Clinical research and vascular surgery

SPECIAL ARTICLE

Clinical research and vascular surgery C o m p i l e d u n d e r t h e d i r e c t i o n o f t h e Society f o r V a s c u l a r S u r g e r y A d H o c C o m m i t t e e o n Clinical R e s e a r c h *

The need for scientifically sound, clinical investigation in the field of vascular surgery is particularly pressing at this time. The subspecialty of vascular surgery is relatively young, and with any new discipline, innovative treatments and operations are often based on empiricism and a trial and error approach. Pioneering operative strategies in the treatment of vascular disease have characterized the first decades of the field, and it is gratifying that this tradition continues. However, the past decade has witnessed an explosive interest in vascular problems from a number of different disciplines resulting in a multitude of medical and interventional treatments, devices, as well as varied operative approaches for similar disorders. It is no longer sufficient to say that a brilliant operation works; one is compelled to further question how well it works compared with what, and at what cost in terms of morbidity, mortality rates, and dollars? These questions are already being asked by other specialty interests, insurers, politicians, government agencies, and our own patients. Because of these concerns, the Society for Vascular Surgery appointed an ad hoc committee to define the need for clinical research in vascular surgery. The Committee's purpose was twofold: (1) to determine areas in vascular surgery where multiple therapeutic options were most in need of scientific scrutiny, and (2) to recommend approaches to define the best therapeutic option. The first part appeared to be straightforward, to simply define areas lacking scientific support in the practice of vascular surgery. However, it became quickly apparent that incomplete agreement existed on these areas of "ignorance." One expert's opinion on a particular treatment could easily be countered by another's, and both had the backing of ample literature, distinguished adherents, and seasoned experience. To bring objectivity to these deliberations, the Committee used a schema devised by David L. Sackett, MD, who developed "rules of evidence" to be used by expert committees in generating recommendations for clinical management. 1 These rules have been successfully *Society for Vascular Surgery Ad Hoc Committee on Cfinical Research: G. Patrick Clagett, MD, Chairman, Eugene F. Bernstein, MD, Robert W. Hobson, II, MD, Donald D. McIntire, PhD, Statistical Consultant, John M. Porter, MD, Robert ~8. Rutherford, MD, and James S. T. Yao, MD. Reprint requests: Executive Director of the Society for Vascular Surgery, Thirteen Elm St., Manchester, MA 01944. 24/6/36130

applied to the vast literature on antithrombotic agents by experts who were then able to publish an authoritative document recommending appropriate use of these drugs in a wide variety of conditions? The Ad Hoc Committee's approach was somewhat the reverse in that it applied Sackett's rules of evidence to define areas in vascular surgery where firm clinical recommendations could not be made because of the lack of scientific data. In brief, Sackert's approach is to look at the strength or level of the evidence, based on a critical review of available literature, in generating a grade for a clinical recommendation (Table I). Level I evidence is the most scientifically sound, and a treatment backed by this generates a grade A clinical recommendation. Level I evidence is based on randomized clinical trials with low false-positive (a) and low false-negative ([3) errors. Low false-positive (a) error means that the positive effect of an experimental treatment is statistically significant and unlikely to be a chance result. A low false-negative ([3) error (or high power) means that the probability o f not detecting a benefit of an experimental treatment is unlikely. Trials with low ot and J3 errors (high power) are usually large and the results definitive. Conversely, level II trials are frequently small, randomized clinical trials and, accordingly, have high false-positive (a) and/or high-false negative (13) errors (low power). An example of a trial with high a error would be one in which an interesting trend is observed suggesting benefit of a treatment; however, conventional levels of statistical significance are not achieved. The very real possibility exists that the positive result was a "fltlke." A trial with high [3 error (low power) is a false-negative one that concludes that the therapy is not efficacious. Because of small numbers of patients, though, the possibility remains that clinically important benefit exists. Because level II evidence based on such trials is inconclusive, the corresponding grade of recommendation, B, is less. Grade C clinical recommendations are made on the basis of levels III, IV, and V evidence (Table I). Level III evidence comes from nonrandomized studies in which patients who received a particular treatment are compared with a contemporaneous cohort who did not receive the treatment. Level IV data refer to studies in which the group of patients receiving an experimental treatment are compared with a historical control often consisting of former patients from the same institution or from the literature. Finally, level V evidence consists of case series, usually retrospective, with no 867

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T a b l e I. Levels o f evidence and grades o f clinical recommendations Level of evidence

Grade of recommendation

Level I: Large RCTs with definitive results (low (x, 13errors)

Grade A

Level II: Small RCTs with equivocal results (high a, 13errors)

Grade B

Level III: Nonrandomized trial with contemporaneous controls Level IV: Nonrandomized trial with historical controls Level V: Case series, no controls

Grade C

controls. In considering the clinical vascular surgical literature, it is immediately apparent that the bulk is comprised of levels III, IV, and V evidence from which only grade C recommendations can be made. With this rigorous framework to determine clinical areas in vascular surgery most in need of scientific scrutiny, the second purpose of the Committee, to recommend approaches to define the best therapeutic option, would logically involve prospective clinical trials. For most clinical questions, the randomized clinical trial (RCT) provides the most scientifically valid answer. The science of the design and conduct of RCTs is the subject of several texts and articles, a6 The Committee then determined that it would develop a list of RCTs that could and should be done in vascular surgery. To accomplish this, the Ad Hoc Committee divided into subcommittees or task forces (Appendix I) based on major clinical areas within vascular surgery. Each task force was asked to (1) develop a list of ROTs and (2) to show that they were feasible and would provide statistically valid answers to the questions posed. The original list addressed more than 50 major clinical dilemmas that might be answered by RCTs (Appendix 1I). However, the reality of translating these into RCTs proved much more difficult. Major stumbling blocks included lack of precision in end points and their assessment; low end point event rate requiring very large trials; the presence of multiple clinical variables affecting end points and the need to stratify clinical variables; differences in surgical expertise among centers in trials comparing operations; and the possibility of some interventional devices becoming obsolete during the course of a trial. It became apparent that there were

many important clinical questions that could not, at present, be answered by an RCT. In dealing with these issues, the Committee developed the clinical trials that follow. There are some warnings about these trials. First, the list is incomplete. Many more meritorious RCTs exist that could be added that would help to unravel clinical dilemmas in vascular surgery. It is obvious that in any developing field new clinical questions will arise with new developments in technology, disease patterns, and medical and surgical treatment. It would be of interest to compare this list of trials to one developed 10 years from now. Second, the RCT is not always the most efficient scientific method to answer a clinical question. 7 Indeed, some of the studies that follow are not RCTs. Natural history studies and other longitudinal trials can provide important information. As an example, the use of duplex ultrasonography and other noninvasive tests allow precise documentation of disease progression and can define natural history as well as the impact of therapeutic intervention. What follows, then, is a series of proposed trials, mostly KCTs, that are designed to answer clinical questions that face us daily. Although many of these trials require large numbers of patients and would, by necessity, be multicenter in nature, many could be performed in a single center or a few centers. Some would require grant support and would be expensive; others could be undertaken with minimal expense and would require no more than a good noninvasive laboratory and a cooperative and dedicated attitude among participating surgeons. It is gratifying to note that in the time taken by the Ad Hoc Committee to deliberate and to prepare this article, some of the proposed trials have been mounted and are underway or are in the planning stages. G. Patrick Clagett, ME) REFERENCES 1. Sackett DL. l
R O U T I N E VERSUS SELECTIVE CAROTID PATCHING Carotid restenosis ( > 50% diameter reduction) is now known to occur in approximately 10% to 20% of patients undergoing carotid endarterectomy.l9 Although only a few clinical episodes are associated with restenosis, routine

carotid patch angioplasty has been introduced to prevent the phenomenon, l°a6 However, routine patching involves a longer carotid occlusion time, two suture lines in place of one, and the use of a patch material, which may add

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additional complications either immediately or in the future? 7-2° In addition, although routine patching clearly decreases the rate of restenosis, it does not eliminate the complication. Small, single-institution randomized studies addressing this problem have not definitively answered these questions. 16,20 Therefore it would appear appropriate to conduct a large prospective, randomized clinical study to evaluate the effect of routine versus selective carotid patching on both the immediate and long-term outcome after carotid endarterectomy. Significant end points for such a study should include operative mortality and morbidity rates, including the incidence of stroke associated with operation, hematoma, nerve injury, and early reoperation, as well as complications relevant to primary closure or patch graft closure of the arteriotomy, and the development of subsequent carotid restenosis. Restenosis would be assessed by serial duplex ~canning. One unanswered aspect of this investigation relates to the appropriate patch material to be used. It would appear that saphenous vein obtained from the groin area is the most commonly used patch material (although hard data are not available regarding this) and would be the material of choice for the proposed study. The same material should be used throughout the study and for both the routine and selective patch groups. Because the anticipated late morbidity associated with saphenous vein patch disruption, infection, or aneurysm is approximately 1%, for routine patching to be effective the immediate operative morbidity in the routine patch group would have to be 1% less than in the selective group, and the rate of restenosis would have to be decreased by approximately 50%, for example, from 20% to 10% at 1 year. Preliminary calculations based on these assumptions suggest that each arm of this study would have to include approximately 600 patients. Because the rate of restenosis may be higher in women, 16 stratification based on gender may alter sample size estimates.

Eugene F. Bernstein, M D REFERENCES

1. Barnes RW, Nix ML, Nichols BT, Wingo JP. Recurrent versus residual carotid stenosis. Ann Surg 1986;203:652-60. 2. Cossman D, Callow AD, Stein A, Matsumoto G. Early restenosis after carotid endarterectomy. Arch Surg 1978; 113: 275-8. 3. Ouriel K, Green RM. Clinical and technical factors influencing

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recurrent carotid stenosis and occlusion after endarterectomy. J VAsc SURG1987;5:702-6. 4. Thomas M, Otis SM, Rush M, Zyroff J, Dilley RB, Bernstein EF. Recurrent carotid artery stenosis following endarterectomy. Ann Surg 1984;200:74-9. 5. Das MB, Hertzer NR, Ratliff NB, O'Hara PJ, Beven EG. Recurrent carotid stenosis. Ann Surg 1985;202:28-35. 6. Moore WS. Cause and noninvasive detection of restenosis after carotid endarterectomy. Am I Surg 1983;146:29-34. 7. Zierler RE, Bandyk DF, Thiele BL, Strandness DE. Carotid artery stenosis following endarterectomy. Arch Surg 1982; 117:1408-15. 8. Piepgras DG, Sundt TM, Marsh WR, Mussman LA, Fode NC. Recurrent carotid stenosis: results and complications of 57 operations. Ann Surg 1986;203:205-13. 9. Bernstein EF, Torero S, Dilley RB. Does carotid restenosis predict an increased risk of late symptoms, stroke or death? Ann Surg 1990;212:629-36. 10. Archie JP. Prevention of early restenosis and thrombosisocclusion after carotid endarterectomy by saphenous vein patch angioplasty. Stroke 1986;17:901-4. 11. Hertzer NR, Beven EG, O'Hara PJ, Krajewski LP. A prospective study of vein patch angioplasty during carotid endarterectomy. Ann Surg 1987;206:628-34. 12. Stmdt TM Jr., ed. Techniques of carotid endarterectomy. In: Occlusive cerebrovascular disease: diagnosis and surgical management. Philadelphia: WB Saunders, 1987;191:225. 13. Katz MM, Jones GT, Degenhardt J, Gunn B, Wilson J, Katz S. The use of patch angioplasty to alter the incidence of carotid restenosis following thromboendarterectomy. J Cardiovasc Surg 1987;28:2-8. 14. Deriu GP, Ballotia E, Bonavina L, et al. The rationale for patch-graft angioplasty after carotid endarterectomy: early and long-term follow-up. Stroke 1984;15:972-9. 15. Awad IA, Little JR. Patch angioplasty in carotid endarterectomy: advantages, concerns and controversies. Stroke 1989;20:717-22. 16. Eikelboom BC, Ackherstaff RGA, Hoeneveld H, et al. Benefits of carotid patching: a randomized study. J VASC SURG 1988;7:240-6. 17. Motte S, Wantrecht JC, Bellens B, Vincent G, Dereume J-P, Decour C. Infected false aneurysrn following carotid endarterectomy with vein patch angioplasty. J Cardiovasc Surg (Torino) 1987;28:734-6. 18. Curley S, Edwards SS, Jacobs TP. Recurrent carotid stenosis after autologous tissue patching. J VASCSUV,G 1987;6:350-4. 19. Hans SS, Girishkumar H, Hans B. Venous patch grafts and carotid endarterectomy. Arch Surg 1987;122:1134-8. 20. Clagett GP, Patterson CB, Fisher DF Jr, et al. Vein patch versus primary closure for carotid endarterectomy. J VASC St~RG 1989;9:213-23.

S A P H E N O U S V E R S U S P R O S T H E T I C P A T C H MATERIALS F O R CAROTID ENDARTERECTOMY Carotid patch angioplasty has been performed on a selective or routine basis in all large series of carotid endarterectomy. The choice of patch material remains in question. Saphenous vein is the most commonly used

material but has been associated with occasional instances of patch rupture, partioflarly, but not only, when veins from the ankle level have been used. 14 The risk of patch rupture or aneurysm appears to be approximately 1%. 3.5

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On the other hand, prosthetic materials have also been used for patch closure. Most recendy, PTFE patch angioplasty has been u s e d - w i t h no reports o f patch rupture, aneurysm, or infection to date. Bleeding from suture holes has been a problem with PTFE patches, but newer sutures have minimized this difficulty. Thus it appears appropriate to consider a prospective randomized clinical trial of the relative risks and benefits of saphenous vein versus prosthetic (PTFE) patch material for carotid endarterectomy. Among the goals of carotid patch angioplasty is the minimization of postoperative internal carotid thrombosis and restenosis. 615 The research proposal must take into account whether selective or routine carotid patch closure would be performed. Either approach is acceptable, but the approach should be consistent in both arms of the trial. To accumulate data more rapidly, however, it would be expeditious if the trial were carried out in centers where routine patch closure is normally performed. Appropriate end points for this study would include immediate operative morbidity and mortality rates, morbidity associated with obtaining the saphenous vein patch material, the development of late patch complications including rupture, infection, and aneurysm formation, and the subsequent development of carotid restenosis. As in the first study, serial duplex scanning would be used to detect restenosis. Because carotid patch angioplasty has been associated with a decreased but continuing incidence of restenosis in the range of 2% to 10%, it appears likely that a 50% reduction of the restenosis rate, for example, to under 4%, and/or a 50% reduction in operative morbidity rate (including silent internal carotid artery (ICA) thrombosis) would be necessary to demonstrate statistically significant benefits for one patch material over another. In addition, the operative blood loss associated with patch closure should also be measured as a criterion of morbidity. On the basis of these estimates we calculate that it would be likely that at least ~ patients would be necessary in each arm of the study, to document a reduction from a restenosis rate of 8% to one of 4%. As with the first study, stratification based on gender may alter these estimates.

REFERENCES

1. Hertzer NK, Even EG, O'Hara PJ, Krajewski LP. A prospective study of vein patch angioplasty during carotid endarterectomy. Ann Surg 1987;206:628-34. 2. Motte S, Wautrecht JC, Bellens B, Vincent G, Dereume JP, Decour C. Infected false aneurysm following carotid endarterectomy with vein patch angioplasty. J Cardiovasc Surg (Torino) 1987;28:734-6. 3. Imparato AM. The role of patch angioplasty after carotid endarterectomy [Editorial]. J VASCSUV,G 1988;7:715-6. 4. Awad IA, Little JR. Patch angioplasty in carotid endarterectomy: advantages, concerns, and controversies. Stroke 1989;20:417-22. 5. Tawes RL, Treiman RL. Vein patch rupture after carotid endarterectomy. J VAsc SURG(In press). 6. Clagett GP, Patterson CB, Fisher DF Jr, et al. Vein patch versus primary closure for carotid endarterectomy. J VAsc SURG 1989;9:213-23. 7. Archie JP. Prevention of early restenosis and thrombosisocclusion after carotid endarterectomy by saphenous ve~ patch angioplasty. Stroke 1986;17:901-4. 8. Katz MM, Jones GT, Degenhardt J, Gunn B, Wilson J, Katz S. The use of patch angioplasty to alter the incidence of carotid restenosis following thromboendatterectomy. J Cardiovasc Surg (Torino) 1987;28:2-8. 9. Clagett GP, Robinowitz M, Youkey JR, et al. Morphogenesis and clinicopathologic characteristics of recurrent carotid disease. J VASCSUWG1986;3:10-23. 10. Barnes RW, Nix ML, Nichols BT, Wingo JP. Recurrent versus residual carotid stenosis. Ann Surg 1986;203: 652-60. ll. Clagett GP, Rich NM, McDonald PT, et al. Etiologic factors for recurrent carotid artery stenosis. Surgery 1983;93: 313-8. 12. Deriu GP, BaUotia E, Bonavina L, et al. The rationale for patch-graft angioplasty after carotid endarterectomy: early and long-term fol/ow-up. Stroke 1984;15:972-9. 13. Eikelboom BC, Ackherstaff RGA, Hoeneveld H, et al. Benefits of carotid patching: a randomized study. J VAsc SURG 1988;7:240-6. 14. Curley S, Edwards WS, Jacobs TP. Recurrent carotid stenosis after autologous tissue patching. I VASCSUV,G 1987;6: 350-4. 15. Hans SS, Girishkumar H, Hans B. Venous patch grafts and carotid endarterectomy. Arch Surg 1987;122:1134-8.

Eugene F. Bernstein, M_D

STAGED VERSUS SIMULTANEOUS CAROTID ENDARTERECTOMY IN PATIENTS U N D E R G O I N G CARDIAC SURGERY The coexistence of severe coronary and carotid artery disease is not common, but when both are present a significantly increased risk of surgery for either condition results.l-6 Up to 16% of patients with coronary disease have significant carotid stenosis, and 50% of patients with extracranial carotid artery disease have coronary disease. The incidence of myocardial infarction after carotid end-

arterectomy and the incidence of cerebral infarction during and after coronary bypass has stimulated a combined (staged or simultaneous) surgical approach in patients with both significant carotid and coronary disease. 7-17 More than 40 articles have been published about this issue. Advanced coexistent carotid and coronary disease intuitively appears to justify a combined surgical approach

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in some patients, but statistical evidence does not confirm this strategy. In addition, the stroke rate and mortality rates in most published reports of patients undergoing simultaneous carotid-coronary repairs is quite high (average stroke rate is 6.3% and mortality rate is 5.6% in 19 published reports of more than 15 patients). Thus a large prospective, randomized clinical trial comparing staged and simultaneous carotid and coronary operations, and perhaps also comparing isolated single procedures in the same patient groups, appears appropriate. It may be necessary to selectively stratify the patients in each group for single left anterior descending artery (LAD) lesions, double vessel coronary disease, triple vessel coronary disease, unilateral and bilateral carotid stenosis, the presence of coronary symptoms, and the presence of cerebral symptoms. Thus a very large number of patients is likely to be required for statistically valid results, and a multicenter study would be most likely to meet these needs. End points for such a study should include operative mortality rates, cerebrovascular morbidity rates (e.g., operative stroke, both transient and permanent), reoperation (either in the neck or chest), intraoperative myocardial infarction, long-term neurologic events (transient ischemic attack [TIA] or stroke), long-term myocardial infarction, and late death. We estimate that approximately 1000 patients would be required in each arm of the trial for a 50% reduction in stroke and/or mortality rate to reach statistical significance (p < 0.05) with 90% power. Stratification according to the numerous variables already mentioned might alter these sample size estimates. A possible approach would be to mount a smaller study randomizing a subgroup of patients with high-risk carotid (such as symptomatic and high-grade stenoses, bilateral disease) and coronary (such as left main or equivalent disease, unstable angina) conditions. Such a study would increase the frequency of end points and dramatically lower the sample size requirements.

Eugene F. Bernstein, ME) REFERENCES

1. Hart RG, Easton JD. Management of cervical bruits and carotid stenosis in preoperative patients. Stroke 1983;14: 290-7. 2. Breslau PJ, Fell G, Ivey TD, Bailey WW, Miller DW, Strandness DE Jr. Carotid arterial disease in patients undergoing coronary artery bypass operations, J Thorac Cardiovasc Surg 1981;82:765-81.

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3. Turnipseed WD, BerkoffHS, Belzer FO. Postoperative stroke in cardiac and peripheral vascular disease. Ann Surg 1980; 192:365-8. 4. Barnes RW, Liebman PR, Marszalek PB, Kirk CL, Goldman MH. The natural history of asymptomatic carotid disease in patients undergoing cardiovascularsurgery. Surgery 1981;90: 1075-81. 5. Barnes RW, Nix ML, Sansonetti D, Turley DG, Goldman MR. Late outcome of untreated asymptomatic carotid disease following cardiovascular operations. J VAsc SURG 1985;2: 843-8. 6. Brener BJ, Brief DK, Alpert ~, Goldenkranz RJ, Parsonnet V. The risk of stroke in patients with asymptomatic carotid stenosis undergoing cardiac surgery: a follow-up study. J VAsc SURG 1987;5:269-77. 7. Babu SC, Shah PM, Singh BM, Semel L, Clauss R_H, Reed GE. Coexisting carotid stenosis in patients undergoing cardiac surgery: indications and guidelines for simultaneous operations. Am J Surg 1985;150:207-11. 8. Hertzer NR, Loop FD, Taylor PC, Beven EG. Staged and combined surgical approach to simultaneous carotid and coronary vascular disease. Surgery 1978;8:803-11. 9. Hertzer NR, Loop FD, Taylor PC, Beven EG. Combined myocardial revascularization and carotid endarterectomy. J Th0rac Cardiovasc Surg 1983;85:577-89. I0. Hertzer NR, Beven EG, O'Hara PJ, Krajewski LP. A prospective study of vein patch angioplasty during carotid endarterectomy: three-year results for 801 patients and 917 operations. Ann Surg 1987;206:628-35. 11. Hertzer NR, Loop RD, Beven EG, O'Hara H, Krajewski LP. Surgical staging for simultaneous coronary and carotid disease: a study including prospective randomization. ~ VAsc SURG 1989;9:455-63. 12. Perler BA, Burdick JF, Williams GM. The safety of carotid endarterectomy at the time of coronary artery bypass surgery: analysis of results in a high-risk patient populations. J VAsc SUV.G 1985;2:558-62. 13. Emery RW, Cohn LH, Whittemore AD, Maunick JA, Couch NP, Collins JJ Jr. Coexistent carotid and coronary artery disease: surgical management. Arch Snrg 1983;118:1035-8. 14. Jones EL, Craver JM, Michalik RA, et al. Combined carotid and coronary operations: when are they necessary? J Thorac Cardiovasc Surg 1964;87:7-16. 15. Lord RSA, Graham AR, Shanahan MX, et al. Rationale for simultaneous carotid endarterectomy and aortocoronary bypass. Ann Vasc Surg 1986;1:201-6. 16. Mehigan iT, Buch WS, Pipkin RD, Fogarty TJ. A planned approach to coexistent cerebrovascular disease in coronary artery bypass candidates. Arch Surg 1977;112:1403-9. 17. Gardner TJ, Horneffer PJ, Manolio TA, HoffSJ, Pearson TA. Major stroke after coronary artery bypass surgery: changing magnitude of the problem. J VAsc SURG 1986;3:684-94.

