Risk factors for restenosis after balloon angioplasty in focal iliac stenosis

Risk factors for restenosis after balloon angioplasty in focal iliac stenosis Hiroshi Yasuhara, MD, Hiroshi Shigematsu, MD, and Tetsuichiro Muto, MD, Tokyo, Japan

Background. The risk factors for restenosis after angioplasty have not yet been established because of the inconsistencies among treated lesions, differences in the techniques used, and variable end points. We evaluated the predictive variables relating to postangioplasty restenosis. Methods. One hundred sixty-one transluminal balloon angioplasties were studied in 138 consecutive patients with focal iliac arterial stenosis (≤4 cm) caused by arteriosclerosis between January 1981 and December 1995. Restenosis was diagnosed on the basis of recurrent symptoms associated with an apparent drop in the ankle-brachial pressure index and angiographic visualization of restenosis. Results. Being younger than 60 years (risk ratio 2.585) and poor runoff (risk ratio 2.328) were found to be important variables predicting restenosis by the Cox regression model. The restenosis-free patency rates were significantly better in patients older than 60 years of age (p = 0.0242), with good distal runoff (p = 0.0487), and without diabetes (p = 0.0111). Conclusions. Being younger than 60 years of age and poor distal runoff are important predictors of restenosis after iliac balloon angioplasty. (Surgery 1998;123:658-65.) From the Department of Surgery I, University of Tokyo, Tokyo, Japan

ANGIOPLASTY HAS BECOME THE TREATMENT modality of choice in a highly select subset of patients with aortoiliac occlusive lesions that are technically amenable to this approach. Most authors agree that the best results are obtained with iliac dilations that reportedly have long-term primary patency rates of 80% to 90%.1-4 However, restenosis at the angioplasty site remains an unsolved problem despite a variety of recently introduced vascular stents.5 In previous reports regarding the results of angioplasty, the study patients underwent several types of endovascular procedures for a variety of arterial lesions. The inconsistencies among the profiles of the study patients have resulted in disparate conclusions being drawn by different investigators. Furthermore, most of the previous studies yielded limited information on the basic mechanisms underlying restenosis because clinical success was based on assessment of clinical outcomes. Therefore we comprehensively studied patients undergoing iliac balloon angioplasty. Multivariate and univariate analyses were used to identify important variables predicting restenosis.

Accepted for publication Nov. 4, 1997. Reprint requests: H. Yasuhara, MD, Department of Surgery I, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. Copyright © 1998 by Mosby, Inc. 0039-6060/98/$5.00 + 0 11/56/88086

658 SURGERY

METHODS Patients. This prospective study involved 138 consecutive patients who underwent a single angioplasty technique (i.e., iliac balloon angioplasty) exclusively for focal iliac stenosis caused by peripheral arteriosclerosis. One hundred sixty-one iliac balloon angioplasties were performed on these patients at the Department of Surgery I of the University of Tokyo from January 1981 to December 1995. There were 130 men and eight women with a mean age of 66 years (49 to 96 years). Balloon angioplasty procedure. Balloon angioplasty was indicated exclusively for focal iliac stenosis less than 4 cm. Main stenotic lesions were confined at 77 sites in the common iliac artery and 68 in the external iliac artery. Sixteen stenotic lesions in the external iliac artery extending to the common iliac artery were classified as external iliac artery stenoses. Patients with total iliac obstruction or long segmental stenoses were excluded from the study. All procedures were performed by a single angiography group comprised of vascular surgeons. The initial technical success of angioplasty was determined from the angiographic appearance immediately after the procedure and hemodynamic measurements with disappearance of the pressure gradient at the angioplasty site associated with improvement of the ankle-brachial pressure index (ABPI) by more than 0.10.6,7 All patients showed clinical category improvement exceeding +1 according to the categories and results classifica-

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Surgery Volume 123, Number 6 Table I. Prognostic variables in 161 balloon angioplasties for iliac stenosis Subcategories Gender Age (yr) Smoking Hypertension Diabetes History of coronary artery disease History of cerebrovascular episodes Angioplasty site including external iliac artery Runoff Concomitant distal bypass grafting Predilation ABPI

