Catheter-directed thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life

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1 Catheter-directed thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life Anthony J. Comerota, MD, Richard C. Throm, BA, Susan D. Mathias, MPH, Signe Haughton, BA, and Mark Mewissen, MD, Philadelphia, Pa Purpose: Treatment designed to eliminate thrombus in patients with iliofemoral deep venous thrombosis (DVT) is theoretically attractive; however, its benefits, compared with those of anticoagulation, have not been definitively demonstrated. Although not previously analyzed, an effective measure of treatment success is likely to be the assessment of health-related quality of life (HRQOL). This study evaluated whether catheterdirected thrombolysis for iliofemoral DVT is associated with improved HRQOL, compared with standard anticoagulation, and whether HRQOL outcome in the thrombolysis group is related to lytic success. Methods: An 80-item self-administered HRQOL questionnaire was developed. It contained the Health Utilities Index, Short Form-12, and disease-targeted scales, including health distress, stigma, health interference, physical functioning, and symptoms (eg, leg swelling, pain, ulcers). The HRQOL questionnaire was confirmed to be reliable and valid by means of psychometric testing. Questionnaires were administered to 98 retrospectively identified patients who had had iliofemoral DVT treated at least 6 months earlier. Sixty-eight patients who were identified through a DVT registry were treated with catheter-directed thrombolysis with urokinase (UK), and 30 patients who were identified by means of a medical record review were treated with anticoagulation alone. The treatment decision was made by the attending physician, and all patients were candidates for both thrombolysis and anticoagulation. Results: Most patients were women (61%), white (95%), married (65%), and had a mean interval since initial DVT of 16 months. The group treated with UK was younger (53 ± 17 years) than the group treated with heparin (61 ± 6 years; P =.039). After treatment, patients treated with UK reported better overall physical functioning (P =.046), less stigma (P =.033), less health distress (P =.022), and fewer post-thrombotic symptoms (P =.006), compared with the patients treated with anticoagulation alone. Within the UK group, phlebographically successful lysis correlated with improved HRQOL (P =.038). Patients classified as lytic failures had similar outcomes to patients treated with heparin. Conclusion: Patients with iliofemoral DVT treated with catheter-directed thrombolysis have better functioning and well-being, compared with patients treated with anticoagulation alone. Successful lysis was directly correlated with improved HRQOL, with patients who were classified as lytic failures having similar outcomes to patients treated with heparin. These data support the need for a future randomized trial, which should include an HRQOL measure as part of the outcome analysis. (J Vasc Surg 2000;32: ) From the Temple University School of Medicine (Dr Comerota and Mr Throm), Lewin-TAG (Ms Mathias), and the Medical College of Wisconsin (Ms Haughton and Dr Mewissen). Competition of interest: nil. Supported in part by an unrestricted educational grant from Abbott Laboratories. Presented at the Forty-seventh Joint Annual Meeting of The Society for Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery, Washington, DC, June 6-9, Reprint requests: Anthony J. Comerota, MD, Department of Surgery, Temple University School of Medicine, Broad and Ontario Sts, Philadelphia, PA Copyright 2000 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter /2000/$ /6/ doi: /mva

2 Volume 32, Number 1 Comerota et al 131 Acute iliofemoral deep venous thrombosis (DVT) is associated with significant post-thrombotic morbidity. 1-3 Treatment that removes the thrombus from the iliofemoral venous system and restores patency appears to improve the patient s clinical condition and reduces long-term post-thrombotic morbidity. 4-7 Although objective outcomes of patency, valve function, and post-thrombotic signs and symptoms have been observed to favor treatment methods designed to eliminate thrombus, 4-9 a health-related quality of life (HRQOL) outcome assessment evaluating treatment alternatives for acute DVT has not been previously performed. The National DVT Registry was organized as a multicenter venous registry to assess the impact of catheter-directed thrombolysis in patients with symptomatic DVT. 10 The outcome was determined by means of phlebography in 287 patients who underwent 312 urokinase (UK) infusions in 303 limbs with DVT. Patients with iliofemoral DVT were demonstrated by means of phlebographic results to have more successful lysis than femoropopliteal DVT, acute DVT responded better than chronic DVT, catheter-directed infusions lysed clot more effectively than systemic infusions, and patients who had an underlying venous stenosis corrected after iliofemoral clot lysis had the highest 1-year patency rate. The objectively documented outcome of patients entered into the venous registry provided an opportunity to evaluate whether catheter-directed thrombolysis for iliofemoral DVT beneficially affected the long-term outcome, as compared with similar patients with iliofemoral DVT who were treated with standard anticoagulation. This study, with a newly designed and validated HRQOL questionnaire, 11 evaluated whether catheter-directed thrombolysis for iliofemoral DVT is associated with improved HRQOL, compared with standard anticoagulation, and whether HRQOL outcome in the thrombolysis group is related to lytic success. METHODS HRQOL data were collected from patients with acute iliofemoral DVT who had received treatment with catheter-directed UK or standard unfractionated heparin intravenously at least 6 months before identification. Patients completed a reliable and valid questionnaire that addressed global issues of functioning and well-being and issues specific to DVT. 11 The questionnaire was completed