S U R G E R Y V E R S U S N O S U R G E R Y F O R 4 T O 5 CM ABDOMINAL AORTIC ANEURYSMS The specific goal of this proposal is to carry out a randomized trial of surgery versus no surgery in asymptomatic patients with small abdominal aortic aneurysms (AAAs) in the size range of 4 to 5 cm. Such patients would

have to be reasonable risks for surgery, so that either surgical or nonsurgical management would be acceptable. The risk of rupture of small AAAs is presently believed to be small. A recent study reported that the risk of rupture

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ofaneurysms less than 5 cm in diameter was 0% at 5 yearsa; whereas another study has suggested that the risk of rupture may be as high as 6% per year even for small AAAs.~ In any case, the natural history of AAAs is for enlargement to occur in due course, and at some point AAAs reach a size at which the risk of death from rupture substantially exceeds the risk of death in elective surgical repair. The "crossover" point is presently unknown, and it may differ for different patients who have varying degrees of risk for surgery. One rationale for repairing small aneurysms in patients who are good risks is that the operation can be done with relative safety; whereas waiting for enlargement to occur may result in higher surgical risk because of aging of the patient and the progression of chronic diseases. The present study is proposed to seek meaningful data regarding the long-term morbidity and mortality results of aggressive versus conservative surgical recommendations. The most important considerations relate to the definition of the study population. Some of the criteria for inclusion seem self-evident; for example, that the patient has no contraindication to surgery and does not pose an unreasonable operative risk. The most difficult problem relates to defining the size acceptable for randomization. Some surgeons might feel that 4 cm is too small, because rupture is rare at this diameter; and others might feel that 5 cm is too large. Nevertheless, a working consensus among the participating surgeons would have to be developed for the study to be feasible. It will also be necessary to develop a reasonable set of assumptions regarding (1) rates of death from operation, (2) rates of death from other causes, and (3) rates of enlargement to predict the proportion of patients initially assigned to the nonsurgical group crossing over into the surgical group at a predefined size or at presentation of symptoms. These issues must be addressed to make reasonable predictions concerning the numbers of patients

that would need to be entered into the trial to reach valid conclusions. The answer to the question addressed by this proposed study is truly unknown. It is an important question, considering that aneurysms are a significant cause of death in North America and that increasing numbers of small aneurysms are being detected by the application of noninvasive imaging techniques. Our Canadian colleagues, under the leadership of William Cole, MD, and with sponsorship of the Medical Research Council, are initiating such a trial; and it is the recommendation of the Ad Hoc Committee on Clinical Research that a United States Trial should be initiated, either independently or in cooperation with the Canadian Trial. M. David Tilson, M D REFERENCES

1. Nevitt MP, Ballard DJ, Hallett JW. Prognosis of abdomi~f aortic aneurysms: a population-based study. N Engl J Med 1989;321:1009-14. 2. Cronenwett JL, Murphy TF, Zelenock GB, et al. Actuarial analysis of variables associated with rupture of small abdominal aortic aneurysms. Surgery 1985;I98:472-83. 3. Johansson G, Nydahl S, Olofsson P, Swedenborg J. Selective management of abdominal aortic aneurysms. Perspect Vasc Surg 1991;4:13-26. 4. Bernstein EF, Dilley RB, Randolph III HF. The improving long-term outlook for patients over 70 years of age with abdominal aortic aneurysms. Ann Surg 1988;207:318-22. 5. Golden MA, Whittemore AD, Donaldson HC, Mannick JA. Selective evaluation and management of coronary artery disease in patients undergoing repair of abdominal aortic aneurysm: a 16-year experience. Ann Surg 1990;212:417-23. 6. Johnston KW. M~ticenter prospective study of non-ruptured abdominal aortic aneurysms. II. Variables predicting morbidity and mortality. J VAsc SURG1989;9:437-47. 7. Collin J. The epidemiology of abdominal aortic aneurysm. Br J Hosp Med 1988;64-5.

P R O P R A N O L O L VERSUS PLACEBO F O R SMALL A B D O M I N A L AORTIC ANEURYSMS Although the morbidity and mortality rates of surgical resection of AAAs have decreased dramatically over the last 3 decades, significant numbers of patients with AAAs are followed conservatively for one or more of several reasons. Patients may be perceived to be prohibitive operative risks, either because of their advanced age or associated chronic disease, or their aneurysm may be so small that the risk of rupture is considered remote. Such patients are usually assessed by serial ultrasound examinations so that an appropriate surgical decision may be made in the event of rapid or significant gradual enlargement. No nonsurgical intervention has been proved to reduce the rate of enlargement or decrease the risk of rupture. Experimental work in two models has suggested that

the natural history of aneurysm enlargement may be modified by propranolol. Propranolol was found to delay the formation of lethal aneurysms in the broad-breasted white turkey model induced with beta-aminoproprionitrile fiamarate (BAPN). 1 This effect was especially interesting, considering that other antihypertensives lacked this protective effect. The authors concluded that the effect of propranolol was independent of its effects on pulse and blood pressure, and they subsequently suggested that there was a direct effect on the crosslinking of matrix proteins. 2 Similar studies of aneurysm development in a spontaneously aneurysm-prone mutant mouse also suggested that the occurrence and enlargement of lesions is delayed. 3 Pharmacologic treatment also resulted in a decrease in the

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solubility of dermal matrix proteins, providing support for the previous suggestion that there might be a direct effect on connective tissue metabolism. 4 Other studies have suggested regulatory effects of the beta-adrenergic system on the production of collagen by fibroblasts cxfltured in vitrO. 5,6

Data about humans on this subject are extremely limited. One small retrospective study suggested that there might be a beneficial effect of beta-blockers on the growth rate of AAAs, based on the infrequence of rapid enlargement among the patients on medication; but the difference in the mean growth rates was not statistically significant. 7 Another study found that patients taking propranolol appeared to have less rapid expansion than did controls as measured by the area of the AAA on CT scanning (0.7 vs 3.7 cm2/yr), but this also did not reach statistical significance. 8 As in the proposal for the study of surgery versus ~,6nsurgery for small AAAs, similar methodologic considerations apply. Decisions must be reached regarding the inclusion and exclusion criteria for acceptance into the study. Stratification for the presence of hypertension might be considered. The size of aneurysms to be accepted for study must be agreed on, and the frequency of follow-up by ultrasonography or CT scanning must be determined. Projected size and duration of the trial must be determined by assumptions regarding growth rate. The advent of screening for AAAs, the aging of the general population, and the increase in general imaging brought about by CT scanning and the more widespread use of ultrasonography have all resulted in a substantial increase in the number of small AAAs known to exist in the

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population. Because the natural history of these lesions is associated with enlargement and eventual risk of death from rupture, the rationale for this proposed trial seems compelling. A/I. David Tilson, 2PI_D

REFERENCES

1. Simpson CF, Kling JIM,Palmer RF, The use ofpropranolol for the protection of turkeys from the development of betaaminoproprionitrile induced aortic rupture. Angiology 1968; 19:414. 2. Boucek RJ, Gunia-Smith Z, Noble NL, Simpson CF. Modulation by propranolol of the lysyl cross-links in aortic elastin and collagen of the aneurysm-prone turkey. Biochem Pharmacol 1983;32:275. 3. Brophy CM, Tilson JE, Tilson MD. Propranolol delays the formation of aneurysms in the male blotchy mouse. J Surg Res 1988;44:687. 4. Brophy CM, Tilson [[E, Tilson MD. Propranolol stimulates the crosslinking of matrix components in skin from the aneurysmprone blotchy mouse. J Surg Res 1989;46:330. 5. Berg RA, Moss J, Baum BJ, Crystal RG. Regulation of collagen production by the beta-adrenergic system. J Clin Invest 1981;17:1457. 6. Lindenschmidt RC, Witschi HP. Propranolol-induced elevation of pulmonary collagen. J Pharmacol Exp Ther 1985;232: 346. 7. Leach SD, Toole AV, Stern N, DeNatale RW, Ti/son MD. Effect of beta-adrenergic blockade on the growth rate of abdominal aortic aneurysms. Arch Surg 1988;123:606. 8. McDaniel MA, Schneider JR. Variables that effect expansion rate and outcome of small abdominal aortic aneurysms. J VASC SURG 1990;11:260-9.

A N T I T H R O M B O T I C THERAPY F O R LOWER EXTREMITY BYPASS The peripheral vascular bypass is an excellent model for evaluating antithrombotic therapy. In contrast to coronary artery bypass grafting (CABG), the primary end point of patency is much easier to define and does not require angiography. In addition, statistical analysis is much simpler because there is only one bypass graft per patient. Despite this, most trials have been carried out in patients undergoing CABG. A recent meta-analysis of 13 trials in patients having CABG concluded that antithrombotic therapy with aspirin is beneficial, particularly if started within 24 hours of surgery.1 Furthermore, a relatively low dose of aspirin (325 mg/day) is equivalent to high-dose aspirin (1 gm/day) in protecting against thrombotic occlusion, and the addition of dipyridamole to aspirin is no better than aspirin alone. Because of the pronounced differences between CABG and peripheral bypasses, these conclusions cannot be directly extrapolated to patients having lower extremity bypass. 2 Five published randomized, prospective trials have

been done of antiplatelet therapy consisting of aspirin plus dipyridamole in patients having lower extremity bypass, s7 Because these trials are small, the possibility of a type I error exists (erroneously concluding that a significant difference is present), or a type II error might exist (erroneously concluding that no significant difference is present). The results of these trials have recently been summarized and suggest that aspirin plus dipyridamole reduces thrombotic occlusion of prosthetic lower extremity bypasses by approximately 50% during the first year after implantation. 8 The recent, large multicenter British trial demonstrated conclusively that no improvement occurred in patency of saphenous vein femoral popliteal bypasses in patients treated with aspirin and dipyridamole. 7 However, treated patients had a significantly lower incidence of myocardial infarction and stroke. As with most other trials of antiplatelet therapy, it is probable that aspirin is the active antithrombotic agent and that dipyridamole is unnecessary. 9 Along with CABG trials, early perioperative antithrombotic therapy appears

874 A d Hoc Committee on Clinical Research

important. In all of the trials showing a beneficial effect, aspirin was begun before operation. These data strongly incriminate early platelet-mediated thrombotic events as being critical to bypass patency, especially for prosthetic bypasses and bypasses to small vessels with limited outflow. 2

Other antithrombotic drugs show promise and might be useful in improving bypass patency. Ticlopidine is a potent antiplatelet agent that interferes with fibrinogen binding to platelet membrane glycoprotein receptors (GPIIb/IIIa receptor complex). Although fundamentally different from aspirin in its mechanism of action, riclopidine shares with aspirin the property of inhibiting platelets for their lifespan after a single exposure to the drug. A recent trial in patients with symptomatic atherosclerotic cerebral vascular disease showed that ticlopidine was superior to aspirin in preventing stroke. ~° In addition to its antithrombotic effect, ticlopidine has been shown in randomized trials of patients with intermittent c!audication to significantly improve symptomatic and hemodynamic end points. 11 These properties make this an ideal agent to test in patients having lower extremity bypass. Because aspirin and ticlopidine work by separate mechanisms, it would be of great interest to combine these agents in a clinical trial testing the hypothesis that their combined antiplatelet activities are summative. Warfarin is another antithrombotic agent that holds promise in patients having lower extremity bypass. Although warfarin has no direct antiplatelet activity, it may dramatically affect platelet-mediated thrombotic events by retarding the generation of thrombin at sites of vascular injury. Recent experimental evidence in models of deep arterial injury 12 and prosthetic-surface interactions is suggest that thrombin is a critical factor in the formation of occlusive platelet thrombi. A single, small randomized, controlled trial showed that warfarin reduced significantly the incidence of thrombotic occlusion of reversed saphenous femoral-popliteal bypasses by approximately 50% after a mean follow-up of 30 months.14 In a separate report of this trial continued for a longer period, the investigators reported a significant reduction in deaths among bypass patients treated with warfarin, is A theoretically attractive antithrombotic regimen would be to combine warfarin and aspirin to retard thrombin generation and to directly inhibit platelets. This potent combination has not been used dinically because of the fear of bleeding complications. Despite this, reports exist of studies of this combination in patients with prosthetic heart valves, 16 cerebral vascular disease] 7 and prosthetic lower extremity bypasses. 18 A large clinical experience is also reported that shows that dosage and intensity of warfarin and aspirin can be carefully controlled to minimize bleeding complications. In randomized trials in patients with deep vein thrombosis and in patients with tissue and mechanical prosthetic heart valves, low-intensity warfarin (prothrombin time controlled at 1.3 to 1.5 times control) has significantly fewer bleeding complications and equivalent antithromboembolic effectiveness in compari-

Journal of VASCULAR SURGERY

son with standard, high-intensity warfarin (prothrombin time controlled at 1.5 to 2.0 times control). 192~ It has also been shown that relatively low-dose aspirin (80 to 325 mg/day) has significantly fewer gastrotoxic side effects, including gastrointestinal bleeding, than high-dose aspirin (1 gm/day) with no loss in antiplatelet, cyclooxygenaseinhibition. 22,23These data suggest that low-intensity warfarin combined with low-dose aspirin might offer superior antithrombotic effectiveness with a minimum of hemorrhagic side effects. The background information cited above provides the rationale for at least two major randomized trials in patients undergoing lower extremity bypass. In the first, low-dose aspirin (80 to 325 mg/day) would be compared with low-dose aspirin plus low-intensity warfarin (prothrombin time 1.3 to 1.5 times control). Aspirin should be given before operation in both groups and warfarin therapy should be initiated in the postoperative period. This trial would have to be open (unblinded) because of the need to monitor and adjust warfarin dosage to tightly control the prothrombin time within the specified range. The second trial would compare low-dose aspirin (80 to 325 mg/day) to low-dose aspirin plus ticlopidine (500 mg/day). This trial could be blinded, but all patients would require periodic monitoring of white blood cell counts because of the 1% incidence of severe, reversible neutropenia that can be caused by ticlopidine. For any trial invoMng lower extremity bypass, randomization should be stratified to ensure comparability of groups on the basis of known factors that might influence patency. These factors would include indication for bypass (intermittent claudication [IC] or limb-threatening ischemia), material for bypass (prosthesis or vein), and site of bypass (above-knee popliteal, below-knee popliteal, and distal). Also, the definitions and standards recommended by the SVS/ISCVS Ad Hoc Committee on Reporting Standards should be used. 24 Follow-up for all patients should extend for at least 2 years. The major end point for analysis would be primary patency. Secondary end points would include secondary patency rates, bleeding complications (with strict definition of major and minor events), amputation, and death. Because the mechanisms of occlusion are different for prosthetic and vein bypasses, 2 primary patency should be determined for each type of bypass. On the basis of published results, one can expect a 2 to 3 year primary patency with aspirin treatment alone to be 50% to 60% for prosthetic bypasses (assumes no distal prosthetic bypasses) and 70% to 80% for vein bypasses. 25'26If one considers a i5% improvement in patency rate with additional drug therapy to be clinically important and expected, at least 400 patients with prosthetic bypasses and 450 patients with vein bypasses would have to be randomized. These numbers may be adjusted upward or downward depending on the difference in patency rates that one expects between treatment groups (the greater the difference to be detected, the fewer the number of patients will be required). For a trim of this size, one should also anticipate a 10% to 15%

Volume 15 Number 5 May 1992

loss o f patients or dropout rate and proportionally increase the number of randomized patients. Thus to detect a 15% difference in primary patency rates between treatments for vein and prosthetic bypasses, a single trial would have to include approximately 1000 patients. This would obviously be a large undertaking and, the study would have to take place at several institutions.

Clinical research and vascular surgery 875

14.

15.

G. Patrick Clagett, AriD REFERENCES

1. Henderson WG, Goldman S, Copeland JG, Moritz TE, Harker LA. Antiplatelet or anticoagulant therapy after coronary artery bypass surgery. Ann Intern Med 1989;111:74350. 2. Clagett GP. Antithrombotic therapy and vascular surgery. Semin Vase Snrg 1988;1:216-27. 3. Green RM, Roedersheimer I~,,DeWeese JA. Effects ofaspitin and dipyridamole on expanded polytetrafluoroethylene graft patency. Surgery 1982;92:1016-26. 4 . Goldman M, Hall C, Dykes J, et al. Does ~nindium-platelet deposition predict patency in prosthetic arterial grafts? Br J Surg 1983;70:635-8. 5. Kohler TR, Kaufman JL, Kacoyanis G, et al. Effect of aspirin and dipyridamole on the patency of lower extremity bypass grafts. Surgery 1984;96:462-6. 6. Clyne CAC, Archer TJ, Atnhalre LK, et al. Random control trial of a short course of aspirin and dipyridamole (Persantin) for femorodistal grafts. Br J Surg 1987;74:246-8. 7. McCollum C, Alexander C, Kenchington G, et al. Antiplatelet drugs in femoropopliteal vein bypasses: a multicenter trial. J VAsc SURG 1991;13:150-62. 8. Clagett GP, Genton E, Salzman EW. Antithrombotic therapy in peripheral vascular disease. Chest 1989;95:128S-39S. 9. Antiplatelet trialists' collaboration: secondary prevention of vascular disease by prolonged antiplatelet treatment. BMJ 1988;296:320-33. 10. Hass WK, Easton JD, Adams HP Jr, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989;321:501-7. 11. Balsano F, Coccheri S, Libretti A, et al. Ticlopidine in the treatment of intermittent claudication: a 21-month doubleblind trial. J Lab Clin Med 1989;114:84-91. 12. Heras M, Chesebro JH, Penny WJ, Bailey KR, Badimon L, Fuster V. Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs. Ciroalation 1989;79:657-65. 13. Hanson SR, Harker LA. Interruption of acute plateletdependent thrombosis by the synthetic antithrombin

16.

17.

18.

19. 20.

21.

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23, 24.

25.

26.

D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone. Proc Nail Acad Sci 1988;85:3184-8. Kretschmer G, Wenzl E, Piza E, et al. The influence of anticoagulant treatment on the probability of function in femoropopliteal vein bypass surgery: analysis of a clinical series (1970 to 1985) and interim evaluation of a controlled clinical trial. Surgery 1987;102:453-9. Kretschmer G, Schemper M, Ehringer H, et al. Influence of postoperative anticoagulant treatment on patient survival after femoropopliteal vein bypass surgery. Lancet 1988;1:797. Chesebro JI-I, Fuster V, Elveback LR, et al. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol 1983;51:1537-41. Miller A, Lees RS. Simultaneous therapy with antiptatelet and anticoagulant drugs in symptomatic cardiovascular disease. Stroke 1985;16:668-75. Flynn WR, Baxter BT, Bergman RT, et al. Prospective assessment of antithrombotic therapy following primary below-knee prosthetic bypass. Presented at the Forty-fourth Annual Meeting of the Society for Vascular Surgery; June 1990; Los Angeles, CA. Hull R, Hirsh J, Ray R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982;307:1676-81. Turpie AGG, Gunstensen J, Hirsh J, Nelson H, Gent M. Randomized comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988;1:1242-5. Saour JN, Sleek JO, Mamo LAR, Gallns AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990;322:428-32. UK-TIA Study Group: United Kingdom transient ischemic attack (UK-TIA) aspirin trial: interim results. BMJ 1988;296: 316-20. Hirsh J, Salzman EW, Harker L, et al. Aspirin and other platelet active drugs. Chest 1989;95:12S-8S. Rutherford RB, Flanigan DP, Gupta SK, et al. Suggested standards for reports dealing with lower extremity ischemia. Prepared by the Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery/North American Chapter, International Society for Cardio~vascularSurgery. J VASCSUt~G 1986;4: 80-94. Bergan JJ, Veith FJ, Bernhard VM, et al. Randomization of autogenous vein and polytetrafluoroethylene grafts in femorodistal reconstruction. Surgery 1982;92:921-30. Veterans Administration Cooperative Study Group 141. Comparative evaluation of prosthetic, reversed, and in situ vein bypass grafts in distal popliteal and tibial-peroneal revascularization. Arch Surg 1988;123:434-8.