tion of the Society for Vascular Surgery/International Society for Cardiovascular Surgery.6 Low-dose heparin (500 IU/hr) was administered for 24 hours after the arterial dilation. Clinical symptoms and associated disease. Balloon angioplasty was performed for grade I symptoms (from mild to severe claudication) in 154 limbs of 131 patients and for grade II symptoms (ischemic rest pain) in seven limbs of seven patients. Patients with grade III symptoms (from minor to major tissue loss [i.e., nonhealing ulcer, focal gangrene with diffuse pedal ischemia, or amputation above the transmetatarsal level]) were excluded from the study. The mean ABPI values were 0.70 ± 0.15 and 0.18 ± 0.14 for the patients with grades I and II symptoms, respectively.7 The angioplasty was performed at 41 and 120 iliac arterial sites in 35 diabetic and 103 nondiabetic patients, respectively. Concomitant revascularization. Balloon angioplasty alone was performed in 90 patients at 105 sites, whereas this procedure was done in association with distal revascularization in 56 limbs of 48 patients. The concomitant balloon angioplasties were performed during operation or within 7 days of distal revascularization during the same hospitalization. Patient follow-up and detection of restenosis. The patients were followed up every 3 to 6 months for a mean period of 5.8 years after successful balloon angioplasty. The follow-up examinations

Male Female Older (>60) Younger (≤60) Yes No Yes No Yes No Yes No Yes No Yes No Good (postdilation ABPI >0.8) Poor (postdilation ABPI ≤0.8) Yes No Good (ABPI >0.35) Poor (ABPI ≤0.35)

% 95.0 5.0 78.9 21.1 87.8 12.2 45.9 54.1 26.4 73.6 14.3 85.7 11.8 88.2 52.2 47.8 59.0 41.0 34.8 65.2 72.0 28.0

included assessment of symptoms and clinical examinations (i.e., pulse palpation and auscultation of the treated vessel and noninvasive laboratory examinations [i.e., ABPI and digital angiography]). The patients were diagnosed as having restenosis when they had recurrent symptoms at least one clinical grade more severe than immediate posttreatment symptoms accompanied by a significant drop in the ABPI values by more than 0.10 from the maximum early postprocedural level6 and visualization of restenosis at the angioplasty site on a follow-up angiogram. The follow-up period ended when the restenosis was initially diagnosed or the iliac artery was obstructed at the angioplasty site. At the end of follow-up, all patients underwent angiography. Statistical analysis. The statistical analysis was performed by both univariate and multivariate analyses with microcomputer statistical software (SAS Statistical Package; SAS Institute, Cary, N.C.). To assess possible risk factors for restenosis, univariate analyses were carried out initially to aid in determining the variables that should be included in a stepwise model. The data regarding age and ABPI were classified into categoric variables with dummy variables (Table I). Comparisons among proportions were made with Pearson’s chi-squared statistic to identify univariate differences among defined variables with respect to the occurrence of

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Table II. Univariate analysis for 161 balloon angioplasties for iliac stenosis Subcategories All patients Age Hypertension Diabetes History of coronary artery disease History of cerebrovascular episodes Angioplasty site including external iliac artery Runoff Concomitant distal bypass grafting Predilation ABPI

No. of dilated sites

No. of restenoses (%)

161 127 34 87 74 118 43 138 23 142 19 77 84 95 66 105 56 116 45

30 (19) 19 (15.0) 11 (32.4) 14 (16.3) 15 (20.6) 16 (13.7) 13 (30.2) 27 (19.6) 3 (13.0) 26 (18.3) 4 (21.1) 15 (19.5) 15 (17.9) 13 (13.7) 17 (25.8) 20 (19.1) 10 (17.9) 18 (15.5) 12 (26.7)

Older (age >60 yr) Younger (age ≤60 yr) No Yes No Yes No Yes No Yes No Yes Good (postdilation ABPI >0.8) Poor (postdilation ABPI ≤0.8) No Yes Good (ABPI >0.35) Poor (ABPI ≤0.35)

restenosis. Fisher’s exact test for 2 × 2 tables was used for small samples. For measured variables, the F statistic was used to compare means between the patients with and without restenosis. The relevant variables were selected from these variables, with univariate p values < 0.15 for inclusion in the initial step of the Cox regression analysis (Table II). For multivariate analysis of the predictive variables relating to restenosis, the Cox proportional hazards model was used. We used the risk ratio as a measure of association. The relative risk was defined as the incidence of restenosis among patients who underwent iliac balloon angioplasty. Applying a backward stepwise procedure, the combination of variables relating to restenosis was determined. The following variables were included in the study: age, smoking history, hypertension, diabetes, history of coronary artery disease, site treated (external vs common iliac artery), cerebrovascular disease, concomitant bypass, and ABPI before and after the angioplasty. The level of significance was set at 0.05. The Wald test was used to assess the significance of individual variables. For the purpose of our study, restenosis-free patency was defined as patency without clinical or angiographic evidence of restenosis. Both primary and restenosis-free patency rates were calculated by the Kaplan-Meier method (product-limit method). The statistical difference between patency curves was determined with the log-rank test. A p value < 0.05 was considered statistically significant.