as many as two times during the course of the study, at the time of initial contact and during follow-up. Study design. The HRQOL questionnaire was administered to 98 patients who were hospitalized and treated for iliofemoral DVT 6 to 44 months earlier (mean, 16 months). Subjects were retrospectively identified; 68 patients were identified from a national DVT registry and were treated with catheter-directed thrombolysis, 10 and 30 patients were identified by their treating physicians or records from their medical center as having been treated with standard unfractionated heparin anticoagulation and were converted to oral warfarin compounds. The assignment to treatment group was not randomized. Recommendations for catheter-directed thrombolysis came from physicians participating in a national DVT registry designed to monitor the clinical and phlebographic outcome of patients treated with thrombolytic therapy for acute DVT. Likewise, the recommendation for standard anticoagulation was made by the physicians, many of whom were not participants in the venous registry. In selecting the heparin cohort, efforts were made to ensure that these patients were candidates for thrombolytic therapy (ie, no contraindication was identifiable). Each patient received an introductory letter from their treating physician that explained the purpose and details of the study and invited patients to participate. Study staff followed up this letter via express mail with a copy of the self-administered questionnaire and an internal review board-approved informed consent form and postage-paid return express envelope. Patients who chose to participate returned the completed questionnaire and signed consent form to the Section of Vascular Surgery at Temple University School of Medicine. The initial questionnaire assessed the patient s current quality-of-life and the patient s recall of their HRQOL 1 month before their symptoms of DVT began. Patients who returned completed questionnaires were mailed follow-up questionnaires 6 months later. Patients completing both questionnaires received nominal compensation for their participation. Study personnel at Temple University School of Medicine tracked the data, monitored returns, and coded and edited the questionnaires. Edited questionnaires were then forwarded to Lewin-TAG for data processing and analysis. Health-related quality of life questionnaire. An 80-item questionnaire was used in this study. It contained the Short Form-12 (SF-12), which is scored to produce two summary measures: the physical component score (PCS-12) and the mental component score (MCS-12). 12 It also contained the Health Utilities Index (HUI) MARK 2/3 version,

3 132 Comerota et al July 2000 Table I. Demographic information by treatment group Sex Heparin Urokinase Characteristic group (N = 38) group (N = 60) P value Male 14 (47) 24 (35) Female 16 (53) 44 (65) Education completed Some high school or technical school graduate 15 (50) 28 (41) Some college 10 (33) 17 (25) College graduate or higher 5 (17) 23 (34) Marital status Married 22 (73) 42 (62) Single 8 (27) 26 (38) Family income < $25, (47) 21 (32) $25,000 to $50,000 9 (30) 21 (32) >$50,000 7 (23) 23 (35) Race White 29 (97) 64 (94) Nonwhite 1 (3) 4 (6) Age, years (mean ± SE) 61 ± ± which includes nine attributes of emotion, cognition, self-care, pain, vision, hearing, speech, ambulation, and dexterity, and additional items and scales specific to DVT. 13 These items included physical functioning, pain, stigma, role functioning, health interference, symptom frequency and bothersomeness, and treatment satisfaction. Statistical analysis. The effects of UK and heparin on HRQOL were compared by means of testing for differences in mean scale scores in the two groups at the time of initial contact and at the final follow-up. The statistical analyses were designed to minimize the possible effects of selection bias in this nonrandomized study. The 13 patients whose clinical history suggested a potential contraindication to thrombolytic therapy or heparin treatment were excluded from all analyses to reduce the possible selection bias. Propensity scores were used to control for demographic variables that differed between groups. 14 The propensity score is the predicted probability of a group membership derived from a logistic regression model. The logistic regression model assessed six demographic variables as possible predictors of group membership. Education, marital status, and age were retained in the model as predictors, but sex, race, and income were dropped. Controlling for the propensity score has the effect of adjusting for any group differences attributable to the effect of the demographic variables. The main results are t tests for group differences from analysis of covariance models that control for the propensity score and the number of days since the last hospitalization. Additional analyses relating to possible selection bias compared demographic variables between groups with chisquare tests for discrete variables and t tests for continuous variables and compared groups on the mean scale scores pretreatment, as recalled by the patient at the time of first contact. For assessment of the sensitivity of the results to loss to follow-up, the analysis at initial contact was repeated for the subset of patients with follow-up data, and analysis of variance was used as a means of comparing the scale scores between patients who dropped out of the study and patients who completed the study, controlling for the treatment group. Further exploratory analyses, which stratified patients by degree of lysis (failed lysis vs partial vs complete; partial and complete lysis vs heparin; failed lysis vs heparin), were conducted. Statistical analyses were carried out with SAS software (SAS Institute, Cary, NC). P values less than.05 were considered statistically significant; P values between.05 and.10 were noted and described as trends. No adjustments were made for multiple comparisons, so the exploratory analyses stratified by degree of lysis should be considered tentative.