EFFECT OF ANESTHETIC T E C H N I Q U E O N OUTCOME AFTER A B D O M I N A L AORTIC SURGERY Controversy exists concerning the benefit o f regional anesthesia and postoperative regional analgesia in patients undergoing vascular surgery. Advantages o f these techniques are reported as a decrease in the neuroendocrine "stress" response to surgery, improved postoperative pul-

monary fimction, better control of the hyperdynamic cardiovascular response to surgical stimuli, and encouragement of earlier a m b u l a t i o n Y However, not all studies have demonstrated a benefit from the use of regional anesthetic and analgesic techniques. 8-10

876 A d Hoc Committee on Clinical Research

Table I. Four treatment groups resulting from a combination o f techniques Group

1 2 3 4

Intraoperative anesthesia

General General General + regional General + regional

Postoperative analgesia

Systemic Regional Systemic Regional

CLinicalstudies have shown that intraoperative regional anesthesia combined with postoperative regional analgesia may reduce the incidence of intraoperative myocardial ischemia and postoperative congestive heart failure, s# The explanation for these observations is probably related to better control of the determinants of myocardial oxygen consumption,6,n-13 decreased mean arterial pressure, 6,14 decreased postoperative requirement for vasodilator therapy, 6,1s,16 and decreased postoperative adrenergic tone. 6 The potentially unique advantages of regional anesthetic and analgesic techniques are related to the fact that drug administration is continuous and is initiated before (prophylaxis) and during (protection) operation, and can be maintained after operation. Regional techniques have the advantage of providing intense analgesia with relatively few systemic side effects. However, some studies of regional anesthesia have demonstrated that uncontrolled reductions in blood pressure may result in myocardial ischemia. 17 In addition, the reduction in myocardial oxygen demand that is observed implies a reduction in myocardial performance with potentially impaired peripheral oxygen delivery, l° Postoperative pulmonary function may also be favorably affected by the use of regional anesthesia and analgesia. These techniques result in less impairment of postoperative vital capacity and peak flow rates and improved diaphragmatic function) 8'19 It is also possible that the use of postoperative regional analgesia serves to avoid the side effects of systemic narcotic administration, especially sedation and hypoxia. 2° In several studies this has resulted in a reduction in the incidence of postoperative pulmonary complications (either pneumonia or atelectasis). 2'4's On the basis of current information, a need exists to study the effect of different intraoperative anesthetic techniques and different postoperative analgesic techniques on cardiac and pulmonary morbidity associated with vascular surgery. Because of their relatively higher risk (and high end point event rate), patients undergoing abdominal aortic surgery are optimal candidates for study. The proposed trial would compare general versus general plus regional (epidural) anesthesia as well as systemic versus regional postoperative analgesia. Thus four treatment groups would result on the basis of the different combinations of these techniques (Table I). All groups would receive preoperative sedation of oral benz~diazepine in addition to the administration of other indicated medications (e.g., antihypertensive medications, nitrates). General anesthesia would consist of barbiturate

Journalof VASCULAR SURGERY

induction; inhalation agents including nitrous oxide, supplemental oxygen, enflurane, and isoflurane; narcotic analgesics including morphine and t~ntanyl as needed; and relaxant medications including vecuronium and pancuronium as needed. Patients receiving general plus regional anesthetic would receive a "light" general anesthetic, with use of the same agents, but at a reduced incremental and total dosage based on patient response. In addition, an epidural catheter would be placed before operation in the low thoracic or high lumbar region for epidural drug administration. A loading dose of local anesthetic, either lidocaine (1% to 1.5%) with epinephrine or bnpivacaine (0.5% or 0.75%) would be given and then continuously administered during the intraoperative period. For systemic postoperative pain control, morphine sulfate (intravenous or intramuscular) would be the primary drug, although other narcotics could be used. Analgesia controlled by the patient would be used who~ appropriate. Patients receiving regional analgesia for postoperative pain would receive analgesic medications in an epidural catheter with a low concentration of bupivacaine (1%/8%) in conjunction with continuous administration of either morphine (150 to 300 lzg/hr) or fentanyl (20 to 50 ~g/hr) after a loading dose of epidural narcotic. Epidural analgesia would be initiated in the recovery room and continued for 48 to 72 hours, after which systemic (usually oral) analgesic medication would be used. The primary effect of this study protocol on drug administration would be to limit the choice of agents used but not the dosage, which would be dictated by patient response. Patients undergoing infrarenal aortic reconstruction for aneurysmal or occlusive disease would be randomized to one of the four treatment groups. Patients with a contraindication to the use of an epidural catheter (preoperative coagulopathy; bacterial infection systemically or at the site of catheter insertion; or the presence of a lower extremity neurologic deficit) would be excluded. The study could not be blinded because of the obvious physiologic effects of epidural anesthetics and narcotics and the questionable ethics of placing an epidural catheter only to administer placebo medication. However, end point analysis would be done by individuals blinded to treatment. Stratification of patients according to preoperative cardiac and pulmonary risk would not be practical. However, specific preoperative risk determinants, such as the American Society of Anesthesiologist's Physical Status classification, the Goldman Cardiac Risk Index, preoperative evaluation of myocardial function (e.g., ejection fraction) or of coronary artery disease (e.g., dipyridamole thallium scanning) and evaluation of pulmonary function would be compared between groups to ensure comparable randomization. Criteria would be required to treat deviations of cardiovascular and pulmonary function from an acceptable and predefined normal range. This could be done by use of an absolute percentage variation from preoperative value (e.g., a 20% increase or decrease in the systolic blood pressure) or a "sliding scale" type of algorithm that

Volume 15 Number 5 May 1992

attempts to maintain tighter control of hemodynamic variables and thereby minimize extremes of absolute values. Other clinical decisions that affect study end points would also require standardization, such as the need for postoperative mechanical ventilation and the timing ofextubation. These criteria would be applied similarly to all treatment groups. Myocardial ischemia is the primary cardiovascular end point. One of the most sensitive mechanisms for its detection, and the technique suggested for use in this study, is continuous electrocardiographic (Holter) monitoring. 21,22This would be initiated in the preoperative period to evaluate the baseline occurrence rate of ischemia and then continued during operation and for 72 hours after operation. The expected incidence of ischemia (defined by a measurable degree of ST segment depression) with this monitoring technique is 25% to 40% in this popula"'~n31'22 If regional anesthesia and analgesia (group 4) reduce myocardial preload, afterload, and heart rate as expected, a 30% to 50% reduction in the incidence of myocardial ischemia could be anticipated (compared with group 1). For patients receiving either regional anesthesia (group 3) or analgesia (group 2), but not both, less reduction in ischemia is likely and is an important question to be addressed in this study. Perioperative myocardial infarction is well correlated with myocardial ischemia, 23 although its incidence is much lower. As a primary end point, comparison of myocardial infarction would require a prohibitively large number of patients. However, this is an important secondary end point that should be documented by serial enzyme testing after operation. The incidence of perioperative myocardial infarction in this patient population is estimated to be 3% to 10%, with the potential for a 50% reduction in the infarction rate by regional anesthesia and analgesia combined (group 4). The onset of postoperative congestive heart failure (CHF) is another primary end point to be diagnosed by both a clinical parameter (e.g., rales on auscultation or an S 3 gallop) and an objective parameter (e.g., pulmonary artery wedge pressure or an abnormal chest radiograph). The occurrence of CHF in the postoperative period may be expected at a rate of 15% to 30%, s with a postulated reduction of 35% to 50% when comparing the use of regional techniques in group 4 with the systemic control group 1. 5,7 Primary end points for postoperative pulmonary complications include the duration of postoperative mechanical ventilation. Prolonged mechanical ventilation (defined as longer than 24 hours) has been decreased by as much as 50% to 75% with the Use of regional anesthesia and analgesia. 5,16 Postoperative pulmonary infectious complications are another primary end point that should be defined by a new chest radiograph abnormality as well as clinical indications of infection (fever, sputum production, elevated peripheral whir e blood cell count and/or positive sputum culture). When defined in this manner, the incidence iS expected to be 25% to 40%, s which may be decreased by 30% to 50% with regional

Clinical research and vascular surgery 877

anesthesia/analgesia. 2,s Postoperative pulmonary dysfunction is expected after intraabdominal surgery and should be monitored by simple tests of lung volume and flow rates (e.g., forced vital capacity and forced expiratory volume in one second (FEV1) or peak expiratory flow rate). These are commonly reduced to 40% to 60% of their preoperative values in the early postoperative period, and pulmonary dysfunction may be lessened by 30% to 40% by regional techniques. 2,3 Other end points of treatment should be evaluated, but their incidence is low or the expected effect of anesthetic management is not yet dear. These include duration of postoperative intensive care; duration of postoperative hospitalization; time to initiation of regular oral intake; postoperative pain control as measured by daily visual analoge scales; cardiogenic shock; arrhythmias; renal failure; epidural hematoma; and death. Because of the need for comparisons between the four groups, it will be necessary to have at least 80 patients in each group. This figure is based on a 50% reduction in the incidence of myocardial ischemia in group 4. With the large number of other end points and the uncertainty regarding their event rate, it would be prudent to randomize 100 patients into each group. Mark P. Yeager, M D Jack L. Cronenwett, M D REFERENCES

I. Shaw JHF, Galler L, Holdaway IM, Holdaway CM. The effect of extradural blockage upon glucose and urea kinetics in surgical patients. Surg Gynecol Obstet 1987;165: 260-6. 2. Hendolin H, Lahfinen J, Lansimics E, Tuppurainen T, Partanen K. The effect of thoracic epidural analgesia on respiratory ffmction after cholecystectomy. Acta Anaesthesio[ Scand 1987;31:645-51. 3. Shulman M, Sandier AN, Bradley JW, Young PS, Brebner J. Posrthoracotomy pain and pulmonary function following epidural and systemic morphine. Anesthesiology 1984;61: 569-75. 4. Cuschieri RI, Morran CG, Howie JC, McArdlc CS. Postoperative pain and pulmonary complications: comparisons of three analgesic regimens. Br J Surg 1985;72:495-8. 5. Yeager MP, Glass DD, Neff RK, Brick-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology 1987;66:7-14. 6. Breslow MJ, Desmond A~[,Christopherson R, et al. Epidural morphine decreases postoperative hypertension by attenuating sympathetic nervous system hyperactivity. JAMA 1989; 261:3577-81. 7. Rciz S, Balfors E, Sorensen MB, Flaggmark S, Nyhman H. Coronary hemodynamic effects of general anesthesia and surgery: modification by epidural analgesia in patients with ischemic heart disease. Reg Anesth 1982;7:$8-20. 8. Hjortso NC, Neumann P, Frosig F, et al. A controlled study of the effects of epidural analgesia with local anaesthetics and morphine and morbidity after abdominal surgery. Acta • Anaesthesiol Scand 1985;29:790-6. 9.: iayr C, Mollie A, Bourgain JL, et al. Postoperative pulmonary complications: general anesthesia with postoperative paten-

878

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11.

12.

13. 14. 15. 16.

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A d Hoc Committee on Clinical Research

teral morphine compared with epidural analgesia. Surgery 1988;104:57-63. Reinhart K, Foehring U, Kersting T, et al. Effects of thoracic epidural anesthesia on systemic hemodynamic function and systemic oxygen supply-demand relationship. Anesth Analg 1989;69:360-9. Baron JF, Decaux-Jacolot A, Edouard A, Berdeaux A, Kamran S. Influence of venous return on baroreflex control of heart rate during lumbar epidural anesthesia in humans. Anesthesiology 1986;64:188-93. Baron JF, Coriat P, Mundler O, Fauchet M, Bonsseau D, Viars P. Left ventricular global and regional function during lumbar epidural anesthesia in patients with and without angina pectoris. Influence of volume loading. Anesthesiology 1987;66:621-7. Lundberg jr, Norgren L, Thomson D, Werner O. Hemodynamic effects of Dopamine during thoracic epidural analgesia in man. Anesthesiology 1987;66:641-6. Damask MC, Weissman C, Todd G. General versus epidural anesthesia for femoral-popliteal bypass surgery. J Clin Anesth 1990;2:71-5. Vanstrum GS, Bjornson KM, Ilko R. Postoperative effects of intrathecal morphine in coronary artery bypass surgery. Anesth Analg 1988;67:261-7. EI-Baz N, Goldin M. Continuous epidural infusion of morphine for pain relief after cardiac operations. J Thorac Cardiovasc Surg 1987;93:878-83.

17. Saada M, Duval A-M, Bonnet F, et al. Abnormalities in myocardial segmental wall motion during lumbar epidural anesthesia. Anesthesiology 1989;71:26-32. 18. Mankikian B, Cantineau JP, Bertrand M, et al. Improvement of diaphragmatic function by a thoracic extradural block after upper abdominal surgery. Anesthesiology 1988;68:37986. 19. Rawal N, Sjostrand U, Chtistoffersson E, et al. Comparison of intramuscular and epidural morphine for postoperative analgesia in the grossly obese: influence on postoperative ambulation and pulmonary function. Anesth Analg 1984;63: 583-92. 20. Catley DM, Thornton C, Jordan C, LeHane JR, Royston D, Jones JG. Pronounced, episodic oxygen desaturation in the postoperative period: its association with ventilatory pattern and analgesic regimen. Anesthesiology 1985;63:20-8. 21. London MJ, Hollenberg M, Wong MG, et al. Intraoperative myocardial ischemia: localization by continuous 12-lead electrocardiography. Anesthesiology 1988;69:232-41. 22. Raby KE, Goldman L, Creager MA. Correlation betweC" preoperative ischemia and major cardiac events after peripheral vascular surgery. N Engl J Med 1989;321:1296300. 23. Slogoff S, Keats AS. Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology 1985;62:107-14.

PHARMACOLOGIC ATTENUATION OF THE SYMPATHETIC RESPONSE; IMPACT ON CARDIAC MORBIDITY IN VASCULAR SURGICAL PATIENTS Coronary artery disease (CAD) is the leading cause of perioperative morbidity and deaths in patients undergoing vascular surgery. 1,2 Clinically manifested CAD is noted in 55% to 70% of these patients, whereas "silent," but significant coronary stenosis is detected in 28% to 37% of the remaining patients by coronary angiography. 1,3 This high prevalence of CAD translates into a significant incidence of cardiac morbidity in patients undergoing vascular surgery. Overall, 7% to 15 % of patients experience perioperative cardiac morbidity, including myocardial infarction (MI) in 2.5% to 17%, CHF in 3% to 5%, and cardiac death in 1% t o 3%. 1,2,4"7 Recent reports suggest that silent perioperative ischemia may predict more significant cardiac morbidity. Continuous perioperative electrocardiographic (ECG) monitoring (Holter recording) has demonstrated a 24% to 39% incidence of perioperative myocardiac ischemia in this patient population. 8'9 The incidence of ischemia does not decrease during the first 7 postoperative days, and most (78% to 80%) of the ischemic burden is clinically silent. 9,1° In patients undergoing coronary revascularization, a strong correlation exists between the occurrence of perioperative myocardial ischemia and subsequent MI. 1~The prognostic importance of perioperative myocardial ischemia in patients undergoing noncardiac surgery remains to be elucidated. If it can be demonstrated that perioperative ischemia

is a sensitive predictor or prelude to other forms of cardiac morbidity then future investigations and therapies could specifically target this relatively frequent end point. Myocardial ischemia occurs when there is an imbalance between myocardial oxygen supply and demand. Endogenous cathecholamines associated with the perioperative stress response increase myocardial oxygen consumption and may precipitate myocardial ischemia. In this setting, attenuation of the sympathetic response, either centrally or peripherally, may favorably affect myocardial oxygen balance by reducing heart rate, blood pressure, and cardiac contractility. We propose that ablation of the perioperative stress response will prove crucial in the ability to favorably affect cardiac morbidity. 12 This can be accomplished by a number of means, including blockade of afferent input to the central nervous system (e.g., with regional anesthesia), attenuation of central sympathetic outflow (e.g., with alpha2-adrenergic stimulation), or via peripheral adrenergic blockade (e.g., with beta-adrenergic blockade). Of the available pharmacologic strategies, attenuation of the sympathetic response with either beta-adrenergic blockade or alpha 2adrenergic stimulation is most promising. The efficacy of beta-blockade in the symptomatic relief of patients with chronic angina, as well as for reduction in deaths and reinfarction rate after MI, is well established.

Volume 15 Number 5 May 1992

Beta-blockade is also effective in aborting the tachycardic response to perioperative stress. 13,14 Only recently has attention focused on the prophylactic use of beta-blockade in the prevention of perioperative ischemia. In a randomized, nonblinded study, Stone et al.lS evaluated the impact of a single preoperative oral dose of a beta-blocker on the incidence of myocardial ischemia in patients with untreated hypertension undergoing noncardiac surgery. Myocardial ischemia occurred in 28% of the group treated with placebo versus only 2% (p < 0.001) of the patients pretreated with one of three beta-adrenergic blocking agents. Pastemack et al) 6 examined the impact of prophylactic metoprolol on cardiac morbidity in 32 patients undergoing AAA resection. In relation to historical controis a reduction occurred in the incidence of perioperative MI from 18% to 3% (p < 0.05), and an even greater reduction occurred in perioperative arrhythmias. Extrapo~tion from this study is limited by the use of nonrandomized historical controls and the potential adverse effect of withdrawing beta-blocker therapy before operation in control patients. In a subsequent study of patients undergoing vascular surgery who were administered prophylactic metoprolol, the same investigators demonstrated a 60% reduction in the number and duration ofischemic episodes, again compared with nonrandomized control patients, some of whom were taken off long-term beta-blockage.17 The impact of alpha2-adrenergic agents on perioperatire outcome is even less well established. Recent investigations have consistently shown lower anesthetic requirement, more stable hemodynamics, and decreased plasma catecholamine levels with the perioperative use of ctonidine? 8~9 The impact of this greater hemodynamic stability on cardiac morbidity remains to be determined. On the basis of the above information we propose a clinical trial in patients undergoing vascular surgery to address the following questions: (1) Does attenuation of the sympathetic response with beta-adrenergic blockade or alpha2-adrenergic stimulation decrease the incidence of perioperative cardiac morbidity? (2) Are there complications of these interventions? (3) What is the optimal degree of suppression of the cardiovascular system? (4) Does perioperative myocardial iscbemia predict the subsequent occurrence of cardiac morbidity? The proposed trial would be prospective, randomized, and blinded to the patient. Consecutive patients undergoing surgery for atherosderotic vascular disease (excluding cardiac or suprarenal aortic surgery) would be enrolled. Patients with a history of bronchospasm, CHF, symptomatic bradyarrhythmia, hypotension, or renal failure would be excluded, as would patients already taking beta-blockers or alphas-receptor agonists. Patients would be randomized to one of four groups: (1) Control: to receive the current standard of care; (2) atenolol, high dose (50 mg orally 2 hours before operation followed by atenolol intravenously in the operating room and every 12 hours thereafter for 72 hours as required to maintain a mean heart rate (HR) of 60 beats/min); (3) atenolol, low dose (25 mg orally 2 hours before operation

Clinical research and vascular surgery 879

with subsequent dosing as for high-dose atenolol except for titration to a mean H R of 75); and (4) clonidine (5 ~g/kg orally 2 hours before operation at which time a 10 cm2 transdermal patch would also be placed to maintain therapeutic plasma concentrations for greater than 72 hours). Two dosage regimens for atenolol are proposed to determine the most favorable degree of cardiovascular depression in terms of risks and benefits. This is relevant because the occurrence of deleterious side effects (bradyarrhythmias, heart failure, or bronchospasm) is likely related to dose. Stratification by type of surgical procedure (aortic versus nonaortic operation) would be carried out. Randomization of a large number of patients should ensure comparability between groups in terms of other important characteristics including age, cardiac history, risk factors, preoperative medications, and anesthetic technique. These characteristics, all potential independent predictors of outcome, would be recorded and compared between groups. Potential medication side effects, including bronchospasm, bradyarrhythmia, and hypotension would also be quantified. The primary end points of this investigation and their expected rate of occurrence would be MI (2.5% to 17%, mode 5%); cardiogenic pulmonary edema (3% to 5%); tachyarrhythmia necessitating treatment (indeterminate); cardiac death (1% to 3%); and overall deaths (2% to 6%). This protocol would also investigate the relationship between perioperative myocardial ischemia (manifest as episodic ST segment depression on Holter recordings) and the primary study end points. If such an association would be demonstrated it would validate subsequent investigations in which perioperative ischemia was the primary end point. Since myocardial ischemia occurs much more frequently than any of the primary end points (expected rate: 24% to 39%, mode 30%), subsequent studies could be done with far fewer patients. On the basis of currently available information, we anticipate a 50% reduction in the incidence of myocardial ischemia and a 30% to 50% reduction in the occurrence of MI and cardiac death in our treatment group(s). At least 100 patients would be required in each group to assess the effect of these treatments on the end point of myocardial ischemia. Because of stratification (aortic/nonaortic vascular surgery) and the uncertainty of other end points, more patients would certainly be required. Furore strategies aimed at reducing perioperative cardiac morbidity should include further elucidation of the impact of cardiovascular drugs (e.g., beta-adrenergic blocking agents, centrally-acting sympatholytics, nitrates, calcium channel blockers, or antithrombotic agents) as well as investigation of techniques that allow earlier recognition of perioperative ischemia (e.g., transesophageal echocardiography and Holter monitoring with real-time analysis capabilities2°). Thomas 3'i. Dodds, AID Jack L. Cronenwett, M_D

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REFERENCES 1. Hertzer NR, Beven EG, Young JR, et al. Coronary artery disease in peripheral vascular patients: a classification of 1000 coronary angiograms and results of surgical management. Ann Surg 1984;199:223-33. 2. Jamicson WRE, Janusz MT, Miyagishima RT, Gerein AN. Influence of ischemic heart disease on early and late mortality after surgery for peripheral occlusive vascular disease. Circulation 1982;66:192-7. 3. Tomatis LA, Fiercns EE, Verbrugge GP. Evaluation of surgical risk in peripheral vascular disease by coronary artcriography: a series of 100 cases. Surgery 1972;71:429-35. 4. Jeffrey CC, Kunsman J, Cullen DJ, Brewster DC. A prospective evaluation of cardiac risk index. Anesthesiology 1983;58: 462-4. 5. Leppo J, Plaja J, Gionet M, et al. Noninvasive evaluation of cardiac risk before elective vascular surgery. J Am Coil Cardiol 1987;9:269-76. 6. Eagle KA, Coley CM~ Newell JB, et al. Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Ann Intern Med 1989;110: 859-66. 7. Raby KE, Goldman L, Creager MA, et al. Correlation between preoperative ischemia and major cardiac events after peripheral vascular surgery. N Engl J Med 1989;321:1296300. 8. Coriat P, Harari A, Daloz M, Viars P. Clinical predictors of intraoperative myocardial ischemia in patients with coronary artery disease undergoing non-cardiac surgery. Acta Anaesthesiol Scand 1982;26:287-90. 9. Wong MG, Wellington YC, London MJ, Mangano DT. Prolonged postoperative myocardial ischemia in high-risk patients. Proc Soc Cardiovasc Anesth 1988;A103. 10. London MJ, Hollenberg M, Wong MG, et al. Intraoperative

11.