p Value 0.021 0.487 0.013 0.573 0.757 0.792 0.053 0.853 0.103

RESULTS Initial success was achieved in 158 procedures (98%), and there were no serious complications or deaths. During the follow-up period, five patients had iliac occlusion after balloon angioplasty, two of whom had grade II clinical symptoms. These patients included four of the 90 patients who had undergone iliac balloon angioplasty alone and one of the 48 who had undergone iliac balloon angioplasty in conjunction with distal revascularization. Thirty patients had clinically significant restenosis, as evidenced by changes in symptoms and follow-up angiographic findings, five of whom had grade II clinical symptoms. Restenosis was observed in 20 of the patients who had undergone balloon angioplasty alone and 10 of those who had undergone both transluminal balloon angioplasty and concomitant revascularization. Another seven patients showed recurrent symptoms at least one clinical grade more severe than immediate posttreatment symptoms, accompanied by significant drops in their ABPI values of more than 0.10 from the maximum early postprocedural level. However, angiography revealed concomitant graft failure in six patients and progression of the arterial obstruction distal to the inguinal ligament level in one. In contrast, angiography revealed restenosis greater than 50% at the angioplasty segment without recurrent symptoms in two patients. Although neither of these patients was classified as having restenosis according to the definition of restenosis in this particular analysis, both had clin-

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Fig. 1. Restenosis-free patency rates for older patients vs younger patients. Vertical bars represent SEM. Dashed line indicates SE exceeding 10% of mean value.

Table III. Summary of angiographic findings and clinical assessments Clinical assessments

Restenosis (>50%) or occlusion

Recurrent symptoms with drop in ABPI (n) No recurrent symptoms (n) Total (n)

Angiographic findings No restenosis

Total

7* 119 126

37 121 158

30 2† 32

Three patients with initial failure were excluded. *Six patients had concomitant distal graft occlusion; one had progression of distal arterial obstruction. †Recurrent

symptoms appeared 6 and 8 months later.

Table IV. Cox regression model for predicting restenosis by stepwise analysis Variable Age 0 = older (>60 yr) 1 = younger (≤60 yr) Runoff 0 = good 1 = poor

Estimated coefficient

SE

Risk ratio

df

p Value

0.9499

0.4075

2.585

1

0.0197

0.8451

0.3848

2.328

1

0.0281

df, Degrees of freedom.

ical symptoms (6 and 8 months, respectively) after completion of the study (Table III). Univariate and multivariate analysis of results: significant combination of predictive variables for restenosis. The regression proportional hazards model indicated that being younger than 60 years of age (p = 0.0197) and poor runoff distal to the angioplasty site (p = 0.0281) constituted an important combination of predictive variables correlating with the occurrence of restenosis after iliac balloon angioplasty. Diabetes had a weaker association with the frequency of restenosis (p = 0.0875) (Table IV).

Other variables, including hypertension, previous history of coronary artery disease, cerebrovascular disease, concomitant bypass, and ABPI before the angioplasty, did not correlate significantly with outcome. Kaplan-Meier analysis of results Influences of advanced age on restenosis. Iliac balloon angioplasty was performed at 127 sites in 98 patients older than 60 years of age and 34 sites in 40 patients 60 years of age or younger. The elderly group included 29 patients with diabetes (30%); the younger group contained 13

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Fig. 2. Restenosis-free patency rates for patients with good vs poor runoff. Vertical bars represent SEM.

Fig. 3. Restenosis-free patency rates for diabetic and nondiabetic patients. Vertical bars represent SEM. Dashed line indicates SE exceeding 10% of mean value.

patients (33%). There was no significant difference in the prevalence of diabetes between the two patient groups. There were no significant differences in the frequency of diabetes or clinical stage between the older and younger patient groups. The mean primary patency rate of the patients older than 60 years of age was 99% in the first year, 99% in the second year, and 95% in the fifth year. The primary patency rate of the patients 60 years of age and younger was 100% in the first year, 97% in the second year, and 94% in the fifth year (i.e., essentially the same as those of the elderly patients). The restenosis-free patency rate of the elderly patients was 93% in the first year, 87% in the second year, and 80% in the fifth year, whereas the

respective rates in the younger patients were 85%, 77%, and 57%. The patency rates of the elderly patients were significantly better (p = 0.0242) than those of the younger patients (Fig. 1). Influences of distal runoff on restenosis. In this study, distal runoff was assessed hemodynamically with postangioplasty ABPI. In this analysis we regarded ABPI as reflecting distal runoff, assuming that the iliac balloon angioplasty had been successful, because there was no pressure gradient along the iliac artery. An ABPI value greater than 0.8 was taken to represent good runoff, because the ABPI in patients with isolated obstruction of the superficial femoral artery was approximately 0.8 in our previous study.

