate use of operation when perioperative complications are acceptably low. Defining the indications for operation by use of the R C T methodology is particularly important at a time when the federal government, third party payers, and clinicians in other specialties are questioning the propriety of our current practice and selection of patients for operation) 6 Clinical outcome analysis was one of the early reasons for the establishment of the American College of Surgeons. Consequently, surgeons can take special pride in the fact that the current Veterans Administration (VA) clinical trial on asymptomatic carotid stenosis was the first to be initiated in this country and was the result of concerns among surgical investigators regarding the efficacy of and indications for carotid endarterectomy.
542
Hobson
WHAT CAN WE EXPECT? Defining the indications for carotid endarterectomy will be the object of clinical investigation during the 1990s. The prospective randomized trials will be of greatest influence because of their rigorous clinical design. Currently, four major trials are underway in North America. The prospective trial on carotid endarterectomy for asymptomatic carotid stenosis as undertaken by the VA group has been reviewed. In addition, the National Institutes of Health has initiated a prospective randomized trial on efficacy of carotid endarterectomy in asymptomatic carotid stenosis under the direction of its principal investigator, Dr, James Toole. 18Although the study's protocol is quite similar to the VA clinical trial, its design provides for a larger sample size and will include both male and female patients, which adds additional significance beyond that anticipated from the VA trial. Both studies will analyze differences in the incidence of TIA and stroke in the two populations. In addition, two important studies are underway in patients with symptomatic carotid occlusive disease, TIA or stroke with minimal deficit. The first study to be initiated is currently under the direction of Barnett et al. 19 as sponsored by the National Institutes of Health, the North American Symptomatic Carotid Endarterectomy Trial (NASCET). The most recent study to be initiated is the Veterans Administration Trial on Symptomatic Carotid Occlusive under the direction of Wilson, Mayberg, and Yatsu. 2° Both studies will evaluate patients with high-grade stenosis and TIA or stroke with minimal deficit who will be randomized to medical management versus carotid endarterectomy. In addition, the NASCET trial will randomize similar patients with lesser stenoses to the two treatment modalities. The difficulty in discussing any of these four trials involves the absence of reported clinical outcome data. Necessarily, the RCT methodology does not allow preliminary reports that then might or might not interfere with clinical follow-up. Consequently, it can be anticipated that these investigators will continue to accm-nulate data until a clinical follow-up of 4 to 5 years has been achieved, or until a statistically significant outcome becomes apparent. Results from the VA Asymptomatic Trial will be available next year, and other results will follow during the subsequent 2 to 5 years. In the final analysis, these results should help us answer the question presented by Warlow, 21 as well as identify subsets of patients who will benefit significantly from operation. In the meantime, our practice should be guided by recent assessments from knowledgeable
Journal of VASCULAR SURGERY
clinicians in vascular surgery, neurosurgery and neurology.2224 Performance of clinical audits on the morbidity and mortality rates of carotid endarterectomy in individual hospitals becomes an important and required surgical obligation. 