12. 13.

14.

15.

16.

17.

18.

19.

20.

myocardial ischemia: localization by continuous 12-lead electrocardiography. Anesthesiology 1988;69:232-41. SlogoffS, Keats AS. Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology 1985;62:107-14. Roizen MF. Should we all have a sympathectomy at birth? Or at least preoperatively? Anesthesiology 1988;68:482-4. Kopriva CJ, Brown CD, Pappas G. Hemodynamics during general anesthesia in patients receiving propranolol. Anesthesiology 1978;48:482-4. Coleman AJ, Jordan C. Cardiovascular responses to anesthesia: influence of beta-adrenoreceptor blockade with metoprolol. Anaesthesia 1980;95:972-8. Stone JG, Flex P, Sear JW, et al. Myocardial ischemia in untreated hypertensive patients: effect of a single small oral dose of a beta-adrenergic blocking agent. Anesthesiology 1988;68:495-500. Pasternack PF, Imparato AM, Baumann FG, et al. The hemodynamics of B-blockage in patients undergoing abdom~.,, inal aortic aneurysm repair. Circulation 1987;76:III1-7. Pasternack PF, Grossi EA, Baumann FG, et al. Beta blockade to decrease silent myocardial ischemia during peripheral vascular surgery. Am J Surg 1989;158:113-6. Flacke JW, Bloor BC, Flacke WE, et al. Reduced narcotic requirement by clonidine with improved hemodynamic and adrenergic stability in patients undergoing coronary bypass surgery. Anesthesiology 1987;67:11-9. Engelman E, Lipszyc M, Gilbart E, et al. Effects of clonidine on anesthetic drug requirements and hemodynamic response during aortic surgery: Anesthesiology 1989;71:178-87. Dodds TM, Delphin E, Stone JG, et al. Detection of perioperative myocardial ischemia using Holter monitoring with real-time ST segment analysis. Anesth Analg 1988;67: 890-3.

N E U R O G E N I C T H O R A C I C OUTLET SYNDROME: SURGICAL VERSUS CONSERVATIVE THERAPY The goal of this trial is to determine the relative value of surgical versus nonsurgical therapy in the management of patients with neurogenic thoracic outlet syndrome (TOS) other than the type associated with a bony anomaly at the cervical thoracic junction, and manifested as prominent hand weakness and wasting. Thus specifically excluded is the rare type of neurogenic TOS described by Gilliatt et aL 1 in 1970, which often is referred to as "classic" or "true" neurogenic TOS. Since 1956 the name TOS has been used as a group title. It encompasses a number of entities attributed to compromise of the subclavian/axillary artery or vein, the brachial plexus, or both, at some site between the inferolateral neck and the axilla.2 For ease o f understanding, TOS can be divided into discrete subgroups, based on the specific structure considered compromised, since typically only one is involved in a particular patient? These subdivisions, which have no consistent relationship to the initial entities collected under the title "TOS" in 1956, include arterial vascular, venous vascular, true neurogenic

TOS, and disputed neurogenic TOS. The vascular types of TOS and true neurogenic TOS are noncontroversial. Although only the arterial vascular and true neurogenic subgroups are consistently associated with a bony abnormality in the thoracic outlet region (usually a complete cervical rib or a rudimentary cervical rib plus a band, respectively, for the arterial and the true neurogenic types), all three of these subgroups have characteristic clinical presentations that are universally accepted. Also, all three are acknowledged to be rare lesions. Paradoxically, the only controversial subgroup o f TOS, the disputed neurogenic TOS, is also the only one frequently diagnosed. Exactly how frequently this occurs varies strikingly from one institution to another, depending on acceptance of this entity by the individual physician? The concept o f disputed neurogenic TOS originated in 1962, when Clagett4 reported that first rib removal should alleviate all types of TOS since that structure, in his view, acted as one arm of a vise compressing the neurovascular structures. In 1966 Roos s introduced a new surgical

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procedure to treat this entity: transaxillary first rib resection. This operation rapidly achieved great popularity because of its reputed safety and simplicity. In 1982 a new type of disputed TOS was described, "the upper plexus" type, which required a new surgical procedure, total scalenectomy. 6 Despite the fact that thousands of surgical procedures have been performed over the past quarter century to treat this disorder, no consensus has been reached regarding almost any of its basic tenents, such as its characteristic clinical presentation, helpful adjunctive tests, most appropriate therapy, and optimal surgical treatment, if such is performed, s Generally all claims regarding the efficacy of surgical treatment for this type of TOS have been provided by the operating surgeons. The assertion that 90% of patients who undergo surgery show marked improvement has been challenged by those skeptical of this disorder, s'r Moreover, "t has recently become apparent that these operations are not without risk. Many patients have sustained, among other injuries, severe, painful lower m m k brachial plexopathies during rib resection, which have resulted in permanent residual symptoms. 8-1° Because the effectiveness of surgical therapy has never been proved with this disorder, and because it is now known that such surgery is capable of causing the patient permanent injury, this seems an appropriate time to determine whether operation for this type of TOS does offer any objective benefits :over conservative therapy. ~ This will be a randomized study, comparing the results in patients undergoing rib resection with results in a control group treated without operation. Both men and women with symptoms considered indicative of brachial plexus compromise within the thoracic outlet as judged by the surgeon and by at least one independent examiner, a neurologist, will be eligible for this study. All patients will be assessed blindly by the independent examiner. Preoperative electromyographic (EMG) examinations will be performed to exclude carpal tunnel syndrome and other nerve fiber disorders, such as cervical radiculopathy. The decision that the patient is an appropriate candidate for rib resection (--4- added scalenectomy) will be made by the surgeon, with agreement by the neurologist who will confirm the patient has no other neurologic disorder. The patient will then be randomized to rib resection surgery or to nonoperative treatment consisting of physical therapy. All operations must include, but are not restricted to, first rib removal (many surgeons now treat this subtype of TOS by performing both first rib:removal and anterior scalenectomy during the same operative procedure). A specific group of physical therapy procedures will be performed at regular intervals on the patients randomized to nonoperative treatment. Specific information in the research protocol must specify the type and frequency of treatments. All patients will be reexamined by the consulting neurologist at the following intervals after randomization to surgery or to nonoperative treatment: at i month, 6 months, 1 year, 3 years, and 5 years. Patients entered in the study must be available during this prolonged evalua-

Clinical research and vascular surgery 881

tion period, and consideration will have to be given to the amount of travel required to meet these requirements. Criteria for exclusion include (1) Known or suspected other neurologic disorders of the limb, either focal or as part of a generalized problem; for example, carpal tunnel syndrome, ulnar neuropathy at the elbow, cervical radiculopathy, and generalized polyneuropathy. (2) Prior operations on involved limb nerves. (3) Bony anomalies in the thoracic outlet region, as determined by any of the neuroimaging techniques. (4) History of prior TOS surgery. (5) Major vascular symptoms in the limb. (6) History of cancer. (7) History of prior significant neck or limb trauma. (8) Psychiatric disorder, as determined by the examiners or by the psychiatric testing procedures. All patients will be given a battery of psychological tests before surgery and on or after the 6-month return visit. Included in this battery will be a pain questionnaire. On the preoperative examination and postoperative follow-ups, detailed histories of the patient's symptoms will be obtained, as well as a determination of the type and amount of drugs being consumed to treat the disorder. End points will consist of the patient's assessment as to the diminution or disappearance of symptoms after operation compared with before operation; alterations in the amount and type of pain medications consumed; results of a pain questionnaire; determination of the patient's resumption of presymptomatic activities, particularly return to work; the patient's assessment of his/her well being. The operative surgeon and the consulting neurologist will assess the patient's postoperative status independently. A secondary objective of the study will be a determination of the agreement between their independent assessments. If one estimates a 25 % difference in the end point event rate between the two groups and considers this difference clinically meaningful, at least 54 patients will be required in each group for 90% power. To allow for dropouts and postrandomization exclusions (e.g., crossovers), 60 patients in each group would be optimal. This is a conservative estimate, and if the difference between groups in end points is more dramatic, fewer patients would be needed. This trial could be mounted in two or three centers with a high volume of patients with TOS. Randomization stratiiication according to sex, age, and duration of symptoms may be considered. Additional stratification for presumed traumatic versus nontraumatic causation may be considered. Stratification would increase the numbers of patients needed.

Asa J. Wilbourn, M D John M. Porter, MI)

REFERENCES

1. Gilliatt RW, LeQuesne PM, Loguc V, Sumner AJ. Wasting of the hand associated with a cervical rib or band. ] Neurol Neurosurg Psychiatry 1970;33:615-24. 2. Peet PM, Henriksen JD, Anderson TP, Martin GM. Thoracic outlet syndrome: evaluation of a therapeutic exerciseprogram. Mayo Clin Proc 1956;31:281-7.

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3. Wilbourn AJ, Porter ~M. Thoracic outlet syndromes. Spine: state of the art reviews 1988;2:597-626. 4. Clagert OT. Presidential address: research and prosearch. J Thoracic Cardiovasc Surg 1962;44:153-66. 5. Roos DB. Transaxillary approach for first rib resection to relieve thoracic outlet syndrome. Ann Surg 1966; 163:354-8. 6. Roos DB. The place for scalenectomy and first rib resection in thoracic outlet syndrome. Surgery 1982;92:1077-85. 7. Porter JM, Rivers SP, Coull BM, et al. Thoracic outlet

syndrome: a conservative approach. Vasc Diag Ther 1982;3: 35-42. 8. Cherington M, Harper I, Machanic B, et al. Surgery for thoracic outlet syndrome may be hazardous to your health. Muscle Nerve 1986;9:632-4. 9. Dale WA. Thoracic outlet compression syndrome: critique in 1982. Arch Surg 1982;117:1437-45. 10. Wilbourn AJ. Thoracic outlet syndrome surgery causing nerve brachial plexopathy. Muscle Nerve 1988;11:66-74.

PROPOSED DESIGN FOR A DOUBLE BLINDED TRIAL TO EVALUATE MEDICATIONS F O R TREATMENT OF INTERMITTENT CLAUDICATION A proposed standard design for intermittent claudication (IC) studies is presented that includes requirements for objective initial diagnosis and quantitative evaluation of results of treatment. The study is designed to test the hypothesis that a certain treatment will improve treadmill walking distance for persons with objectively diagnosed IC.

Background of current status of claudication study design In 1973 representatives of pharmaceutical companies held a meeting in Washington D.C. with a stated purpose of developing a common protocol for clinical trials of peripheral vasodilators. The intent was to produce a document acceptable to the U.S. Food and Drug Administration (FDA) as definitive methodology for evaluation of the effectiveness of these agents, At that time little was known regarding the reproducibility and/or feasibility of treadmill walking as a response parameter. In a similar manner the effect of most therapeutic agents on treadmill walking was unknown, and therefore it was impossible to predict the magnitude of changes that might be induced by treatment and to predict necessary sample sizes for proposed trials. Because of this deficiency, the FDA requested a methodology study examining the reproducibility and variability of treadmill walking. A small study (involved 11 patients) was mounted, and despite its inadequacies, the results were used to help design an experimental protocol that was distributed to manufacturers. ~ Although the protocol was never adopted by the FDA as official policy, all approved, trials of new pharmacologic agents since then have followed this general outline. Although the protocol is serviceable, in the years that have passed since its development, it has become apparent that a number of changes may be appropriate. The brief protocol that follows is based on this previous protocol with changes by the author.

Detection of lower e x t r e m i t y arterial occlusive disease Objective confirmation of the presence of arterial occlusive disease of the lower extremities can be obtained

by either invasive (arteriographic) or noninvasive means. Noninvasive testing is based on use of Doppler ultrasoun["" flow detectors to measure distal extremity blood pressure, which has excellent correlation with direct intraluminal pressure measurement and arteriography. The few patients with IC who have normal ankle pressure at rest can be detected by the results of limb blood pressure measurements performed after treadmill walking.

Diagnosis of claudication The diagnosis of IC can only be established by the combination of the typical history and the presence of a significant fall in ankle blood pressure after treadmill walking in which the patient's typical symptoms are reproduced? Such a finding on treadmill testing is a mandatory entrance requirement for all patients participating in IC trials. P a r a m e t e r s u s e d t o evaluate t r e a t m e n t results Multiple parameters have been used in previous studies to evaluate the outcome of IC treatment or natural history. In those studies in which treadmill walking was included with other parameters, an improvement in treadmill walking invariably accompanied the improvements in other parameters? Given the ease of measurement of treadmill walking, and the lack of proven superiority of any other parameter, treadmill walking distance is presently considered the parameter of choice for evaluation o f IC treatment. Both distance to initial symptoms and total walking distance are recorded.

Requirement for placebo controls in claudication treatment studies Studies of the natural history of IC have demonstrated that a significant number of patients improve with the passage of time without specific treatment. 4,s In a similar manner exercise has a well-documented beneficial effect on IC symptoms.6,7 It is obvious that any study purporting to show benefit for a particular treatment o f l C must compare the results of that treatment with a control group treated

Volume 15 Number 5 May 1992

with placebo, especially when the index of improvement evaluated is treadmill walking. Study design Patient selection. Ambulatory claudication studies are directed toward outpatients with stable, symptomatic, occlusive atherosclerotic disease of the lower extremities. To be included, the candidate must be able to walk at least 50 meters on a treadmill at a speed of 1.5 mph and 0 degree grade without experiencing ctaudication but for not more than 500 meters before the onset of claudicarion. Exclusion criteria. The following types of patients and conditions are excluded from claudication trials: (1) Ischemic rest pain, ulceration, and/or gangrene; (2) Severe neuropathy; (3) Cardiac, pulmonary, or other disease that would interfere with treadmill walking; (4) Myocardial infarction in last 6 months; (5) Alcohol or other drug abuse; (6) Other major medical problem/recent major surgery; (7) Pregnancy potential. Concomitant medication. N o drugs known to have similar or synergistic effect to the agent being tested should be permitted. Pentoxifylline is specifically excluded. Duration o f study. All patients will enter at least a 3-week, single-blind, pretreatment, placebo-washout and adaptation period, followed by a continuous period of at least 6 weeks on either drug or placebo. N u m b e r o f patients. Required sample sizes depend on the magnitude of the drug effect on treadmill walking as well as on the variance in distance walked when repeated examinations on the same patient are compared. An extremely effective drug producing a marked effect will require fewer patients for proof of efficacy than one with more minor effects. For any given study, more variance in treadmill walking distance means more patients are required. Required sample sizes for medication trials depending on anticipated improvement are seen in Table I. A baseline walking distance of 100 meters is assumed. It is generally accepted that at least 200 patients will have to be randomized and that at least 100 must be available for final analysis, given the general efficacy of currently contemplated drugs. The potential difference between statistical and clinical significance must be considered. Selection work-up and pretreatment placebo period. The following are required: (1) Complete history and physical. (2) ECG obtained before and after treadmill use. (3) Complete blood count (CBC), urinalysis, routine chemistry panel. This work-up will be obtained at the initial visit within 2 weeks before entry. Visit 1 will be used for the performance of the selection treadmill test. If the candidate meets this and all other criteria, formal entry into the pretreatment placebo period will be established. At this time, and at each subsequent visit, a supply of placebo sufficient to last until the next visit will be given. A visit 2 weeks after visit 1 will be used to check adherence to therapy and to observe placebo effects. Patients who report complete disappearance of daudica-

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Clinical research and vascular surgery

Table I. *Required sample sizes for medication trials depending on anticipated improvement No. meters improved walking by drug over placebo

Probability of type H error (labeling an effeetivo drug as ineffective) 0.20

0.15

0.10

Ifstand~d error ofwalking distanceis 25meters 15 44t 51 60 20 26 29 34 25 17 19 22 50 5 6 7 Ifstandard error ofwalking distanceis 50 n a e ~ 15 180 200 260 20 100 115 130 25 64 72 84 50 17 19 22 Ifstandard error ofwalking distanceis 75meters 15 400 450 550 20 290 325 388 25 130 162 190 50 36 41 48

0.05

76 42 27 8 375 160 110 27 650 475 235 59

~Assuming an average initial walking distance of 100 meters. tNumber of patients in each group who must complete the study (i.e., placebo and control). All calculations assume an c~of 0.05 (probability that the difference is due to the drug). tion will be dropped from the study. Those who continue to meet the study criteria will perform the treadmill test for adaptation purposes. Two treadmill tests will be performed each time an exercise study is required. E s t a b l i s h m e n t of" p r e t r e a t m e n t c o n t r o l values for purposes o f analysis Treadmill claudication distance. The maximum value on the last visit of the pretreatment placebo period should be used as the control, as long as the maximum results recorded on the last two consecutive visits do not differ by more than 20% of the larger of these two values. Up to two additional tests at weekly intervals can be made, and should agreement within 20% fail to exist after the four visits, the patient should be dropped from the study.

D r u g treatment period. After satisfying all criteria of the pretreatment placebo period for at least 3 weeks, the patient will be randomly assigned to either the active medication or the placebo group. Frequency and number o f visits. Subjects will be seen at the end of the second and fourth weeks of this period and at 2- to 4-week intervals thereafter, receiving sufficient study drugs in coded packages each visit. A record of the amount of remaining drug from the previous period will be kept. Clinical observations (parameters to be studied). At the last two visits in the pretreatment placebo period, and at each subsequent visit, the following observations will be recorded: (1) Interim history, including cigarette smoking (it is desirable for smoking history to be con-

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884 A d Hoc Committee on Clinical Research

firmed by objective testing such as cotinine, or carboxyhemoglobin). (2) Walking activity (less/same/more). (3) Physical examination including blood pressure, pulse, lower extremity examination. (4) Treadmill dandication test. Potential problems Some patients with diabetes and/or renal failure have peripheral arteries sufficiently calcified that they cannot be compressed with an external cuff. These patients can be included, but alternate means will be required to assess their hemodynamic status, such as pulse volume recording and toe pressure measurement. It is desirable that generally equal numbers of smokers and diabetics be included in the treatment and placebo limbs of the trial. Randomization stratification to achieve this objective must be considered, but will require more patients.

REFERENCES

1. Department of Health and Human Services, File F-85-31822, Document Control 47243, Rockville, MD. 2. Carter SA. Response of ankle systolicpressure to leg exercise in mild or questionable arterial disease. N Engl I Med 1972;272: 578-82. 3. Larsen DA, Lassen NA. Effects of daily muscular exercise in patients with intermittent claudication. Lancet 1966;2:1093-6. 4. Boyd AM. The natural course of arteriosclerosis of the lower extremities. Angiology 1960; 11:10. 5. Kannel WB, Skinner JJ, Schwarz MJ, et al. Intermittent claudication: incidence in the Framingham study. Circulation 1970;41:875. 6. Sortie D, Myhre K. Effects of physical training in intermittent claudication. Scand J Ctin Lab Invest 1978;38:217-22. 7. Dahllof AG, Holm J, Schersten T, Sivertsson R. Peripheral arterial insufficiency: effect of physical training on walking tolerance, calf blood flow, and blood flow resistance. Scand J Rehab Med 1976;8:I9-26.