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Iliac balloon angioplasty was performed at 95 sites in 75 patients with ABPIs greater than 0.8 after the procedure and 66 sites in 63 patients with ABPIs below 0.8. The mean primary patency rates of the patients with ABPIs greater than 0.8 were 100% in the first year, 98% in the second year, and 96% in the fifth year. The corresponding rates of the patients with poor runoff were 98%, 98%, and 93%, not significantly different from those of patients with good runoff. The restenosis-free patency rate of patients with good runoff was 95% in the first year, 89% in the second year, and 82% in the fifth year, whereas the corresponding rates for patients with poor runoff were 85%, 79%, and 66%. Distal runoff thus had a significant effect on primary restenosis-free patency rates (p = 0.0487) (Fig. 2). Influences of diabetes on restenosis. The mean primary patency rate of the diabetic patients was 100% in the first year, 100% in the second year, and 89% in the fifth year. The corresponding primary patency rates of the nondiabetic patients were 99%, 98%, and 96%, not significantly different from those of the patients with diabetes. The restenosis-free patency rate of the diabetic patients was 90% in the first year, 79% in the second year, and 53% in the fifth year, whereas the respective rates of nondiabetic patients were 92%, 88%, and 83%. The patency rates of the nondiabetic patients were significantly better than those of the diabetic patients (p = 0.0111) (Fig. 3). Influences of concomitant operations on restenosis. The mean primary patency rate after iliac balloon angioplasty alone was 98% in the first year, 97% in the second year, and 94% in the fifth year. The corresponding primary patency rates after angioplasty and concomitant grafts were 100%, 100%, and 97%, essentially the same as those of the patients who underwent angioplasty alone. The restenosis-free patency rate after angioplasty alone was 91% in the first year, 85% in the second year, and 76% in the fifth year, whereas the respective rates after angioplasty and concomitant vascular reconstruction were 92%, 84%, and 75%. There were no significant differences in patency rates between the two groups. DISCUSSION The marked discrepancies among the previous results of angioplasty are mainly the result of differences in patient selection, criteria for evaluating the results, and methods of data analysis.8 In this study, patients with iliac stenotic lesions alone underwent angioplasty to minimize disparities caused by patient selection.

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The aforementioned discrepancies are undoubtedly caused in part by differences in the criteria used to judge success. In previous reports regarding restenosis after angioplasty, primary patency rates or improvements in vascular laboratory test values were often used to determine clinical success. The acceptable primary patency rate in this study was comparable to those of several previous reports.1-3,8-13 However, the mechanism or characteristics of restenosis cannot be assessed by primary patency rates alone. The criterion of clinical success has also been used instead of primary patency rates. The definition of clinical success varies from subjective recurrent symptoms to objective measurements such as ABPI or pulse-volume recordings,1,2,13 which makes the study of restenosis somewhat confusing. Rutherford and Becker7 advocated establishing objective criteria for successful percutaneous therapy on the basis of documented continued symptomatic and hemodynamic improvement with the thigh-brachial index rather than the ABPI. The definition of restenosis in this study included recurrent symptoms worsened by one or more clinical grades accompanied by a significant drop in ABPI values and findings on follow-up angiography. Although the ABPI was used in this study to assess so-called clinical success, follow-up angiography was used to confirm restenosis in symptomatic cases. By applying multivariate analysis, previous studies have demonstrated that clinical outcome depends on the angioplasty site, the indication, severity of the lesion, distal runoff, the number of sites dilated, and histories of previous angioplasty and diabetes, all of which significantly affect clinical success (not the development of restenosis).10,12,14 Several reportedly important variables were excluded from this study because the patients had only focal iliac stenosis with no history of prior angioplasty. However, it should be noted that effects of gender cannot be assessed properly because of the limited numbers of women in the study. Controversy persists as to the importance of runoff in achieving a favorable outcome after angioplasty. Some authors have suggested that the adequacy of runoff may be of little or no importance in determining early or late results.1,15 There have also been several reports indicating that runoff is important in terms of clinical success.2,3,8,11,13 We believe this difference of opinion to be attributable to differences in patient profiles and the assessments of runoff. This study demonstrated that favorable runoff significantly influenced the outcome. Our results are potentially