26 Until data are available from randomized trials, operation can be recommended only by individual surgeons or groups able to accomplish the procedure within prescribed limits for perioperative complications. ='23 Conversely, we recommend against premature changes in the indications for performance of carotid endarterectomy, as has been suggested by recent clinical analyses. It should be recognized that the reported reduction in the number of carotid endarterectomies performed in this country is based on no prospective clinical data and may in fact be limiting application of operation to an important subset of patients, lr Rather than being intimidated to reduce our practic~ of carotid endarterectomy, we should remain firm in our positions regarding the indications for operation provided the procedure can be offered to our patients with low surgical morbidity and mortality rates based on current clinical audits within our hospitals. This current approach seems both ethical and clinically responsible. As the clinical trials are completed during the next 5 years, I am reassured that many members of the Society for Vascular Surgery are participants in these RCTs designed to evaluate the efficacy of carotid endarterectomy. REFERENCES 1. Hobson RW. Role of carotid endarterectomy in asymptomatic carotid stenosis: a Veterans Administration cooperative study. Stroke 1986;17:534-9. 2. Barnes RW. Understanding investigative clinical trials. J VAS~ SURG 1989;9:609-18. 3. Failure ofextracranial-intracranialarterial bypass to reduce the risk ofischemic stroke: the EC/IC bypass study group. N Engl J Med 1985;313:1191-200. 4. Levine RJ. Ethics and regulation of clinical research, 2nd ed. Baltimore: Urban and Schwarzenberg, 1986, 5. Fried C. Medical experimentation: personal integrity and social policy. Amsterdam: North-Holland Publishing, 1974. 6. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141-5. 7. Shaw LW, Chalmers TC. Ethics in cooperative clinical trials. Ann NY Acad Sci 1970;169:487-95. 8. Humphries AW, Young JR, SantiUi PH, Beven EG, deWolfe BG. Asymptomatic significant internal carotid artery stenosis: a review of 182 instances. Surgery 1976;80:695-8. 9. Fields WS. The asymptomatic carotid bruit: operate or not? Stroke 1978;9:264-71. 10. Moore WS, Boren C, Malone JM, Goldstone J. Asymptomatic carotid stenosis: immediate and long-term results after prophylactic endarterectomy. Am J Surg 1979;138:228-33. 11. Mohr JP. Asymptomatic carotid arterydisease. Stroke 1982; 13:431-3.
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12. Yatsu FM, Hart RG. Asymptomatic carotid bnlit and stenosis: reappraisal. Stroke 1983;14:301-4. 13. Shaw DA, Venables GS, Carffidge NEF, Bates D, Dickinson PH. Carotid endarterectomy in patients with transient cerebral ischaemia. [1Neurol Sci 1984;64:45-53. 14. Fields WS, Maslenikov V, Meyer IS, Hass WK, Remington RD, MacdoJnald M. Joint study of extracranial arterial occlusion, V. Progress report of prognosis following surgery or nonsurgical treatment for transient cerebral ischemic attacks and cervical carotid artery lesions. JAMA 1970;211: 1993-2003. 15. Chambers BR, Norris JW. The case against surgery for asymptomatic carotid stenosis. Stroke 1984;15:964-7. 16_ Roederer GO, Langlois YE, Jager KA, et al. The natural history of carotid arterial disease in asymptomatic patients with cervical bruit. Stroke 1984;15:605-13. 17. Pokras R, Dyken ML. Dramatic changes in the performance of endarterecr,omy for disease of the extracranial arteries of the head. Stroke 1988;19:1289-90. 18. ACASS (Asymptomatic Carotid Artery Stenosis Study): a prospective multicenter review of morbidity/mortality in carotid endarterectomies [Abstract]. Stroke 1986;17:146.
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19. Barnett HJM. Carotid endarterectomy: three critical evaluations. North American symptomatic carotid endarterectomy study group. Stroke 1987;18:987-9. 20. Wilson SE, Mayberg MR, Yatsu FM. Defining the indication for carotid endarterectomy. Surgery 1989;104:932-3. 21. Warlow C. Carotid endarterectomy: does it work? Stroke 1984;15:1068-75. 22. Callow AD, Caplan LR, CorreU JW, et al. Carotid endarterectomy: what is its current status? Am J Med 1988;85: 835-8. 23. Beebe HG, Clagett GP, DeWeese JA, et al. Assessing risk associated with carotid endarterectomy. (Special report: AHA stroke council carotid endarterectomy risk). Stroke 1989;20: 314-5. 24. Interim assessment: carotid endarterectomy (Report of the American Academy of Neurology, Therapeutics and Technology Assessment Subcommittee). Neurology 1990;40: 682-3. 25. Thompson JE. Don't throw out the baby with the bath water. J VASC SURG 1986;4:543-6. 26. Hobson RW, Towne J. Carotid endarterectomy for asymptomatic carotid stenosis. Stroke 1989;20:575-6.