Lloyd M. Taylor, M D John A4. Porter, M_D

T H E EFFECT OF LIPID L O W E R I N G O N T H E I N C I D E N C E OF RECURRENT CAROTID STENOSIS Fifty percent or greater recurrent stenosis after carotid endarterectomy occurs in approximately 20% ofpatients.~,2 Although the clinical impact of these lesions is low, with only 1% to 4% of patients requiring reoperation, recurrent stenosis remains an extremely important lesion. It clearly reduces the potential benefit of operative intervention in carotid disease compared with medical therapy. Of special interest is the observation that this lesion appears to be an excellent model in which to study myointimal hyperplasia, a A certain amount of myointimal hyperplasia occurs after every cardiovascular reconstructive procedure, and this must represent a part of the normal reparative processes. This process, however, is prone to unrestrained progression in certain individuals. A variety of initiating factors for myointimal hyperplasia have been proposed• These generally fall into two categories-mechanical factors, including clamp and other local operative trauma or residual intimal or medial flaps; and systemic factors, including smoking, hypertension, and hyperlipidemia. 4 Technical imperfections at the time of carotid endarterectomy have always been the most obvious of the many factors believed to contribute to the development of early restenosis, s Sawchuck et al.6 concluded that no relationship existed between the presence of a minor residual defect seen on intraoperative ultrasonography and the subsequent development of significant recurrent stenosis. However, Bandyk et al. 7 found that if these are large enough to produce a flow disturbance at the completion of the endarterectomy, they

do correlate with a higher incidence of restenosis. In a prospective study Reilly et al.s also found a positive association between intraoperative defect size and the severity of later restenosis. However, regression analysis revealed that systemic factors, including hypertension, smoking, and hypercholesterolemia, were more important contributors to the overall risk of developing restenosis. The magnitude of the smoking and hypertension effect appeared to be about equal, whereas the magnitude of the cholesterol effect varied with the absolute serum level. Others have noted an association of one or more of these factors with restenosis. 4 In attempting to construct an effective treatment program for patients after carotid endarterectomy, we have concentrated on the lipid levels because tobacco cessation therapy is notoriously unsuccessful,9 and most hypertensive patients are already receiving some type of treatment. We recently completed a study comparing 20 patients with carotid restenosis occurring within 2 years of the original surgery to an age- and sex-matched carotid endarterectomy group without restenosis. The groups were comparable in smoking pack years, number of active smokers, number of hypertensives, and number of diabetics. They were significantly different in several lipid parameters, but the best individual discriminators on logistic regression analysis were apo.B levels (p < 0.003) and high-density lipoprotein (HDL) cholesterol levels (p < 0.01). Apo B and H D L cholesterol levels have been shown repeatedly to be powerful predictors of cardiovas-

Volume 15 Number 5 May 1992

cular risk. Since this group included hypercholesterolemic and hypertriglyceridemic patients, clinical trial recruitment would be simplified by identifying high risk individuals with use of these two parameters. W i t h diet and currently available drags, dramatic lowering of plasma lipids can be achieved with minimal side effects and excellent patient compliance. At present many lip!d treatment centers are using double and triple drug regimens to routinely lower plasma cholesterol, triglycerides, and apo B levels into the low normal range and achieve concomitant increases in H D L ? ° Previous, less successful regimens, have been shown to limit lesion progression, n and in some cases cause a reduction in lesion severity, lz'13 in peripheral vascular disease. W e propose a trial of aggressive lipid lowering after carotid endarterectomy to determine if such treatment can limit the incidence of recurrent stenosis. The suggested entry criteria include patients undergoing carotid endar,erectomy, age less than 75 years, who have total plasma apo B levels greater than 120 mg/dl and/or an H D L cholesterol less than 37.5 mg/dl. Individuals who have extremely high cholesterol (> 400 mg/dl) or triglyceride (> 599 mg/dl) levels will be excluded because it may be unethical to withhold lipid lowering therapy from these patients. Treatment of the experimental group will consist of standard aggressive diet and drug therapy. This includes niacin, lovostatin, and fibric acid derivatives depending on the individual lipid abnormality. Treatment should be undertaken at an established lipid clinic with dieticians and physicians familiar with the treatment of lipid disorders and with frequent follow-up lipid measurements, Since postendarterectomy hyperplasia is often well established within only a few weeks, treatment should begin either before operation or very soon after operation. The control group will receive American Heart Association step 1 dietary counseling. Ultrasonography (or possibly arteriography) must be performed during operation to ensure absence of technical problems. Frequent follow-up carotid duplex examinations should be carried out at suggested intervals of 1, 3, and every 6 months thereafter. If we assume that these individuals are at higher risk for restenosis than are postcarotid patients as a whole, their restenosis rate may be expected to be approximately 30% at 1 year if untreated. Since hyperlipidemia is certainly not the only factor affecting restenosis, the rate of restenosis may be estimated to be reduced by one half by successful lipid lowering. In this case, one would need approximately 140 patients in each limb of a randomized trial to reach a significance level of 0.05 and power of 0.90. The presumed rate of restenosis is critical, since at a restenosis rate of 40% we would only need 90 patients per group, whereas at a restenosis rate of 20% we would need 220 subjects per group. To ensure that the residual defects play a minimal role, it is critical that each patient have a near-normal outcome

Clinical research and vascular surgery 885

on carotid duplex examination or operative arteriogram before lea~ng the operating room. As with any treatment versus no-treatment trial, the major problem anticipated is the handling of the control group. Ideally these individuals would receive close follow-up without drug therapy and no more than "routine" dietary counseling. In previous trials this has proved to be difficult. With the current level of population awareness concerning dietary cholesterol and the risk of hypercholesterolemia, a true control group is difficult to achieve. This may need to be accepted and dietary counseling with placebo medications may be one alternative. Treatment centers should be limited to those where apoprotein analyses are routinely performed. This may be a problem limiting both recruitment and participation.

Joseph H. Rapp, M D REFERENCES

1. Baker WH, Hayes AC, Mahler D, Littooy FN. Durability of carotid endarterectomy. Surgery 1983;94:112-5. 2. Zierler RE, Bandyk DF, Thiele BL, Strandness DE Jr. Carotid artery stenosis following endarterectomy. Arch Surg 1982; 117:1408-15. 3. Clagett GP, Robinowitz M, YoukeyJR, et al. Morphogenesis and ctknicopathologic characteristics of recurrent carotid disease. J VAsc SURG 1986;3:10-23. 4. Clagett GP, Rich NM, McDonald PT, et al. Etiologic factors for recurrent carotid artery stenosis. Surgery 1983;93:313-8. 5. Callow AD. Restenosis after carotid artery surgery. Int Surg 1984;69:247-55. 6. Sawchuck AP, Flanigan DP, Machi J, Schuler JJ, Sigel B. The fate of unrepaired minor technical errors detected by intraoperative ultrasound during carotid endarterectomy [Abstract]. Presented at the Twelfth Annual Meeting of the Midwcstern Vascular Surgical Society, Sept. 23-24, 1988, Rochester, MN. 7. Bandyk DF, Kaebnick HW, Adams MB, Townc JB. Turbulence occurring after carotid bifurcation endarterectomy: a harbinger of residual and recurrent carotid stenosis. J VAsc SURG 1988;7:261-4. 8. Reilly LM, Okuhn SP, Rapp JH, et al. Recurrent carotid stenosis: a consequence of local or systemic factors? The influence of unrepaired technical defects. J VAsC SU~.G 1990;11:448-60. 9. Krupski WC, Rapp JH. Smoking and atherosclerosis. Perspect Vase Surg 1989;1:103-34. 10. Illingworth DR, Bacon S. Treatment ofheterozygous familial hypercholestcrolemia with fipid-lowering drugs. Arteriosclerosis 1989;9:1121-34. 11. Duffield RGM, Lewis B, Miller NE, Jamieson CW, Brunt JNH, Colchester ACF. Treatment of hyperfipidemia retards progression of symptomatic femoral atherosclerosis. A randomized controlled trial. Lancet 1983;2:639-42. 12. Zelis R, Mason DT, Braunwald E, Levy RI. Effects of hyperproteinemias and their treatment on the peripheral circulation. J Clin Invest 1970;49:1007-15. 13. Kuo PT, Hayase K, Kostis JB, Moreya AE. Use of combined diet and colestipol in long-term (7-7 1/2 years) treatment of patients with type II hyperlipoproteinemia. Circulation 1979; 59:199-211.

Journal of VASCULAR SURGERY

886 A d Hoc Committee on Clinical Research

INTRAOPERATIVE, INTRAARTERIAL THROMBOLYSIS AFTER ARTERIAL THROMBECTOMY The objective of this study is to determine if the intraoperative, intraarterial infusion of thrombolytic agents is of any beneft after thromboembolectomy for acute arterial occlusion, and to determine which of two thrombolytic agents, urokinase or recombinant tissue plasminogen activator (rt-PA) is more efficacious. Strict definitions of major and minor bleeding events must be formulated and local and distant bleeding complications carefully identified and recorded. The intraarterial delivery of thrombolytic agents for acutely thrombosed arteries and bypass grafts has had increasing popularity during the 1980s, and at many centers is well accepted as an important therapeutic alternative. 1 At least two clinical studies and one experimental study have demonstrated that significant residual thrombi frequently remain after best attempts at balloon catheter thromboembolectomy for acute arterial occlusion. 2-4 Spencer and Eisman s demonstrated clinically that side branch occlusion of arteries occurred after 8 hours of the acute occlusive event. Laboratory confirmation of this clinical observation was provided by Dunnant and Edwards, 6 who demonstrated that arteriolar thrombosis occurred after 6 hours of complete inflow occlusion in the canine hindlimb. The extensive degree of thrombosis that can be demonstrated clinically and experimentally indicates that simple mechanical thrombectomy may not restore adequate perfusion to the nutrient blood vessels. A controlled canine hindlimb perfusion study showed that thrombolysis after the best attempt at balloon catheter thromboembolectomy produced significantly improved angiographic results compared with control limbs. 4 In an isolated ischemic muscle preparation, urokinase infusion resulted in significant muscle salvage and significantly less injury after reperfusion compared with control muscles. 7 At least five clinical publications have evaluated the use of inttaoperative, intraarterial fibrinolysis. 812 The early report of Cohen et al. s dampened the enthusiasm of many surgeons for intraoperative thrombolysis. In this study, streptokinase was used in doses ranging from 25,000 to 250,000 units with repeated injections over 30 to 150 minutes of inflow occlusion. Bleeding complications occurred in 42% of the patients. Quinones-Baldrich et al.9 reported five patients with angiographically proven residual thrombi after balloon catheter thrombectomy who were treated with intraarterial streptokinase limiting the dose to 100,000 units infused over 30 minutes. All patients had successful lysis without bleeding complications. Norem et al) ° demonstrated an additional clinical benefit from intraoperative thrombolysis. They found in 19 patients that additional thrombus could be mechanically retrieved 30 minutes after the intraarterial infusion of streptokinase. All patients had angiographic improvement without significant bleeding complications. Comerota et al.ll demon-

strated the efficacy of intraoperative, intraarterial thrombolytic agents for salvage of limbs in patients with distal arterial thrombosis. Streptokinase and urokinase were used as adjunctive therapy in patients remaining ischemic because of distal thrombi after repeated attempts at balloon catheter thrombectomy and/or bypass. A new technique of isolating the limb and infusing high doses of urokinase was described.ll Drainage of the venous effluent eliminated any possible systemic effect. The report demonstrated uniform safety of intraoperative thrombolysis. Parent et al.12 treated 28 patients with acute ischemia and residual thrombus after balloon catheter thrombectomy. Seventeen patients had operative angiograms demonstrating the thrombi. Fifteen of those 17 had successful lysis after intraoperative thrombolytic therapy. Although most intraarterial lysis to-date~" has been achieved with streptokinase and urokinase', accumulating data suggest that rt-PA is safe and efficacious for lysing intraarterial thrombi) 3 It has been shown to lyse with greater rapidity than other agents, although the reason for this is unknown. The background information cited above provides the rationale for a major prospective, randomized trial in patients undergoing thromboembolectomy for acute arterial ischemia. All patients entered into this study should be evaluated according to the de~nitions and standards recommended by the SVS/ISCVS Ad Hoc Committee on Reporting Standards. 14Follow-up of all patients should extend at least 1 year. Acute symptoms of arterial/graft occlusion of less than 10 days and requiring surgical thromboembolectomy will be present in each patient. Patients will undergo mechanical thromboembolectomy followed by operative arteriography. Patients with a postthromboembolectomy arteriogram showing retained thrombus will be randomized into one of three groups for intraarterial infusion; treatment with urokinase, rt-PA, or a control group with heparinized saline infusion. Urokinase patients will receive a 30-minute infusion of 250,000 units ofurokinase. Those randomized to rt-PA will receive a 30-minute infusion of 10 mg of rt-PA. Control patients will receive a 30-minute intraarterial infusion of heparinized saline solution. Thirty minutes after the initiation of study drug infusion, a repeat balloon catheter thromboembolectomy will be performed and the operative arteriogram repeated. Regional venous and systemic blood samples will be obtained before drug infusion, immediately before reperfusion, and immediately after reperfusion to compare and evaluate regional and systemic fibrinolysis and breakdown of fibrinogen. A single systemic sample 2 hours after infusion will be obtained to determine the fibrinogen level as this point. The physical examination will be repeated after operation, and objective results will be obtained of the noninvasive evaluation (Doppler derived indexes and pulse volume recordings), and all patients will be followed at

Volume 15 Number 5 May 1992

3-monthly intervals or greater for at least 1 year. Strict definitions of major and minor bleeding events will be formulated, and local and distant bleeding occurrences will be carefully identified and recorded. Major end points for analysis include angiographic resolution of distal thromboemboli (angiograms should be interpreted blindly by independent examiners) and limb salvage. Secondary end points include bleeding complications and long-term limb salvage. On the basis of published results, one may expect a beneficial response in 70% to 80% of patients treated with a lyric agent. It is uncertain how many patients will have a beneficial response to heparin alone. However, if one assumes that 50% to 60% of those treated with heparin alone will respond, 150 patients would appear to provide an adequate number for randomization between three groups (50 patients per group). This number may need to be adjusted upward to identify subtle 4~fferences between thrombolytic agents. In light of the numbers of patients with acute arterial occlusion in any one center, it is obvious that this study will require a multiinstitutional effort.

Anthony J. Comerota, AID REFERENCES

1. Comerota AJ. Intra-arterial thrombolytic therapy. In: Comerota AJ, ed. Thrombolytic therapy. Orlando: Gruue and Stratton, 1988:125-52. 2. Greep J, Allman PJ, Janet F, Bast TJ. A combined technique for peripheral arterial embolectomy. Arch Surg 1972;105: 869-74. 3. Flecha FR, Pories WJ. Intraoperative angiography in the immediate assessment of arterial reconstruction. Arch Surg 1972;105:902-7.

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4. Quifiones-Baldrich W~, Ziomek S, Henderson TC, Moore WS. Intraoperative fibrinolytic therapy: experimental evaluation. J VASCSURG 1986;4:229-36. 5. Spencer RC, Eisman B. Delayed arterial embolectomy: a new concept. Surgery 1964;55:64-8. 6. Dunnant JR, Edwards WS. Small vessel occlusion in the extremity after various periods of arterial obstruction: an experimental study. Surgery 1973;75:240-5. 7. Belkin M, Valeri R, Hobson RW. Intraarterial urokinase increases skeletal muscle viability after acute ischemia, l VASC SURG 1989;9:161-8. 8. Cohen LH, Kaplan M, Bernhard VM. Intraoperative streptokinase: an adjunct to mechanical thrombectomy in the management of acute ischemia. Arch Surg 1986; 121: 708-12. 9. Quifiones-Baldrich WJ, Zierler RE, Hiatt JC. Intraoperative fibrinolytic therapy: an adjunct to catheter thromboembolectomy. J VASCSURG 1985;2:319-26. 10. Norem RF, Short DH, Kerstein MD. Role of intraoperative fibrinolytic therapy in acute arterial occlusion. Surg Gynecol Obstet 1988;167:87-91. 11. Comerota AJ, White JV, Grosh JD. Intraoperative, intraarterial thrombolytic therapy for salvage of limbs in patients with distal arterial thrombosis. Surg Gynecol Obstet 1989; 169:283-9. 12. Parent NE, Bernhard VM, Pabst TS, et al. Fibrinolytic treatment of residual thrombus after catheter embolectomy for severe lower limb ischemia. J VAsc SURG 1989;9: 153-61. 13. Meryerovitz ME, Goldhaber SZ, Reagan K, et al. Recombinant tissue-type plasminogen activator vs. urokinase in peripheral arterial and graft occlusions: a randomized trial: Radiology 1990; 175:75 -8. 14. Ad Hoc Committee on Reporting Standards. SVS/ISCVS. Suggested standards for reports dealing with lower extremity ischemia. J VAsc SURG1986;4:80-94.

V E N O U S THROMBECTOMY A N D A R T E R I O V E N O U S FISTULA VERSUS A N T I C O A G U L A T I O N IN THE TREATMENT OF ILIOFEMORAL V E N O U S THROMBOSIS The objective of this study is to obtain a detailed comparison of the clinical outcome of anticoagulation versus iliofemoral venous thrombectomy and artetiovenous fistula in the treatment of patients with iliofemoral venous thrombosis. Iliofemoral venous thrombosis represents the most severe form of acute deep vein thrombosis (DVT). Its frequently disastrous sequelae have been well summarized) Therapeutic options for patients suffering iliofemoral venous thrombosis include anticoagulation, thrombolytic therapy, and venous thrombectomy. The long-term morbidity of anticoagulation alone is well known. It is interesting to note that many investigators have observed an unexpectedly high failure rate when treating iliofemoral venous thrombosis with systemic thrombolytic therapy. Operative thrombectomy of the iliofemoral venous segment has not been used widely in the

United States largely because of the discouraging results published more than 20 years ago. Favorable reports concerning iliofemoral venous thrombectomy were published in the early 1960s. 2'3 The frequently quoted report by Hailer and Abrams 2 is representative of these. Several years later, Karp and Wylie~ pointed out a high incidence of recurrent thrombosis after iliofemoral venous thrombectomy. An extremely influential paper was that of Lansing and Davis s who reported that 94% of patients followed after venous thrombectomy had substantial postthrombotic symptoms. Subsequent reports documenting good results from venous thrombectomy have not been widely accepted by surgeons in the United States. In 1986 an important study published by Plate et al.7 reviewed the results of a multicenter Scandinavian trial comparing anticoagulation

888

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Ad Hoc Committee on Clinical Research

to venous thrombectomy and arteriovenous fistula formation in the treatment of patients with iliofemoral venous thrombosis. This appeared to be a credible study because it was prospectively randomized, completely evaluated patients before operation, used objective end points during follow-up, and compared standard anticoagulation with operation. At 6-month follow-up, leg swelling, varicose veins, and venous daudication were more frequent in those treated with anticoagulation alone. Phlebography demonstrated a patent iliofemoral venous segment in 35% of the anticoagulated patients compared with 76% of the patients operated on (p < 0.025). Patent femoropopliteal segments with competent valves were observed in 26% of the anticoagulated group compared with 52% of the thrombectomy group (2o < 0.05). It is interesting to note that 42% of patients treated by operation had no complaints of the postthrombotic syndrome compared with 7% of those treated with anticoagulation (p < 0.005). In a similar manner Kismer and Sparkuhl demonstrated good-toexcellent results after iliofemoral venous thrombectomy in 86% of 72 patients followed for an average of 4 years, s The diagnostic and technical refinements that appear to have been important in producing improved results of iliofemoral venous thrombectomy include the following: (1) The identifcation of the proximal and distal extent of the thrombus. (2) The application of regional and/or general anesthesia. (3) Complete balloon catheter thrombectomy of the proximal (iliac) veins. (4) Massage technique and/or Esmarch wrap expulsion of distal venous thrombus. (5) Completion phlebography in the operating room. (6) Providing outflow via femoral-femoral bypass if affected iliac vein remains obstructed after thrombectomy. (7) Creation of an arteriovenous fistula. (8) Maintaining therapeutic anticoagulation after operation. (9) The application of external pneumatic compression after operation. An additional consideration might be infusion of intraoperative fibrinolyfic agents to lyse residual thrombus in the iliofemoral venous segment should mechanical thrombectomy not remove all thrombus adherent to the vein walls. Because of the significant morbidity faced by patients suffering iliofemoral venous thrombosis and the current controversy surrounding its therapy, a prospective study performed in the United States evaluating anticoagulation versus venous thrombectomy with adjuncti~ee arteriovenous fistula should be performed. On the basis of previously reported data, one would expect a 30% to 40% improvement in patency rate to be achieved With operative intervention. Assuming a 10% to 15% dropout rate, 115 patients entered into this study resulting in 50 :patients able to be evaluated in each group followed over the long-term should allow adequate statistical analysis. End points would include early and long-term patency of the iliofemoral system (as assessed by objective means); signs, symptoms, and objective laboratory evidence of the postthrombotic syndrome; bleeding complications; and recurrent venous thromboembolism.

All patients considered for this study should have ascending phlebography, demonstrating the proximal and distal extent of the ipsilateral iliofemoral venous thrombosis as well as demonstrating that the contralateral iliofemoral venous system is patent and that the vena cava is free of thrombus. All patients should have a ventilation perfusion scan performed before operation. Venous duplex imaging of both lower extremities should be performed in addition to hemodynamic venous studies. Patients will be randomized to anticoagulation alone or operative thrombectomy and arteriovenous fistula formation with postoperative anticoagulation. Patients randomized to anticoagulation will receive standard therapy. 9 Patients randomized to operative intervention will undergo a longitudinal common femoral venotomy to maximize the egress of thrombus from the involved veins. An Esmarch bandage will be applied to the entire lower extremity to deliver the distal thrombus. A. venous thrombectomy catheter will be used to retrieve t ~ iliofemoral thrombus. A completion phlebogram will be performed by injecting contrast through the venotomy with imaging of the iliofemoral segment including a portion of the vena cava. If obstruction persists in the common iliac vein, and egress from the iliac venous system remains compromised, a cross pubic venous bypass will be performed with 8 mm externally supported PTFE. A temporary ipsilateral arteriovenons t~smla will be fashioned. After operation, patients will be continued on anticoagulation with heparin, have external pneumatic compression devices applied to both lower extremities, and be subsequently treated with long-term warfarin. It is recommended that oral anticoagulation be continued for a period of at least 12 months. After operation patients will have a repeat lung scan and ipsilateral phlebogram in addition to noninvasive venous studies. Follow-up at 3-month intervals for 1 year and every 6 months thereafter is recommended for 5 years. At these intervals, the following data will be obtained: standard questionnaire evaluation of postrhrombotic symptoms, venous duplex imaging, venous Doppler study of the popllteal valve, and determination of venous recovery time. Ambulatory venous pressure may also be determined. Because of the number of patients required for this relatively uncommon condition and because of the long-term follow-up, multiinstitutional involvement will be required. Anthony J. Comerota, M D REFERENCES

1. O'Donnell TF, Browse NL, Burnand KG, et al. The socioeconomic effect of an iliofemoral venous thrombosis. J Surg Res 1977;22:483-8. 2. HaUer JA Jr, Abrams BL. Use of thrombectomy in the treatment of iliofemoral venous thrombosis in forty-five patients. Ann Surg 1963;158:561. 3. Mahomer H, Castleberry IW, Coleman WO. Attempts to restore fimction in major veins which are the site of massive thrombosis. Ann Surg 1957;146:510.

Volume 15 Number 5 May 1992

4. Karp RB, Wylie EJ. Recurrent thrombosis after ilio-femoral venous thrombosis. Surg Forum 1966;17:147. 5. Lansing AM, David WM. Five-year follow-up study of iliofemoral venous thrombectomy. Ann Surg 1968;168:620-8. 6. Rutherford R. The role of thrornbectomy in the management of iliofemoral venous thrombosis. In: Rutherford R, ed. Vascular surgery. 3rd ed. Philadelphia: WB Saunders, 1989: 1569-74.

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7. Plate G, Einarsson E, Ohlin P, et al. Thrombectomy with temporary arteriovenous fistula: the treatment of choice in iliofemoral venous thrombosis. J VASe SUR~ 1984;1:867. 8. Kismer RL, Sparkuhl MD, Surgery in acute and chronic venous disease. Surgery 1979;85:31-43. 9. Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembofic disease. Chest 1989;95:37S-51S.