664 Yasuhara, Shigematsu, Muto

important because the hemodynamic assessment of runoff with the ABPI is unique. At the end of the angioplasty procedure, we always confirmed both the disappearance of the pressure gradient measured by the angioplastic catheter and adequate dilation of the stenotic lesion. This would apparently justify our major assumption that there is no pressure gradient proximal to the common femoral artery. There is another reported method of estimating runoff with angiographic findings, as outlined in the “Suggested Standards for Reports Dealing with Lower Extremity Ischemia,” by the Ad Hoc Committee, Society for Vascular Surgery/North American Chapter of the International Society for Cardiovascular Surgery.16 We did not use this method because it evaluates only external iliac artery runoff, neglecting the superficial femoral and deep femoral arteries, in cases in which the common iliac artery was treated. Although there is a possibility that our ABPI measurements underestimated distal runoff, particularly in patients with diabetes, the great importance of distal runoff was clearly demonstrated. We believe that this strengthens our conclusion. Cambria et al.17 found that percutaneous transluminal angioplasty for patients with limb-threatening ischemia was associated with a high frequency of restenosis.17 In this study, clinical symptoms did not influence the incidence of restenosis. Although the patient population of Cambria et al. was different from that of our study, there is a possibility that limb-threatening ischemia reflects poor runoff because these patients probably had multiple segmental stenoses. Residual stenosis at the angioplasty site is reportedly one of the causes of restenosis. In this study, angiographic confirmation after the procedure allowed exclusion of this parameter from the variables. Few studies have focused on the importance of patient age as a risk factor for poor clinical outcome, regardless of whether multivariate analysis was used to identify predictive variables.12,14 There is a possibility that differences in variables or end points may have underscored the importance of patient age. Another reason for previous studies having apparently failed to identify age as an important variable may be inconsistencies among angioplasty procedures applied in the study population. Although Johnston3 analyzed his results on the basis of stratification of patients with iliac percutaneous transluminal angioplasty alone, he failed to identify age as being related to clinical outcome. We believe that age data should be classi-

Surgery June 1998

fied with a dummy variable used for the sake of multivariate analysis. The effects of age in this study are supported by several previous reports describing atherosclerosis in older populations as being characterized by a slowly progressive course.18,19 Furthermore, Levy et al.20 pointed out frequent failure of primary arterial reconstruction or a need for repeated revascularization in patients with premature atherosclerosis. Their results indicate that most primary treatment failures occur within the first postoperative year, although no distal progression of arterial disease was apparent. We speculate that the rapid development of intimal hyperplasia at the anastomosis may account for the frequent early failure observed in our study. There are many implications of the relative youth of those with an apparently higher risk of restenosis. First, the frequent occurrence of restenosis in the younger patients suggests that the process of restenosis might be influenced by cellular activation. The mechanisms of restenosis after angioplasty are not yet fully understood. The development of neointimal hyperplasia is thought to be a crucial step in the process of restenosis,21,22 which bears considerable resemblance to that of atherosclerosis.23 Balloon dilation or vascular trauma may activate a variety of cells, including smooth muscle cells, endothelial cells, or platelets, at the angioplasty site. It is likely that advancing age is associated with less activation of these cells, which are involved in the process of hyperplasia. Second, the intuitive selection of younger patients with a higher prevalence of associated morbid conditions is likely to have influenced clinical outcome. However, there was no significant difference in the frequency of diabetes or advanced-stage ischemia between the two age groups in our study. Third, there is a possibility that the patient’s age may reflect factors that were not included in this study, such as platelet function, morphologic characteristics of the stenotic lesion,24 and the association of hyperhomocysteinemia.14 We endeavored to select variables allowing the prediction of restenosis from the clinical aspect. Further analytic studies are needed to identify the influences of other factors. REFERENCES 1. Spence RK, Freiman DB, Gatenby R, Hobbs CL, Barker CF, Berkowitz HD, et al. Long-term results of transluminal angioplasty of the iliac and femoral arteries. Arch Surg 1981;116:1377-86. 2. Gallino A, Mahler F, Probst P, Nachbur B. Percutaneous transluminal angioplasty of the arteries of the lower limbs: a 5 year follow-up. Circulation 1984;70:619-23.