4 Volume 32, Number 1 Comerota et al 133 Table II. Mean scale scores posttreatment Urokinase Heparin Scale item* (mean ± SE) (mean ± SE) P value Intial contact mean, 16 months N = 68 N = 30 Health Utilities Index 0.81 ± ± Health interference ± ± Role functioning physical ± ± Stigma ± ± Health distress ± ± Overall symptoms ± ± Follow-up mean, 22 months N = 48 N = 13 Health Utilities Index 0.73 ± ± Health interference ± ± Role functioning physical ± ± Stigma ± ± Health distress ± ± Overall symptoms ± ± Adjusted for propensity scores (education, marital status, age) and number of days since hospitalization. *Higher scores represent higher functioning/less interference/fewer symptoms/less distress. RESULTS Initially, 178 patients were invited to participate. Of those, 111 patients completed and returned the initial questionnaire (65% response rate), and of these, 98 patients were treated for iliofemoral DVT and formed the basis of the study. Thirteen patients were excluded for contraindication to UK or heparin. Patient demographics are listed in Table I. Most patients were women (61%), white (95%), married (65%), and had a mean interval since the initial DVT of 16 months. The patients in the UK group were younger than the patients in the heparin group (53 ± 17 vs 60 ± 16 years ; P <.039). Patients were asked to recall their pretreatment HRQOL (as of the reference hospitalization) at the time of initial contact, which was 6 months to 2 years later (range, days). The treatment groups did not differ significantly in average time between the reference hospitalization and initial contact (P =.19). No difference was found in functioning and well-being between groups before the development of DVT. After treatment, as reported at the initial follow-up (mean, 16 months), patients treated with catheter-directed thrombolysis reported a trend toward a higher mental summary scale (P =.087) and improved HUI (P =.078). Patients treated with catheter-directed thrombolysis reported better overall role physical functioning (P =.046), less stigma (P =.033), less health distress (P =.022), and fewer overall symptoms (P =.006), compared with patients who were treated with anticoagulation alone (Table II). The mean scale scores at final follow-up (mean, 22 months) show a trend toward less stigma in the lytic group (P =.10), and the reduction in health distress and overall symptoms remained significantly less than in the group of patients treated with heparin (Table II). Most of the thrombolysis patients provided data at the later follow-up (48 of 68; 71%), but fewer than half of the anticoagulation-only patients did (13 of 30 [43%]). The analyses given in Table II were repeated on the subset of 61 patients for whom follow-up data were available to assess the possible impact of the loss to follow-up. All the comparisons continued to favor the thrombolysis group, usually with similar magnitudes; despite the reduced number of patients, the difference remained statistically significant for stigma (P =.047), health distress (P =.005), and overall symptoms (P =.027), but was not significant for overall physical functioning (P =.19). A comparison of the patients who dropped out of the study with the patients who were available for follow-up revealed the patients who dropped out had better overall symptoms at initial contact (P =.020). A trend toward less health distress at initial contact among the patients who dropped out was found (P =.084). Therefore, the less symptomatic and less distressed patients were the ones dropping out. Table III evaluates the mean scale scores of the thrombolysis group at initial contact (mean, 16 months posttreatment) and final follow-up (mean, 22 months posttreatment) by the degree of lysis by means

5 134 Comerota et al July 2000 Table III. Mean scale scores of thrombolysis group by degree of lysis Groups Failure Partial Complete Scale item* (mean ± SE) (mean ± SE) (mean ± SE) P value Initial contact mean, 16 months N = 8 N = 25 N = 18 Health Utilities Index 0.78 ± ± ± Health interference ± ± ± Role functioning physical ± ± ± Treatment satisfaction ± ± ± Stigma ± ± ± Health distress ± ± ± Overall symptoms ± ± ± Follow-up mean, 22 months N = 5 N = 19 N = 13 Health Utilities Index 0.69 ± ± ± Health interference ± ± ± Role functioning physical ± ± ± Stigma ± ± ± Health distress ± ± ± Overall symptoms ± ± ± Adjusted for propensity scores (education, marital status, age) and number of days since hospitalization. *Higher scores represent higher functioning/less interference/fewer symptoms/less distress. of posttreatment phlebography. Health distress was less and overall symptoms were significantly fewer in patients having successful lysis, compared with patients in whom treatment failed. At initial contact, there was a trend toward less stigma in patients having successful lysis, which