A M U L T I C E N T E R PROSPECTIVE R A N D O M I Z E D TRIAL TO DETERMINE THE OPTIMAL TREATMENT OF PATIENTS W I T H CLAUDICATION A N D ISOLATED SUPERFICIAL FEMORAL ARTERY OCCLUSIVE DISEASE: CONSERVATIVE VERSUS E N D O V A S C U L A R VERSUS SURGICAL THERAPY Currently accepted management of treatment of patients with claudication caused by short segmental superficial femoral artery occlusive disease includes exercise, various endovascular procedures (including percutaneous transluminal balloon angioplasty [PTA], atherectomy, and laser-assisted balloon angioplasty [LABA]), and surgical therapy (femoral popliteal bypass or endarterectomy). The optimal method of treatment in terms of patient risk, benefit and cost has not been established and remains controversial. Conservative therapy of patients with claudication has long been advocated because of the low risk of limb loss. Boyd et al. 1 reported this risk to be only 8% at 5 years, and 12% at 10 years, Imparato et al.2 reported that 75% of patients with claudication will remain stable or their symptoms will even improve with conservative therapy, and that only 25% will ultimately have progressive disease requiring surgical intervention. Added to this good prognosis is the major improvement in claudicafion distance that a formal graded exercise program will produce in 40% to 60% of patients. Recently, Creasy et al? reported a prospective randomized study that showed that patients with daudication with discrete femoropopfiteaI occlusive lesions, when placed on a supervised exercise regimen, walked significantly (about three times) farther on average than similar patients treated with percutaneous balloon angioplasty at the 1-year follow-up point. However, with the advent and development of various endovascular procedures in the past decade, some physicians, particularly interventional radiologists, now advocate percutaneous transluminal balloon angioplasty (PTA) as the preferred treatment for patients with claudication with discrete superficial femoral artery occlusive disease. Reports of this approach claim a low complication rate of less than 5%, a technical success rate of 72% to 97%, and 1- to 3-year patency rates of 73% to 90%. 4.9 It is claimed these patencies rival those for femoropopllteal bypass, but carry a much lower morbidity and mortality rate. Furthermore, the recent advent of laser technology has

increased the ability to treat totally occluded as well as stenotic lesions, albeit as a prelude to balloon angioplasty. Sanborn et al.10 have reported an initial success rate for LABA of more than 90%, including a 56% successful recanalization rate in patients with lesions "impossible" to treat with conventional balloon angioplasty, l°-n The various new atherectomy catheters also have increased the range of lesions treatable with transluminal percutaneous methods, in particular, the eccentric hard calcified plaques. The initial (technical) success rates have been 87% for the Simpson athrectomy catheter, 12 92% for the Auth (Auth Co., Deer Park, N.Y.) Rotablator, (Ahn SS. 1989. Unpublished data), and 92% for the Transluminal Extraction Catheter (Wholey MH, 1990. Personal communication). However, these devices, like LABA, carry a 20% to 40% restenosis rate within 6 to 12 months. Surgical therapy (bypass or endarterectomy) has traditionally been reserved for severe disabling claudication or limb threat and carries 57% to 72% 5-year overall patency rates) 3 Results of surge!T for patients with isolated femoral popliteal lesions with moderate to stable clandication have not been analyzed in large numbers. Abstracting from larger series, patients with clandication and good distal runoff generally have better results with a 5-year patency rate of as high as 82% and operative mortality rate of less than 3%. I4-1sAdvocates o f surgery point out that patients have much better overall long-term results when treated with surgical procedures than with percutaneous techniques and that morbidity and mortality rates have steadily been reduced. However, the controversy over the optimal therapy for patients with claudication with isolated femoral popliteal disease cannot be settled by comparing such reports. Patients vary significantly in lesion severity, runoff status, and risk factors. Many of the reports of endovascular procedures disregard initial failure, which may be as high as 25%, and use symptomatic improvement rather than objective noninvasive criteria for estimating patency. Wilson et al.16 reported a prospective randomized study

890 A d Hoc Committee on Clinical Research

comparing transluminal balloon angioplasty versus surgical therapy for aortoifiac occlusive disease and showed that the results of the two methods were similar. A comparable study looking at isolated femoral popliteal occlusive disease has not yet been conducted in this country and is clearly needed. The problem with any study comparing endovascular approaches with each other or, as in this case with surgery or noninterventional treatment, is that rapid technologic advancements have spawned quite a number of devices that are constantly being improved along with the guidance systems that ultimately determine their degree of technical success. Thus ira single endovascular device, be it a balloon, laser or atherectomy device, were to be chosen for randomized comparison, interventionalists would fikely declare the results of any long-term study invalid and point to the new and better technology now in use. It is therefore recommended that we compare the results of (1) the best available endovascular techniques for the lesion in question with (2) the best nonoperative approach and (3) the most appropriate direct surgical revascularization. This will require the cooperation of experienced and skilled personnel in vascular medicine, interventional radiology, and vascular surgeons in each participating center. Relatively healthy, active "disabled claudicators" with isolated femoropopliteal occlusive lesions less than 10 cm in length with less than 40% popliteal narrowing and at least two-vessel runoff would be eligible. Standard noninvasive hemodynamic criteria should be used to assess the presence and severity of arterial insufficiency. 17 Specifically excluded would be (1) Those with serious associated diseases, specifically symptomatic coronary artery disease, renal insufficiency, COPD or known coagulopathies. (2) Those with previous failed revascularization in the same or other leg. (3) Those with bilateral femoropopliteal disease in whom disease in the contralateral extremity would obscure assessment of symptomatic relief in the treated extremity. Randomization would occur after arteriography. All patients would be treated with long-term aspirin therapy (325 mg/day), and those treated with intervention (open surgical or endovascular) would be heparinized during the procedure. Oral anticoagulation with warfarin has been advocated by some to enhance patency after interventional procedures. However, no strong evidence exists, pro or con, that warfarin anticoagutation is beneficial in this circumstance) 8 Because it might confound interpretation of outcomes, antithrombotic therapy with warfarin would be specifically prohibited. The treatment groups require careful consideration and would have to be agreed on by all of the participating centers. The best conservative therapy appears to be that described by Creasy et al., 3 which consists of a supervised exercise program, on a treadmill three times per week. The best percutaneous method remains controversial, but currently the gold standard remains percutaneous balloon angioplasty. Despite the promising early technical success rate of atherectomy and LABA, the long-term

Journal of VASCULAR SURGERY

patency rates have been disappointing, with a &month restenosis rate of at least 36% to 50%) °~2 Furthermore, with the availability of the Teruma guide wire, many total occlusions can be recanalized with use of standard balloon angioplasty techniques. Thus balloon angioplasty should be given first consideration and used preferentially, particularly in short ( < 3 cm) lesions. However, evolving technology may change this. Furthermore, recognizing the limitations of balloon angioplasty in totally occluded and calcified arteries, the adjunctive use of lasers or atherectomy devices should be allowed as indicated. Thus the "best" endovascular therapy may require a combination of techniques. The best surgical therapy is also somewhat controversial. Because there has been no statistically significant difference in most clinical trials between PTFE and saphenous vein for above-knee femoropopliteal bypass, both techniques will be used. The decision regarding choic~ of bypass conduit will be left to individual participatirig surgeons. Some have advocated endarterectomy of these isolated femoral popliteal lesions) 9'2° This may be appropriate for accessible, short ( < 3 m) lesions with a normal appearing vessel back to the femoral bifurcation. In brief, as with endovascular therapy, "best" surgical treatment may involve a variety of acceptable techniques. All patients should have their status documented by clinical symptoms, segmental Doppler pressures, plethysmography, treadmill exercise, and angiograms on entry into the study. All patients in the study should undergo follow-up symptomatic evaluation with noninvasive testing (including treadmill exercise) at 1, 3, 6, 9, 12, 15, and 18 months, and then, every 6 months up to 3 years. Each patient will undergo a follow-up angiogram at 1 month and whenever noninvasive testing suggests deteriorization. Determination of primary and secondary patency and reporting of complications will be by suggested SVS/ISCVS Reporting Standards criteria. 17 The total health care cost for the patient would be determined at 1 month and for each 12-month interval. Study end points need precise definition and consideration. "Successful outcome" will require change in clinical classification and objective evidence of hemodynamic improvement and of patency (e.g., the initial technical failures of percutaneous procedures will count as a failure of primary patency). In addition to symptomatic and hemodynamic improvement, morbidity and mortality rates, 2 complication severity index, 2 and total costs will be recorded. At entry, documentation for a number of variables will be necessary to ensure balanced groups. Runoff status and other factors potentially affecting outcome, such as smoking, sex, hyperlipidemia, and diabetes mellitus should be monitored to document random distribution. On the basis of the currently available data of patients treated with conservative therapy, one would expect that the exercise group would show significant improvement in walking distance but not with hemodynamic studies. Less than 25% of these patients would have progressive

Volume 15 Number 5 May 1992

symptoms and require crossover into the endovascular or surgical treatment arms. The immediate technical success rate o f percutaneous procedures is expected to be 80% to 90%. However, the 3-year primary patency rate, including technical failures, will likely be less than 40%, although the secondary patency rate may be approximately 65%. Repeat procedures may drive up the total cost of the percutaneous methods and eventually match the total cost of surgical therapy. The surgical group should achieve a 3-year primary patency rate of approximately 70%, with a secondary patency rate o f 80% to 85%. Complication rates o f surgical and percutaneous methods will probably be similar. The total cost in the endovascular and surgical groups may well be similar, but both of these therapeutic approaches will probably be much more costly than exercise during the first year. However, it would not be surprising if the surgical - r o u p has the least cost at the end of a 5-year follow-up period. Since it involves three randomization groups, this study will require a large number of patients and multiple institutions. To show a 15% to 20% difference between any two of the groups, one would need at least 400 patients. Stratifcafion based on runoff and risk factors would dramatically increase the number of patients required.

Sam Ahn, M D Robert B. Rutherford, M D REFERENCES

1. Boyd AM. Natural course of arteriosclerosis of lower extremities. Proc R Soc Med 1962;53:591. 2. Imparato AM, Kim GE, Davidson T, et al. Intermittent claudication: its natural course. Surgery 1975;78:795. 3. Creasy TS, McMillan PJ, Fletcher EWL, et al. Is percutaneous transluminal angioplasty better than exercise for claudication? Eur J Vasc Surg 1990;4:135-40. 4. Gruntzig A. Die perkutane transluminale Rekanalisation chronischer arterienverschlusse mit einer neuen Dilatationstechnik. Baden-Baden: Verlag Gerhard Witzstrock, 1977:24. 5. Johnson KW, Colapinto RF. Transluminal dilatation-a surgeon's viewpoint. Vasc Diagn Ther 1981;2:15. 6. Spence RK, Freeman DB, Gatenby R, et al. Long-term results of transluminal angioplasty of the lilac and femoral arteries. Arch Surg 1981;116:1377.

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7. Waltman AC, Greenfield AJ, Novelline R_A,et al. Transluminal angioplasty of the lilac and femoropopliteal arteries. Current status. Arch Surg 1982;117:1218. 8. Zeitler E, Richter EI, Roth FJ, et al. Results ofpercutaneous transluminal angioplasty. Radiology 1983;146:57-60. 9. Harris RW. Percutaneous transluminal angioplasty of the lower extremities by the vascular surgeon. Presented at the Fifth Annual Meeting of the Western Vascular Society Meeting January 25-28, 1990; Coronado, CA. 10. Sanborn TA, Greenfield AJ, Gruben JK, et al. Human percutaneous and intraoperative laser thermal angioplasty: Initial clinical results as an adjunct to balloon angioplasty. J Vasc SURG 1987;5:83-90. 11. Cumberland DC, Sanborn TA, Taylor DA, et al. Percutaneous laser thermal angioplasty: initial clinical results with a laser probe in total peripheral artery occlusion. Lancet 1986;1: 1457-9. 12. Simpson JP, Selman MR, Robertson GC, et al. Transluminal atherectomy for occlusive peripheralvascular disease. Am Coil Cardiol 1988;61:96-101. 13. Bernhard VM. Bypass to the popliteal and infrapopliteal arteries. In: Rutherford RB, ed. Vascular surgery. 2nd ed. Philadelphia: WB Saunders, 1984:607-19. 14. Darling RC, Linton RR. Durability of femoropopliteal reconstructions. Am J Surg 1972;123:472. 15. Curler BS, Thompson JE, Kleinsasser L~[,et al. Autologous saphenous vein femoropopliteal bypass: analysis of 298 cases. Surgery 1976;79:325. 16. Wilson SE, Wolf GL, Cross AP. Veteran's Administration Cooperative Study No. 199. Percutaneous transluminal angioplasty vs operation for peripheral arteriosclerosis: report of a prospective randomized trial in a selected group of patients. J Vase Suv,G 1989;9:1-9. 17. Rutherford RB,Flanigan DP, Gupta SK, et al. Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery/North American Chapter, International Society for Cardiovascular Surgery. Suggested standards for reports dealing with lower extremity ischemia. J VAsc SURG 1986; 4:80-94. 18. Clagett GP, Genton E, Salzman EW. Antithrombotic therapy in peripheral vascular disease. Chest 1989;95:128S39S. 19. Inahara T, Scott CM. Endarterectomy for segmental occlusive disease of the superficial femoral artery. Arch Surg 1981;116: 1547. 20. Walker PM, Imparato AM, Riles TS, et al. Long-term results in superficial femoral artery endarterectomy. Surgery 1981; 89:231.

STAGED VERSUS SIMULTANEOUS AORTOBIFEMORAL BYPASS A N D I N F R A I N G U I N A L BYPASS Despite numerous advances in lower extremity arterial reconstruction, the proper treatment o f patients with multilevel arterial occlusive disease involving both the aortoiliac and femoropopliteal segments remains controversial. Although the exact incidence o f such multilevel disease (MLD) is unknown, it has been estimated to be

from 25% to 70% of patients undergoing arterial reconstruction, depending on the patient population and the indications for operation. 1-7 Although the clinical presentation and subsequent management o f such patients will vary, depending on the precise location and severity of the occlusive process,

892 A d Hoc Committee on Clinical Research

identification of combined segment arterial disease is important for a number of reasons. First, prognosis for limb and life is worse in patients with MLD. Second, if left untreated, proximal arterial occlusive lesions may cause premature thrombosis of distal reconstructions, and conversely, untreated distal disease may result in a greater rate of proximal graft closure. Finally, if left uncorrected, distal lesions may prevent a proximal inflow operation from achieving a satisfactory degree of hemodynamic and/or clinical improvement. Patients with MLD who undergo aortofemoral (and presumably other proximal) bypasses alone may not obtain significant symptomatic relief in 25% to 50% of cases, 1-7yet current management of such patients has generally emphasized correction of the inflow occlusion first. The principal determinant of success with this approach appears to be provision of adequate inflow to the deep femoral artery and the capabilities of the deep femoral-geniculate collateral network around the femoropopliteal occlusion to transmit better inflow into the distal popliteal artery. Because of the high clinical failure rate in patients undergoing such procedures, numerous authors have attempted to develop clinical and/or hemodynamic criteria that could reliably predict which patients were likely to benefit from this approach, s An alternate approach to MLD involves combined repair/bypass of both arterial segments. Despite the theoretic appeal of complete correction, the increased complexity of such reconstructions requires additional operating time and increases the potential for complications. Although this question has never been addressed in an appropriate prospective study, a retrospective analysis of 403 procedures performed in the early 1970s comparing patients who underwent total repair of M L D versus a historical control group in whom inflow procedures alone had been performed found a diminished patency rate for the combined total repair without a concomitant increase in limb salvage. 2 Furthermore, the need for reoperation was significantly higher in the group undergoing total repair. More recently, however, excellent results have been obtained with a two-team approach to concomitant combined reconstruction.l° The only retrospective study available found a cumulative patency of 77% in patients undergoing partial repair versus 39% for the group with total reconstructions. 2 In those patients undergoing limb salvage operations, the corresponding figures for amputation were 8% and 36%, respectively, with reoperation required in 7% versus 23% for the two groups. However, the two groups were not operated on concurrently, and no standardization existed of the techniques used for inflow or outflow reconstruction. Accordingly, the data may not be relevant to the proposed trial that would test the hypothesis that total repair is superior to staged repair in patients with M L D and does not result in an increase in serious morbidity and mortality rates. All patients with the combination of aortoiliac and ipsilateral femoropopliteal arterial occlusive disease on their initial noninvasive evaluation would be considered candidates for the study. After appropriate angiograms to

Journal of VASCULAR SURGERY

confirm the presence of aortoiliac and superficial femoral artery occlusive disease, the hemodynamic significance of each lesion must be documented. Since noninvasive studies have not been completely successfifi in classifying such lesions in those cases in which the significance of the proximal disease is not obvious (as in absent or weakened femoral pulse with total proximal occlusion or high-grade or multiple stenoses), femoral artery pressure studies should be performed or, alternatively, pull back pressures at angiography could be measured across the aortoiliac stenoses.ll If the superficial femoral artery is stenotic rather than occluded, objective hemodynamic confirmation of the significance of that lesion would be necessary. The following anatomic features would be required for participation in the study: (1) a hemodynamicatly significant extensive stenosis/occlusion of the common or external iliac artery, or distal aorta, requiring proximal reconstruction rather than an endovascular procedure; (2) a patent ipsilateral comme ~ femoral and/or deep femoral artery that is "adequate" for distal anastomosis; (3) an occlusion or hemodynamically significant stenosis of the ipsilateral superficial femoral artery; and (4) anatomy suitable for a femoral-popliteal or proximal tibial bypass. Once suitable patients have been identified, randomization into one of two groups would be performed after an appropriate informed consent had been obtained. Patients should be stratified according to whether intermittent claudication or limb-threatening ischemia is present) 2 Group 1 patients would undergo combined total repair, including reconstruction of both the inflow lesion and a synchronous, ipsilateral, femoral popliteal or tibial bypass. G r o u p 2 patients would undergo partial repair, involving only the aortoiliac segment. In both groups, if the deep femoral artery origin were stenotic, an adjunctive deep femoral artery reconstruction (profundaplasty) could be performed as part of the distal anastomosis) 3 All patients would undergo lower extremity hemodynamic measurements before discharge. These would include multilevel segmental limb pressures and pulse volume recordings to document the hemodynamic improvement after reconstruction. Within 6 weeks after operation, patients would be restudied and treadmill testing performed, where possible, to document exercise tolerance. Patients in group 2 who failed to have significant relief of symptoms or whose limbs remained in jeopardy (because of failure to heal open lesions or distal amputations) would undergo appropriate staged femoropopliteal or distal bypass. Hemodynamic studies would be repeated at 6-month intervals from the anniversary of operation for a minimum of 5 years. In addition to the perioperative morbidity and mortality rates for each of the two types of procedures, specific end points for the study would be noted. The primary end point would be relief of symptoms, or in the case of distal tissue loss, limb salvage that had necessitated the arterial reconstruction. In those patients in whom surgery had been performed for relief of claudication, standardized walking distance before and after surgery would be documented for both groups of patients. In those in whom critical ischemia was present before operation, early limb salvage would be

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noted. A secondary end point would be long-term patency of all reconstructions in the ipsilateral limb. In patients undergoing multiple, ipsilateral reconstructions, failure of any one of the reconstructive procedures would be considered a "failure" of that limb. Long-term limb salvage and relief of symptoms would also be noted for both groups. In addition, the need for reoperation in the respective groups would also be noted. Any patient with a documented decrease in anklebrachial index of 0.2 or greater during the follow-up period would be required to undergo angiography to define the status of the ipsilateral arterial reconstructions. Furthermore, the acute onset of new ischemic symptoms in a reconstructed extremity at any time between regularly scheduled noninvasive evaluations would be considered an appropriate indication for urgent repeat studies. Any segment that had occluded but was salvaged by use of "'hrombolytic therapy or balloon angioplasty would be considered as secondarily patent for the purposes of the study. Although this study is conceptually simple, a number of factors exist that add considerably to its complexity. Although MLD is common, the rigorous hemodynamic and anatomic requirements for participation in the study would significantly limit the number of suitable participants and would virtually mandate that the trial be performed on a multicenter basis, since it is unlikely that most institutions would have adequate numbers of patients to complete such a trial locally. Since the study would require a minimum of 5 years of follow-up and would require frequent noninvasive testing, it could be expensive. Finally, since patients with such diffuse lower extremity involvement tend to be older and have a high incidence of associated coronary artery disease, one could anticipate a fairly high, postoperative mortality rate in each cohort. This would reduce the patients available for long-term follow-up and require large numbers of patients in each arm of the study to support statistically valid conclusions. To detect a 20% to 30% difference in initial clinical success (total repair superior to staged repair), approximately 150 patients would have to be entered. Because of possibly greater numbers needed to detect differences in secondary end points (long-term patency, limb salvage), an additional 50 to 75 patients should be entered. Since total correction may be associated with an increased perioperative morbidity and mortality rate, continuous monitoring of perioperative adverse events should be used. Alerting and stopping hales would be invoked if significant differ-

Clinical research and vascular surgery 893

ences develop. To minimize adverse perioperative events among patients having total repair, only centers providing the expertise of a two-team approach should be enlisted. 1° Richard F. Kempczinski, M D REFERENCES

1. Brewster DC, Perler BA, Robison JG, Darling RC, Aortofemoral graft for multilevel occlusive disease. Predictors of success and need for distal bypass. Arch Surg 1982; 117:1593600. 2. Heyden B, Vollmar J, Voss EU. Principles of operation for combined aortoiliac and femoropopliteal occlusive lesions. Surg Gynecol Obstet 1980;151:519-24. 3. Martinez BD, Hertzer NR, Beven EG. Influence of distal arterial occlusive disease on prognosis following aortobifemoral bypass. Surgery 1980;88:795-805. 4. O'DonneU Jr TF, McBride KA, Callow AD, et al. Management of combined segment disease. Am J Surg 1981;141: 452-9. 5. Ouriel K, DeWeese JA, Ricotta JJ, Green RM. Revascularization of the distal profunda femoris artery in the reconstructive treatment of aortoiliac occlusive disease. J VASCSURG 1987;6:217-20. 6. Samson RH, Scher LA, Veith FJ. Combined segment arterial disease. Surgery 1985;97:385-96. 7. Sterpetti AV, Feldhaus RJ, Schultz RD. Combined aortofemoral and extended deep femoral artery reconstruction. Functional results and predictors of need for distal bypass. Arch Surg 1988;123:1269-73. 8. Rutherford RB, Jones DN, Martin MS, Kempczinski RE, Gordon RD. Serial hemodynamic assessment of aortobifemoral bypass. J VASCSUinG1986;4:428-35. 9. Sumner DS, Strandness Jr DE. Aortoiliac reconstruction in patients with combined lilac and superficial femoral arterial occlusion. Surgery 1978;84:348-55. 10. Dalman RL, Taylor Jr LM, Moneta GL, Yeager RA, Porter JM. Simultaneous operative repair of multilevel lower extremity occlusive disease. J VASCSURG1991;13:211-21. 11. Flanigan DP, Ryan TJ, Williams LR, Schwartz JA, Gray B, Schuler JJ. Aortofemoral or femoropopliteal revascularization? A prospective evaluation of the papaverine test. J VASC SURG 1984;1:215-23. 12. Rutherford RB, Flanigan DP, Gupta SK, et al. Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery/North American Chapter, International Society for Cardiovascular Surgery. Suggested standards for reports dealing with lower extremity ischemia. J VASCSURG 1986; 4:80-94. 13. Pearce WH, Kempczinski RF. Extended autogenous profimdaplasty and aortofemoral grafting: an alternative to synchronous distal bypass. J VAsc SURG 1984;1:455-8.