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Surgery Volume 123, Number 6 3. Johnston KW. Iliac arteries: reanalysis of results of balloon angioplasty. Radiology 1993;186:207-12. 4. Brewster DC, Darling RC. Optimal methods of aortoiliac reconstruction. Surgery 1972;84:739-48. 5. Murphy KD, Encarnacion CE, Le VA, Palmaz JC. Iliac artery stent placement with the Palmaz stent: follow-up study. J Vasc Intervent Radiol 1995;6:321-9. 6. Ahn SS, Rutherford RB, Becker GJ, Comerota AJ, Johnston KW, McClean GK, et al. Reporting standards for lower extremity arterial endovascular procedures. J Vasc Surg 1993;17:103-7. 7. Rutherford RB, Becker GJ. Standards for evaluating and reporting the results of surgical and percutaneous therapy for peripheral arterial disease. Radiology 1991;181:277-81. 8. Walden R, Siegel Y, Runbinstein ZJ, Morag B, Bass A, Adar R. Percutaneous transluminal angioplasty: a suggested method for analysis of clinical, arteriographic, and hemodynamic factors affecting the results of treatment. J Vasc Surg 1986;3:58390. 9. Jorgensen B, Skovgaard N, Norgard J, Karle A, Holstein P. Percutaneous transluminal angioplasty in 226 iliac artery stenoses: role of the superficial femoral artery for clinical success. Vasa 1992;21:382-6. 10. Morin JF, Johnston KW, Wasserman L, Andrews D. Factors that determine the long-term results of percutaneous transluminal dilatation for peripheral arterial occlusive disease. J Vasc Surg 1986;4:68-72. 11. Kadir S, White RI, Kaufman SL, Barth KH, Williams GM, Burdick JF, et al. Long-term results of aortoiliac angioplasty. Surgery 1983;94:10-4. 12. Johnston KW, Rae M, Hogg-Johnston SA, Colapinto RF, Walker PM, Baird RJ, et al. Five-year results of a prospective study of percutaneous transluminal angioplasty. Ann Surg 1987;206:403-12. 13. Van Andel GJ, Van Erp WF, Krepel VM, Breslau PJ. Percutaneous transluminal dilatation of the iliac artery: longterm results. Radiology 1985;156:321-3. 14. Currie IC, Wilson YG, Scott J, Day A, Stansbie D, Baird RN, et al. Homocysteine: an independent risk factor for the failure of vascular intervention. Br J Surg 1996;83:1238-41.

15. Neiman HL, Bergan JJ, Yao JS, Brandt TD, Greenberg M, O’Mara CS. Hemodynamic assessment of transluminal angioplasty for lower extremity ischemia. Radiology 1982;143:63943. 16. 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. 17. Cambria RP, Faust G, Gusberg R, Tilson MD, Zucker KA, Modlin IM. Percutaneous angioplasty for peripheral arterial occlusive disease: correlates of clinical success. Arch Surg 1987;122:283-7. 18. Valentine RJ, McGillivray DC, DeNobile JW, Snyder DA, Rich NM. Intermittent claudication caused by atherosclerosis in patients aged forty years and younger. Surgery 1990;107:5605. 19. Jelnes R, Gaardsting O, Jensen KH, Baekgaard N, Tonnesen KH, Schroeder T. Fate in intermittent claudication: outcome and risk factors. Br Med J 1986;293:1137-40. 20. Levy JL, Olin JW, Piedmonte MR, Young JR, Hertzer NR. Carotid endarterectomy in adults 50 years of age and younger: a retrospective comparative study. J Vasc Surg 1997;25:326-31. 21. Russell R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-9. 22. Dartsch PC, Bauriedel G, Schinko I, Weiss HD, Hofling B, Betz E. Cell constitution characteristics of human atherosclerotic plaques selectively removed by percutaneous atherectomy. Atherosclerosis 1989;80:149-57. 23. Blankensteijn JD, Van Vroonhoven TJ, Lampmann L. Role of percutaneous transluminal angioplasty in aorto-iliac reconstruction. J Cardiovasc Surg 1986;27:466-8. 24. Spijkerboer AM, Nass PN, de Valois JC, van der Graaf Y, Eikelboom BC, Mali WP. Iliac artery stenoses after percutaneous transluminal angioplasty: follow-up with duplex ultrasonography. J Vasc Surg 1996;23:691-7.

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