A P R O S P E C T I V E S T U D Y TO C O M P A R E I N S I T U BYPASSES W I T H R E V E R S E D V E I N F O R L O W E R LIMB REVASCULARIZATION Most vascular surgeons agree that autogenous tissue makes the best conduit for the below-knee popliteal or tibial arterial bypass. However, although relatively minor controversies remain relating to the technique of the

construction and the effect of site of proximal and distal anastomoses as well as rnnoffstatus, the choice between the in situ versus reversed technique has generated the most controversy. Currently, different groups have presented

894 A d Hoc Committee on Clinical Research

excellent short- and long-term studies with both the reversed saphenous vein technique, and the in situ technique. 1-3 Leather et al.2 published the results of their initial experience with the utilization of the in situ technique, which represented a significant improvement in the results of lower limb revascularization, but it has been difficult for others to separate the real benefits of this technique form concomitant technical advances and perioperative care. For example, subsequent reports have also documented similarly excellent results using reversed saphenous vein. 1,4 Thus the question remains as to which, if either, technique is intrinsically superior or under what circumstances is one better than the other. Because it is technically more demanding and associated with a significant "learning curve," some surgeons are unwilling or unable to change over to the in situ technique, s This has also affected the validity of previous randomized trials that have attempted to settle this issue. Over the last 20 years significant advances have been made in the ability to successfully perform a distal bypass. Advances such as loupe magnification, use of finer suture, better intraoperative evaluation of technical adequacy, use of pneumatic tourniquets and other less traumatic techniques for occluding blood vessels during construction, and an increased ability to detect abnormalities of and to manipulate the coagulation system have resulted in improved success of these difficult bypasses. Because of the importance of these technical advances, and also because of the improvements in perioperative care with time, it is inappropriate to use historical controls for comparative analysis. Obvious difficulties exist comparing series because of variations in patient mix (claudicator/limb salvage rates, proportion of primary reconstructions, of diabetics, of poor runoff, and the like). Ideally, for clinical series to be comparable, the patient cohort has to have similar degrees of occlusive disease and equivalent incidence of other factors that adversely affect outcome. For example, in the series by Taylor et al. 4 20% of the patients had intermittent clandication as their indication for surgery compared with a similar series from Milwaukee in which 3% of the patients had claudication. 3 On the other hand, in situ series are usually primary operations; reversed vein series may contain a significant proportion of previous graft failures. The site of distal anastomosis is important, and the popliteal : tibial ratio may vary widely in different series. This is important because a popliteal anastomosis is more difficult with the in situ technique, whereas it has advantages over reversed:vein for tibioperoneal anastomosis. Finally, there is the lack of any definitive data in the literature dealing with the nature and quality of the saphenous vein. Little attention has been directed to evaluating the quality of the vein. Undetected scarring, frequency of branching of bifid segments, and differences in diameter may significantly affect outcome. Over the past 20 years, thinking has changed regarding minimally acceptable diameter for infrainguinal bypass. Earlier teachhags suggested that saphenous vein diameter should be

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4 m m or greater. Darling et al.6 reported in 1967 that the patency rate was poor with veins less than 4 mm. Similar results were reported by other authors, 7-1° but subsequent studies have successfully used vein of 3.5 m m in diameter, H'12 and Corson et al.~3 and Leather et al. 2 have noted success with veins as small as 2.5 m m in diameter. In our own experience 2 m m is the minimum acceptable diameter for tibial bypasses. It is unlikely that such veins will be represented in a reversed vein series. Finally, the effect of length of the graft has never been settled. H o w does the length of the conduit affect shortand long-term patency? Is it better to use a good quality vein anastomosed to an isolated popliteal segment, or a longer, narrower vein to a more distal tibial artery? H o w does the patency of a 2.5 mm vein graft from the common femoral to dorsal pedal artery compare with the patency of a similar vein from the popliteal artery to the same distal artery? Part of the problem with these questions is the difficulty of any one surgeon's series having sufficient numbers to adequately address these issues. These considerations underscore the necessity of performing a cooperative prospective study with multiple centers of excellence in limb salvage surgery, to achieve adequate numbers to allow stratification of all of the significant variables affecting outcome and allow valid comparisons to be made. A multicenter trial with centers selected for high volume-distal bypass limb salvage experience is necessary. To avoid learning curve problems, centers must be experienced in in situ technique. A randomized trial enlisting centers with excellent results in both in situ and reversed bypass techniques would be ideal. Establishment of strict criteria with objective adjudication of past results would be mandatory before allowing a center to enter the trial. As an alternative to a strict randomized trial, consideration should be given to performing a prospective, nonrandomized study. This would avoid the potential problem of a randomized study being primarily carried out by those experienced in (and favoring) one technique over the other. Equal numbers of centers doing primarily in situ or reversed vein technique could be allowed to perform their favorite (best) technique only, in a nonrandomized fashion, but with equal numbers, same data collection and in sufficient numbers that other variables would balance out. Stratification for below-knee popliteal and for peroneal-tibial distal anastomosis would be required. Long-term follow-up is important with studies that use duplex scanning to document primary patency at regular intervals of 1, 3, 6, 9, and 12 months, then every 6 months for 3 to 5 years. Assisted primary patency would also be calculated. Close graft surveillance with intervention for "failing" but still patent grafts, is anticipated to significantly influence outcome, especially for in situ grafts. All patients who are candidates for infrageniculate single segment vein bypass with an intact ipsilateral greater saphenous (documented by duplex scanning or venogram) would be admitted to the study. They would be stratified

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for the presence or absence of critical limb ischemia. The (smallest) diameter of the vein used would be noted as being (a) greater than 4 mm, (b) those between 3 to 4 ram, and (c) those less than 3 mm. Length of conduit would be categorized as (a) less than 40 cm, (b) between 40 to 80 cm, and (c) greater than 80 cm. The site of the proximal anastomosis would be grouped into (a) groin (common femoral, superficial femoral, and deep femoral origins), (b) distal superficial femoral artery (origins 10 cm or more distal to the femoral bifurcation), (c) popliteal, and (d) proximal tibial. The site of distal anastomoses would be categorized into (a) below-knee popliteal, (b) tibial/peroneal, or (c) pedal. To ensure balanced in situ and reversed vein groups, it would be important to have equal number of patients with these variables in both groups. The primary end point would be primary patency. Secondary end points could include relief of symptoms, •*~'nb salvage, secondary patency, hemodynamic response W use of SVS/ISCVS reporting standards, wound, and other perioperative complications. Grafts requiring ligation of artetiovenous fistulas or lysis of competent valves within 30 days of operation would not be considered to have lost primary patency unless thrombosis occurred. Any graft requiring procedures after 30 days should be counted as having lost primary patency. Data would be collected on discharge from the hospital and at 30 days, and the patients would then be seen at 3-month intervals for the first 18 months, and 6-month intervals thereafter. At the follow-up examinations, patients would have full surveillance by noninvasive studies, including duplex scanning. The sample size would have to be large enough to detect a 10% diaSeerencebetween the various groups. It is estimated that approximately 200 patients would be required for the primary comparison of in situ-to-reversed vein bypass. However, stratification for degree of ischemia and site of distal anastomosis (below-knee popliteal, dbial) would increase this to 800 to 1000 patients, With centers that perform a high volume of such bypasses, it would probably take 1 to 2 years for all centers to recruit enough patients. Follow-up would need to be at least 3 years.

Jonathan B. Towne, M D

Clinical research and vascular surgery 895 REFERENCES

1. Taylor LM, Phinney ES, Porter JM. Present status of reversed vein bypass for lower extremity revascularizafion. J VASC SURG 1986;3:288-97. 2. Leather RP, Shah DM, Chang BB, Kaufman JL. Resurrection of the in sire saphenous vein bypass. Ann Surg 1988;208: 435-42. 3. Bandyk DF, Kaebnick HW, Stewart GW, Towne JB. Durability of the in situ saphenous vein bypass: a comparison of primary and secondary patency. J VAsc SUV,G 1987;2:256-68. 4. Taylor LM, Edwards JM, Porter JM. Present status of reversed vein bypass grafting: five-year results of a modern series. J VASCSUV,G 1990;11:193-206. 5. Levine AW, Bandyk DF, Towne JB, et al. Lessons learned in adopting the in situ saphenous vein bypass. I Vasc SUe,G 1985;1:145-53. 6. Darling Re, Linton RR, Razzuk MA. Saphenous vein bypass grafts for femoro-popliteal ocdusive disease: a reappraisal. Surgery 1967;61:31-40. 7. Bernhard VM, Ashmore CS, Evans WE, Rodgers RE. Bypass grafting to distal arteries for limb salvage. Surg Gynecol Obstet 1972;135:219-24. 8. Edwards WS, Holdefer WF, Mohtashemi M. The importance of proper caliber of lumen in femorai-popliteal artery reconstruction. Surg Gynecol Obstet 1966;122:37-40. 9. Gutelius J-R, Kreindler S, Luke JC. Comparative evaluation of autogenous vein bypass graft and endarterectomy in superficial femoral artery reconstruction. Surgery 1965;57: 28-35. 10. Thompson JE, Garrett WV. The application of distal bypass operations for limb salvage. Surgery 1980;87:717-8. 11. LoGerfo FW, Corson JD, Mannick JA. Improved results with femoropopliteal vein grafts for limb salvage. Arch Surg 1977;112:567-70. 12. Watelet J, Cheysson E, Poels D, et al. In situ versus reversed saphenous vein for femoropopliteal bypass: a prospective randomized study of 100 cases. Ann Vasc Surg 1986;1:44152. 13. Cors0n i'D, Karmody AM, Shah DM, Naraynsingh V, Young HL, Leather RP. In situ vein bypasses to distal tibial and limited outflow tracts for limb salvage: increased patency and utilization of the saphenous vein use "in situ." Surgery 1984;96:756-63. 14. Leather RP, Shah DM, Karmody AM. Infrapopliteal arterial bypass for limb salvage: increased patency and utilization of the saphenous vein use "in situ." Surgery 1981;90: 1000-8.

A U T O G E N O U S S A P H E N O U S VEIN VERSUS PTFE BYPASS F O R ABOVE-KNEE FEMOROPOPLITEAL R E C O N S T R U C T I O N Autogenous saphenous vein provides the most durable conduit for infrainguinal vascular reconstruction, yet from 20% to 50% of such grafts fail within 5 years. H° Subsequent secondary procedures for "failed" vein grafts have provided disappointing results, with 5-year patency rates approximating only 40%. 11-14In contrast, secondary intervention for failing grafts, detected by close postoper-

ative surveillance, 1417 yields much better patency rates (75% to 80%). The overall performance of prosthetic material in infrainguinal bypass has been significantly worse than vein, with the single exception of above-knee (AK) bypass, especially when applied for disabling claudication, ~8-24where 5-year patency rates of close to 60% have been recently documented (Table I). In fact, in most

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896 A d Hoc Committee on Clinical Research

Table I. Above-knee femoropopliteal bypass with PTFE Author

Year

McAuley et al. TM Sterpetti et al) 9 Charlesworth et al.20 Veith et al.s Quifiones-Baldrich et al.2I Whittemore et al.23 Prendiville et al.24

1983 1985 1985 1986 1988 1989 1990

5-Year No. of cumulative patients patencyrate

90 90 53 91 101 64 44

44% 58% 39% 38% 63% 62% 57%

trials no significant difference has occurred in patency between vein and prosthesis (specifically PTFE) for femoral-AK popliteal bypass. These observations have prompted some to hypothesize that an initial (stage I) AK prosthetic reconstruction, followed by a more distal secondary (stage II) reconstruction with vein graft in those that failed might provide more favorable additive long-term results when compared with an initial (stage I) reconstruction with use of autogenous vein AK, presuming most secondary (stage II) reconstructions in this group would then become a below-knee (BK) prosthetic bypass, where results range from 10% to 40%, depending on proportion o f popliteal versus tibial anastomoses.~-2; However, although such theoretic projections favor the prosthetic AK followed by vein BK scenario versus the vein AK followed by prosthetic BK sequence, they do not allow for the impact of surveillance and intervention for the failing graft nor for the potential availability of a vein graft from other sites (contralateral greater saphenous, either or both lesser saphenous or arm veins). Such a trial, carried through secondary reconstruction to so-called tertiary patency is proposed. The goal of this prospective randomized study then, is to determine the outcome, as defined by graft patency and limb Salvage, associated with initial (stage I) AK reconstruction followed through secondary (stage II) BK reconstruction after primary failure. The primary reconstruction (stage I) will be randomized between PTFE and autogenous saphenous vein. The secondary reconstruction (stage 1I) should stress the use of autogenous material where feasible because of the unacceptably low patency of infrageniculate, and particularly infrapopliteal prosthetic bypass. Graft surveillance programs with appropriate intervention for the failing graft would be applied to both groups~ The patient population will consist of individuals requiting primary infrainguinal reconstruction for claudication, or occasionally early ischemic rest pain or the blue toe syndrome, but not truly those in a limb Salvage situation. They must also have a suitably patent A K • segment ofpopliteal artery with no distal stenosis over 30% and a minimum of two-vessel runoff. Adequate arterial inflow must also be assured so that no proximal iliofemoral stenotic lesion in excess of 20% exists, that may necessitate a simultaneous inflow procedure. Finally, they must have an ipsilateral saphenous vein that is suitable in diameter

( > 4 ram) and length. Complete noninvasive studies and adequate artetiography will be required, and standard risk factor analysis (as suggested in SVS/ISCVS standards) will be carried out. Appropriate patients would then be randomized to receive AK bypass with either saphenous vein or PTFE (6 mm thin wall ePTFE) as the initial (stage I) reconstruction. Operative technique should be standardized as much as possible and should probably include the use of preoperative and postoperative aspirin, intraoperafive intravenous heparin unless specifically contraindicated, and postoperative dextran 40. Completion arteriography should be routine. Postoperative surveillance protocols should indude Doppler ankle pressure determinations and duplex scans with appropriate documentation of symptoms and physical findings at 3-month intervals to 18 months, and then every 6 months thereafter. Appropriate criteria regarding secondary intervention need to be defined, but we suggest the" recurrence of ischemic symptoms or the noninvasive detection of an (arbitrary) 50% graft stenosis, confirmed by arteriography, to justify revision of a patent graft. Primary, secondary, and, in this two-stage study, the so-called tertiary patency will also be calculated. The end points of relief of symptoms and limb salvage will also be assessed. Sample size requirements are based on the following considerations. In all likelihood, revision will be required in 25% of autogenous reconstructions and in some 40% of prosthetic grafts during the first 5 years. Five-year failure rates for BK secondary reconstructions are arbitrarily estimated at 25% for vein and 75% for prosthesis. With use of these figures and assuming complete crossover of vein to prosthesis (and vice versa) for stage II reconstructions, a 9% advantage to stage I prosthetic bypass would result. Surveillance methods and better vein use for stage II in the vein-first group might equalize or reverse this advantage. So a patency difference in the range of 10% is projected, with 500 cases contributed by 10 centers being requested. It is presumed that to follow these cases through reoperation may require 7 to 10 years to achieve significance. Anthony D. Whittemore, 2VID REFERENCES

1. DeWeese JA, Rob CG. Autogenous venous grafts ten years later. Surgery 1977;82:775. 2. Maini BS, Mannick JA. Effect of arterial reconstruction on limb salvage: a ten-year appraisal. Arch Surg 1978;113:1297. 3. Taylor LM Jr, Phinney ES, Porter JM. Present status of reversed vein bypass for lower extremity revascularization. J VASCSURG 1986;3:288-97. 4. Fogle MA, Whittemore AD, Couch NP, Mannick IA. A comparison of in situ and reversed saphenous vein grafts for infrainguinal reconstruction. J VASCSURG 1987;5:46-52. 5. Veith FJ, Gupta SK, Ascer E, et al. Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J VASCSURG1986;3:104-14. 6. Bandyk DF, Kaebnick HW, Stewart GW, Towne JB. Durability of the in situ saphenous vein arterial bypass: a comparison of primary and secondary patency. J VASCSURG 1987;5:256-68.

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7. Leather RP, Shah DM, Chang BB, Kaufman JL. Resurrection of the in situ saphenous vein bypass. Ann Surg 1988;208: 435-42. 8. Rutherford RB, Jones DN, Bergentz SE, et al. Factors affecting the patency of infrainguinal bypass. J VAsc SURG 1988;8:236-46. 9. Kent KC, Whittemore AD, Mannick JA. Short-term and mid-term results of an all-autogenous tissue policy for infrainguinal reconstruction. J VASC SURG 1989;9:107-14. 10. Taylor LM Jr, Edwards JM, Porter JM. Present status of reversed vein bypass grafting: five-year resuks of a modern series. J Vasc SUttG 1990; 11:193-206. 11. Szilagyi DE, Elliot JP, Smith R_F,Hageman JH, Good RK. Secondary arterial repair. Arch Surg 1975;110:48503. 12. Whittemore AD, Clowes AW, Couch NP, Mannick JA. Secondary femoropopliteal reconstruction. Ann Surg 1981; 193:35-42. 13. Brewster DC, LaSalleAJ, Robison JG, Strayhorn EC, Darling RC. Femoropopliteal graft failures: clinical consequences and ":~ successof secondary reconstructions. Arch Surg 1983;118: 1043-7. 14. Cohen JR, Mannick JA, Couch NP, Whittemore AD. Recognition and management of impending vein-graft failure. Arch Surg 1986;121:758-9. 15. Le MC, Luscombe JA, Figg-Hoblyn L, Taylor LM Jr, Porter JM. Decreased graft flow velocity is a reliable early indication of impending failure of reversed vein grafts. J Vase Tech 1988;12:133-7. 16. Bandyk DF, Schmitt DD, Seabrook GR, Adams MB, Towne JB. Monitoring functional patency of in sire saphenous vein

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17. 18. 19.

20.

21.

22. 23.

24.

bypasses: the impact of a surveillance protocol and elective revision. J VASCSURG1989;9:286-96. Edwards JE, Taylor LM Jr, Porter JM. Treatment of failed lower extremity bypass grafts with new autogenous vein bypass grafting. J VASCSURG 1990;11:136-45. McAuley CE, Steed DK, Webster MW. Seven-yearfollow-up of expanded polytetrafluoroethylene (PTFE) femoropopliteal bypass grafts. Ann Surg 1984;199:57-60. Sterpetti AV, Schult RD, Feldhaus RJ, Peetz DJ Jr. Sevenyear experience with polytetrafluoroethylene as above-knee femoropopliteal bypass graft. Is it worthwhile to preserve the autologous saphenous vein? J VAsc SURG 1985;2:907-12. Charlesworth PM, Brewster DC, Darling RC, Robison JG, Hallet JW. The fate ofpolytetrafluoroethylene grafts in lower limb bypass surgery: a six-year follow-up. Br J Surg 1985; 72:896-9. Quifiones-BaldrichWJ, Busuttil RW, Baker JD, Vescera CL, Machleder HI, Moore WS. Is the preferential use of polytetrafluoroethylene grafts for femoropopliteal bypass justified? J VAsc SURG1988;8:219-28. Kent KC, Donaldson MC, Attinger CE, Couch NP, Mannick JA, Whittemore AD. Femoropopliteal reconstruction for claudication. Arch Surg 1988;123:1196-8. Whittemore AD, Kent KC, Donaldson MC, Couch NP, Mannick JA. What is the proper role of polytetrafluoroethylene grafts in infrainguinal reconstruction? J VAsc SURG 1989;10:299-305. Prendiville EJ, Yeager A, O'Donnell TF, et al. Long-term results with the above-knee popliteaI expanded polytetrafluoroethylene graft. J VASCSURe 1990;11:517-24.

CLINICAL R E S E A R C H TRIALS U S I N G N O N I N V A S I V E V A S C U L A R TESTING Hemodynamic and anatomic abnormalities produced by arterial and venous disease can be identified and measured in the noninvasive vascular laboratory. Clinical application of noninvasive testing began using indirect techniques that relied on the detection of hemodynamic alterations distal to pressure- and flow-reducing occlusive lesions. Methods that used Doppler ultrasonography and plethysmography formed the cornerstone for the noninvasive diagnosis of cerebrovascular and peripheral arterial occlusive disease, deep venous thrombosis (DVT), and chronic venous insufficiency. Continued developments in ultrasound imaging, including duplex ultrasonography and more recently color flow imaging, have resulted in greater emphasis on direct anatomic studies that can not only detect the presence of disease, but can also localize its extent and characterize the underlying pathologic process. Duplex scanning can identify normal and abnormal peripheral vascular anatomy with an accuracy comparable to invasive contrast studies. An important advantage of noninvasive testing methods is the ability to be performed serially, thus adding to a temporal ~derstanding of disease processes. Noninvasive diagnostic methods have served as valuable research tools and have expanded our knowledge of the natural history of vascular disease. A recent example of the

research contributions in this field is the recognition with duplex scanning of disease progression in the internal carotid artery as a risk factor for subsequent neurologic events? This observation muld not have been made with indirect methods or arteriography. Current clinical applications of noninvasive testing include the evaluation of patients with suspected peripheral arterial, cerebrovascular, or venous diseases. In most patients with suspected vascular disease, noninvasive testing is used to supplement physical examination and presenting symptoms, but it is an important essential in the diagnosis of venous thrombosis and the surveillance of arterial bypass grafts because most patients with clinically important lesions are asymptomatic, or presenting symptoms and signs are unreliable for diagnosis or exclusion of disease. In these two important areas of noninvasive vascular testing a diversity of technologies and new clinical questions have arisen that are ideal for formal clinical studies. Randomized clinical studies with specific noninvasive testing protocols should add to our knowledge in these areas and establish which measurements or testing procedures are most appropriate to establish a diagnosis, assess results of treatment, and clearly define the natural history of the underlying disease process.

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898 A d Hoc Committee on Clinical Research

Design of studies must take into account prevalence of disease in the population studied, the reliability of the gold standard (e.g., arteriography, venography), and sample size) Important in the planning and conduct of these studies should be an attempt to avoid answering questions of secondary interest. This permits sample size to be kept small and avoids the organizational difficulties of using multiple centers with uncontrolled, unrecognized variables. Although large multicenter trials appear to be in vogue, recent concerns expressed regarding the design, conduct, and supervision of this form of research should be heeded. 3 Diagnosis and t r e a t m e n t o f deep venous t h r o m b o s i s Several diagnostic techniques have been introduced to supplant contrast venography for the detection of acute DVT including serial impedance plethysmography (IPG), B-mode ultrasonography, and duplex ultrasonography. On the basis of both retrospective and prospective series of inpatients and outpatients with suspected DVT, the diagnostic accuracy of these modalities compared with contrast venography has been reported to be in excess of 90%) 7 It has become apparent, however, that while this may be true in patients with suspicious symptoms, indirect techniques such as plethysmography are not as accurate in asymptomatic patients with nonocclusive thrombi. 8'9 A high (20% to 40%) false-positive rate has been reported when IPG is used in the postoperative period, and in patients with known chronic venous thrombosis) ° It would therefore be appropriate to conduct a study to determine ifIPG still has a role in the diagnosis or exclusion of clinically important DVT in patients at high risk. Conversely, duplex ultrasonography and color duplex systems provide detailed anatomic data and flow data in patients with occlusive thrombi in the femoropopliteal venous segment but are subject to both erroneous and equivocal scans in the diagnosis of iliac vein or calf-vein thrombosis, or accurate determination of the age of the thrombotic process. Recent experience with color duplex ultrasonography suggests this newer technology may improve the diagnostic accuracy of conventional duplex scanning because of an improved ability to visualize collateral channels, pelvic and infrapopliteal vessels, and nonoccluding thrombus, n A comparative study of IPG, and duplex ultrasonography (grey scale, color) for establishing the diagnosis of acute lower limb venous thrombosis could provide data of diagnostic accuracy relative to clinical presentation, patient outcome, and cost-effectiveness. Patients should be studied prospectively and randomized with respect to the initial noninvasive testing procedure (IPG or duplex scanning). Serial IPG examinations would be required if the initial test is normal to exclude progression of calf-vein or nonoccluding thrombus. All patients should undergo venography to determine diagnostic accuracy of each noninvasive test method relative to site of thrombosis (iliac, femoropopliteal, infrapopliteal). Stratification of patients with rest~ect to r~resenceof le~ symptoms, ambulatory status, or

recent surgical procedure is necessary when reporting primary and secondary end points relative to testing method used. Grading schemes for disease severity, risk factors, and outcome criteria should follow the suggested reporting standards in venous disease prepared by the SVSflSCVS Ad Hoc Committee of Reporting Standards.12 Extended follow-up of both treated and untreated patients should be carried out to determine the incidence of pulmonary embolus, DVT, and chronic limb symptoms.

Study 1 Hypothesis. Serial IPG has a role in the diagnosis of clinically significant DVT in asymptomatic surgical patients at high risk (e.g., after total knee or hip replacement). Studydesign. A prospective study of high-risk surgical patients (DVT prevalence of 30% to 40%) would be performed with patients having serial IPG and duplex ultrasonography. The technicians performing each tes ~" would be blinded as to the results of the other test. Testing would be performed before operation, day 1, day 3, day 7, and day 14. Ventilation-perfusion scanning would be performed before operation and on day 7, and lower limb venography would be performed on day 7 after operation. At the conclusion of the study, the following questions could be answered: (1) What is the diagnostic accuracy (sensitivity, specificity, positive and negative predictive value) of serial IPG for the diagnosis of DVT in the lower limb veins? (2) What is the diagnostic accuracy of duplex ultrasonography in the diagnosis of acute DVT in the lower limb veins? (3) What is the incidence of pulmonary embolism in patients who have negative studies of either type? At least 150 patients would need to be studied to determine diagnostic accuracy of these surveillance techniques. A much larger number would be required to definitively answer the clinical relevance of DVT not diagnosed by noninvasive tests (e.g., calf vein thrombosis, nonoccluding thrombi, and the like). This study could be performed in a single institution that had a large volume of patients at high risk for postoperative DVT.

Study 2 Hypothesis. Duplex ultrasonography is superior to IPG in the diagnosis of patients with symptoms of DVT. Studydesign. Patients with symptoms of DVT would undergo IPG and duplex ultrasonography. The technicians performing each test would be blinded as to the resuks of the other test. All patients would undergo venography, At the conclusion of this study an assessment could be made of whether IPG remains an appropriate screening test for symptomatic patients or whether it should be replaced with duplex ultrasonography. Cost-effectiveness analysis should be a part of this study since IPG is cheaper than duplex ultrasonggraphy. However, the cost of missed diagnoses of DVT as well as the added costs of serial IPG in the case of calf vein thromboses might favor duplex ultrasonograpby. If one assumes that approximately 50% of patients with symptoms actually have DVT, at least 200 patients would be needed for this study.

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Study 3 Hypothesis. Duplex ultrasonography can be used to assess adequacy of treatment of DVT. Study design. Patients with proximal (popliteai, femoral, iliac) DVT, confirmed by venography, would receive standard anticoagulation therapy consisting of heparin (7 to 10 days) and sodium warfarin (3 months)J 3 Before initiation of anticoagulation, all patients would have blood drawn for extensive hematologic workup to detect prothrombotic or hypercoagutable states. Extra plasma should be stored frozen for future assay as new biochemically defined hypercoagulable states are identified. Clinical risk factors for DVT would also be carefully assessed. All patients would receive serial duplex scanning before therapy and daily while the patient is on heparin anticoagulation; at 2 weeks; and then once a month for the duration of oral anticoagulant therapy) 4 Lower extremity ~,enography would be performed after 7 days of therapy. Patients would be followed clinically at 6-week intervals for 1 year and then at 3-month intervals thereafter to assess resolution rate of DVT, incidence of recurrent DVT, pulmonary embolus, and the development of chronic venous insufficiency. Diagnosis of recurrent D V T would be made by repeat venography. Chronic venous insufficiency would be assessed clinically (edema, presence of venous stasis changes, and the like) and by standardized noninvasire tests that could include careful duplex ultrasonography, venous refill times by photoplethysmography, and ambulatory venous pressure measurements. The data from this study could be used to derive correlates between fixed variables (clinical risk factors, hypercoagulable states, anatomic location and extent of DVT) and progression or regression of D V T assessed by serial duplex ultrasonography. Furthermore, the influence of progression on clinical end points such as recurrent venous thromboembolism and chronic venous insufficiency could be determined, is This study would essentially be a natural history study of progression of DVT (defined by duplex ultrasonography) on standard anticoagulant therapy. As such, this is a longitudinal study and not a RCT. It might allow identification of a subset of patients with common risk factors who are prone to progression despite standard anticoagulant therapy. These may also be the patients who develop recurrent venous thromboembolism during or after cessation of oral anticoagulant therapy and who are prone to develop chronic venous insufficiency. The logical next step would be to perform randomized clinical trials in such high risk patients to assess different anticoagulant regimens (comparing standard therapy with more intense or more prolonged therapy). In addition, this subset might provide an interesting group in which to compare anticoagulant versus thrombolyfic therapy. S t u d y f o r surveillance o f i n f r a i n g u i n a l arterial b y p a s s Vascular laboratory surveillance of infrainguinal arterial bypasses for occlusive and aneurysmal lesions that threaten graft patency is a generally accepted but unproved concept in vascular surgery. Depending on graft type

Clinical research and vascular surgery 899

(autologous vein, prosthetic), and the runoff arterial tree, graft failure rates in excess of 30% occur by 5 years. Regular clinical evaluation by history taking and pulse palpation often fail to detect impending graft failure. Justification for graft surveillance is further supported by the observed 20% to 30% incidence of stenotic lesions identified by surveillance protocols using either arteriography or noninvasive hemodynamic testingJ 618 The goal of graft surveillance is to not only identify stenotic or aneurysmal lesions but to provide the physician with reliable parameters that predict which bypasses are at risk for sudden thrombosis. Asymptomatic vein graft strictures detected by both angiography and duplex scanning have been associated with a significandy increased risk of graft occlusion in comparison to normal g r a f t s J 9 Revision of a failing graft without interruption in patency is particularly important for autologous vein conduits because most will not maintain patency after thrombectomy/thrombolysis alone or with vein-patch angioplasty. 2° The most appropriate method or methods of infrainguinal bypass graft surveillance have not been determined. Doppler-derived extremity pressure measurements, pulse volume recordings, graft velocity waveform analysis, and duplex scanning have been used alone and in combination to identify the "at risk" graft. It is important to emphasize that little published information exists about the natural history of patients who develop deterioration of ankle systolic pressure or other hemodynamic parameters of graft function. A recent retrospective case-study found a deterioration in aulde-brachial index (ABI) after bypass grafting did not predict impending femoropopliteal of femorotibial graft failure. 21 By contrast, Green et al.22 reporting on a retrospective comparison of graft surveillance techniques found grafts harboring lesions that decreased ABI by 10% or greater and were associated with an abnormal duplex scan (low graft flow and/or stenosis), had 66% incidence of thrombosis within 3 months, compared with a 14% risk of failure if only the ABI was abnormal and 4% risk of failure if only the duplex scan was abnormal. Serial color duplex scans have been advocated for all postoperative follow-up, but this approach is expensive, time-consuming, and may identify a spectrum of lesions of which only a portion place the graft at risk for sudden thrombosis. 23,24 The relationship between degree of graft stenosis identified by duplex scanning and risk of thrombosis requires further study. The observations cited above justify a clinical study that compares how graft surveillance techniques influence patency, patient outcome, and medical costs. Hypothesis. Intensive surveillance with noninvasive tests of infrainguinal bypasses predicts bypass failure, improves patency, and is cost-effective. Study design. Patients would be enrolled before bypass and randomized to intensive surveillance plus intervention or intensive surveillance without intervention. Subjects should be stratified at randomization with respect to the indication for operation, graft type, and runoff anatomy. This would ensure a balanced distribution of these variables between groups. Reporting standards suggested by the SVS/ISCVS Ad Hoc Committee should be

900

Ad Hoc Committee on Clinical Research

used. 2s A combination o f indirect (pressure measurements, pulse volume recordings) and direct (color duplex imaging) testing methods would be used to monitor functional patency of infrainguinal bypasses. Graft hemodynamics should be directly measured by either calculation of blood flow velocity, volume flow, or both. Surveillance intervals would be standardized for all patients. In patients randomized to intensive surveillance plus intervention who demonstrate deterioration of limb hemodynamics or duplex evidence of anatomic abnormalities (e.g., focal graft stenoses), angiography, and correction (either open surgical or endovascular) of confirmed lesions would be carried out. Specific criteria for abnormalities detected by noninvasive tests as well as the degree of severity of lesions seen on angiography that would require correction would be determined before beginning the trial. In patients randomized to intensive surveillance without intervention, knowledge of the results of noninvasive tests would be withheld from patients and their physicians. Intervention would be triggered only by the development of recurrent or new ischemic symptoms along with changes in pulse examination and other clinical findings. The major end points for analysis would be unassisted (primary) and assisted (secondary) patency rates. In addition to the clinical utility and cost-effectiveness of noninvasive graft surveillance, the most useful test or combination of tests could be determined. Because of the heterogeneous patient population undergoing infrainguinal bypass grafting and a 10% to 15% prevalence of "graft stenosis," a sample size in excess o f 500 patients would be required to detect a 15% difference in primary or secondary patency rates. Comparison of graft surveillance techniques would be hampered by the expected decrease in patient survival (approximately 5% per year). Because of the large sample size, the study would require participation of multiple institutions.

Dennis F. Bandyk, M D David S. Sumner, M D Brian L. ThMe, M D James S. T. Yao, M D REFERENCES 1. Roederer GO, Langlois YE, lager ICA~ et al. The natural history of carotid arterial disease in asymptomatic patients with cervical bruits. Stroke 1984;15:605-13. 2. Sumner DS. Evaluation of noninvasive testing procedures, data analysis and interpretation. In: Bernstein EF, ed. Noninvasive diagnostic techniques in vascular disease. 3rd ed. St. Louis: CV Mosby, 1985:861-89. 3. StrandnessDE Jr. Randomized cllnical trials: enough bangfor the buck? J VAse SUV,G 1991;13:544-5. 4. Hull RD, Hirsch J, Carter CJ, et al. Diagnostic efficacy of impedance plethysmography for clinicallysuspected deep-vein thrombosis: a randomized trial. Ann Intern Med 1985;102: 21-8. 5. Huisman MV, Buller HR, TenCate JW, et al. Serial impedance plethysmography for suspected deep venous thrombosis in outpatients. N Engl J Med I988;314:823-8. 6. Lensing AWA, Prandoni P, Brandies D, et al. Detection of

lournal of VASCULAR SURGERY

deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989;320:342-5. 7. Cranley JJ. Diagnosis of deep venous thrombosis, in: Bernstein EF, ed. Recent advances in noninvasive diagnostic techniques in vascular disease. St. Louis: CV Mosby, 1990: 207-12. 8. Comerota AJ, Katz ML, Grossi RJ, et al. The comparative value of noninvasive testing for diagnosis and surveillance of deep venous thrombosis. J VASCSURG 1988;7:40-9. 9. Patterson RB, Fowl RJ, Keller JD, et al. The limitations of impedance plethysmography in the diagnosis of acute venous thrombosis. J VAse SUt~G1989;9:725-30. 10. Wright DJ, Shepard AD, McPharlin M, Ernst CB. Pitfalls in lower extremity venous duplex scanning. J VASC SURG 1990;ii:675-9. 11. Persson AF, lones C, Zide R, lewell ER. Use of the triplex scanner in diagnosis of deep venous thrombosis. Arch Surg 1989;124:593-6. 12. Porter JM, Rutherford RB, Clagett GP, et al. Reporting standards in venous disease. J VASC SURG 1988;8:172-81-" 13. Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest I989;95:37S-51S. 14. Krupski WC, Bass A, Dilley RB, Bernstein EF, Otis SM. Propagation of deep venous thrombosis identified by duplex ultrasonography. J VASCSURG 1990;12:467-75. 15. Strandness DE. Thrombus propagation and level of anticoagnlation. J VASe SURG 1990;i2:497-8. 16. Szilagyi DE, Elliott IP, Hageman JH, et al. Biologic fate of autogenous vein implants as arterial substitutes. Ann Surg 1973;178:232-46. 17. GriggMJ, NicolaidesAN,Wolfe JHN. Detection and grading of femorodistal vein graft stenoses. J VAse SURG 1988;8: 661-6. 18. Bandyk DF, Schmitt DD, Seabrook GR, et al. Monitoring fimctional patency of in situ saphenous vein bypasses: the impact of a surveillance protocol and elective revision. J Vase SURG i989;3:286-96. 19. Moody P, de Cossart LM, Douglas HM, Harris PL. Asymptomatic strictures in femoro-popliteal vein grafts. Eur J Vase Surg 1989;3:389-92. 20. Whittemore AD, Clowes AW, Couch NP, et al. Secondary femoropopliteal reconstruction. Ann Surg 198I;193:35-42. 21. Barnes RW, Thompson BW, MacDonald CM, et al. Serial noninvasive studies do not herald postoperative failure of femoropopliteal or femorotibial bypass grafts. Ann Surg 1989;210:486-94. 22. Green RM, McNamara J, Ouriel K, DeWeese JA. Comparison of infrainguinal graft surveillance techniques. J Vase SURG 1990;1i:207-15. 23. DisselhoffB, Buth J, laldmowicz l- Early detection ofstenosis of femoro-distal grafts: a surveillance study using color-duplex scanning. Eur J Vase Surg I989;3:43-8. 24. Sladen JG, Reid JDS, Cooperberg PL, et al. Color flow duplex screening of infrainguinal grafts combining low- and highvelocity criteria. Am J Surg 1989;i58:107-12. 25. Rutherford RB, Flanigan DP, Gupta SK, et al. Suggested standards for reports dealing with lower extremity ischemia. J VAsc SURG 1986;4:80-94. 435-42. 26. Rutherford RB, Jones DN, Bergentz SE, et al. Factors affecting the patency of infrainguinal bypass. J VAsc SUI~G 1988;8:236-46. 27. Kent KC, Whittemore AD, Mannick JA. Short-term and mid-term results of an all-autogenous tissue policy for infralnguinal reconstruction. J VASC SURG I989;9:107-14.

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28. Taylor LM lr, Edwards JM, Porter JM. Present status of reversed vein bypass grafting: five-year resuks of a modern series. J VAsc SURG 1990;11:193-206. 29. Szilagyi DE, Elliot JP, Smith RF, Hageman JH, Good RK. Secondary arterial repair. Arch Surg 1975;110:485-93. 30. Whittemore AD, Clowes AW, Couch NP, Mannick JA. Secondary femoropopliteal reconstruction. Ann Surg 1981; 193:35-42. 31. Brewster DC, LaSalleAJ, Robison JG, Strayhorn EC, Darling RC. Femoropopllteal graft failures: clinical consequences and success of secondary reconstructions. Arch Surg 1983;118: 1043-7. 32. Cohen JR, Mannick JA, Couch NP, Whittemore AD. Recognition and management of impending vein-graft failure. Arch Surg 1986;121:758-9. 33. Le MC, Luscombe JA~ Figg-Hoblyn L, Taylor LM Jr, Porter IM. Decreased graft flow velocity is a reliable early indication of impending failure of reversed vein grafts. J Vasc Tech 1988;12:133-7. a4. Bandyk DF, Schmitt DD, Seabrook GR, Adams MB, Towne JB. Monitoring fimctional patency of in sire saphenous vein bypasses: the impact of a surveillance protocol and elective revision. J VASCSURG1989;9:286-96. 35. Edwards J-E, Taylor LM [Jr, Porter JM. Treatment of failed lower extremity bypass grafts with new autogenous vein bypass grafting. J VASCSURG 1990;11:136-45.

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36. McAuley CE, Steed DK, Webster MW. Seven-yearfollow-up of expanded polytetrafluoroethylene (PTFE) femoropopliteal bypass grafts. Ann Surg 1984;199:57-60. 37. Sterpetti AV, Schult RD, Feldhaus RJ, Peetz DJ Jr. Sevenyear experience with polytetrafluoroethylene as above-knee femoropopliteal bypass graft. Is it worthwhile to preserve the autologous saphenous vein? J VASC SURG 1985;2:907-12. 38. Charlesworth PM, Brewster DC, Darling RC, Robison JG, Hallet JV/. The fate of polytetrafluoroethylene grafts in lower limb bypass surgery: a six-year follow-up. Br J Surg 1985; 72:896-9. 39. Quifiones-BaldrichWJ, Busuttil RW, Baker JD, Vescera CL, Machleder HI, Moore WS. Is the preferential use of polytetrafluoroethylene grafts for femoropopliteal bypass justified?J VASe SURG 1988;8:219-28. 40. Kent KC, Donaldson MC, Artinger CE, Couch NP, Mannick JA, Whittemore AD. Femoropopliteal reconstruction for ctaudication. Arch Surg 1988;123:1196-8. 41. Whirtemore AD, Kent KC, Donaldson MC, Couch NP, Mannick JA. What is the proper role of polytetrafluoroethylene grafts in infrainguinal reconstruction? I VASC SURG 1989;10:299-305. 42. Prendiville EJ, Yeager A, O'Donnell TF, et al. Long-term results with the above-knee popllteal expanded polytetrafluoroethylene graft. J VASCSURG 1990;11:517-24.

APPENDIX I T a s k forces Task force 1: Cerebrovascular disease and abdominal aortic aneurysms Eugene F. Bemstein, MD, Chairman Louis R. Caplan, MD M. David Tilson, MD Task force 2: Anticoagulants, antithrombotic drugs, and perioperative care and monitoring G. Patrick Clagett, MD, Chairman Jack L. Cronenwett, M D Thomas M. Dodds, MD Paul M. Walker, MD Mark P. Yeager, MD Task force 3: Vascular trauma, renal and splanchnic arterial disease Robert W. Hobson, II, MD, Chairman Raymond H. Alexander, MD F. William Blaisdell, MD Richard H. Dean, MD Malcolm O. Perry, MD Norman M. Rich, MD Task force 4: Thrombolytic therapy, drugs for treating intermittent claudication, cholesterol lowering drugs and other antilipemics, and thoracic outlet syndrome John M. Porter, MD, Chairman Anthony J. Comerota, MD Joseph H. Rapp, M D Lloyd M. Taylor, Jr., MD Asa J. Wilboum, MD

Task force 5: Lower extremity ischemia, interventional techniques, angioscopy and endovascular surgery Robert B. Rutherford, MD, Chairman Samuel S. Ahn, MD Richard F. Kempczinski, MD Jonathan B. Towne, MD Anthony D. Whittemore, MD Paul M. Walker, MD Task force 6: Noninvasive and other diagnostic vascular tests and venous insufficiency (medical and surgical treatment) James S. T. Yao, MD, Chairman Dennis F. Bandyk, MD David S. Sumner, MD Brian L. Thiele, MD Statistical consultant to Ad Hoc Committee on Clinical Research Donald D. McIntire, PhD