became significant by the time of final follow-up (22 months). Table IV shows the mean scale scores at initial contact and final follow-up in patients having either partial or complete lysis compared with patients who underwent heparin treatment. Patients demonstrating either partial or complete lytic success had better physical role functioning, less stigma and health distress, and fewer overall symptoms at initial contact. The initial observations of less stigma and health distress and fewer overall symptoms remained significant at 22 months. The mean scale scores at initial contact and final follow-up of patients in whom lytic therapy failed were compared with those of the group that underwent heparin treatment. Although no benefit to failed lysis was found, no adverse outcome on quality-of-life was found when lytic therapy was unsuccessful. All patients expressed general satisfaction with their treatment. Treatment satisfaction was not related to the treatment received, success of thrombolysis, or measures of HRQOL (Tables III and IV). DISCUSSION The results of the treatment of iliofemoral DVT with catheter-directed thrombolysis demonstrated significantly improved HRQOL in many areas of function and well-being in patients treated with UK, compared with patients treated with standard anticoagulation, approximately 16 months after treatment. A strong trend toward improvement of the HUI and significantly better role physical functioning, less stigma, less health distress, and fewer overall symptoms were found. Although the study was purely observational in nature, patients were comparable in their reported HRQOL before their DVT. Not surprisingly, patients who had successful lysis reported better HRQOL than patients who had lytic failure. The lytic failure group and heparintreatment group were comparable in outcome. No benefit to patients who failed thrombolysis was found; similarly, failure of catheter-directed thrombolysis appears not to diminish the HRQOL in the long-term, compared with standard anticoagulation. The patients expression of treatment satisfaction was independent of either the success of catheterdirected thrombolysis or the long-term HRQOL. Patients apparently did not link long-term outcome with their treatment of acute DVT, and they were incapable of realizing that the treatment received for their acute DVT could alter subsequent post-thrombotic symptoms. Lack of randomization to treatment group is an obvious limitation of this study, allowing for the potential of treatment bias. If a treatment bias exist-

6 Volume 32, Number 1 Comerota et al 135 Table IV. Mean scale scores comparing patients who had either partial or complete lysis with patients who had heparin treatment Complete + partial Heparin Scale item* (mean ± SE) (mean ± SE) P value Intial contact mean, 16 months N = 43 N = 30 Health Utilities Index 0.83 ± ± Health interference ± ± Role functioning physical ± ± Treatment satisfaction ± ± Stigma ± ± Health distress ± ± Overall symptoms ± ± 4.19 <.001 Follow-up mean, 22 months N = 32 N = 13 Health Utilities Index 0.71 ± ± Health interference ± ± Role functioning physical ± ± Stigma ± ± Health distress ± ± Overall symptoms ± ± Adjusted for propensity scores (education, marital status, age) and number of days since hospitalization. *Higher scores represent higher functioning/less interference/fewer symptoms/less distress. ed, patients with more severe symptoms might have been selected for thrombolytic therapy. In this case, the results would be even more dramatic. However, it is also possible that patients who were treated with heparin had more health-related comorbidity at the time of their acute DVT, in which case a worse quality-of-life might be expected. The exact extent of DVT could not be compared between these groups. Patients treated with catheter-directed thrombolysis had phlebographic documentation of the proximal extent of their thrombus as part of the protocol for treatment. Because that information would not alter treatment in patients receiving standard anticoagulation, the proximal extent of their venous thrombosis was not defined. Because these patients were identified retrospectively and the criteria for inclusion specified that the index DVT must have occurred 6 months before the completion of the questionnaire, all patients were asked to recall information approximately 6 months or more earlier for the pre-dvt assessment. Although this is a recognized limitation of this study, the questions addressing the patients pre- DVT physical functioning focused on objective measures, such as defined physical limitations and days lost from work because of lower-extremity symptoms. Even if there was a recall bias, it would not affect the posttreatment quality-of-life results, because patients responses were based on their current functioning. Unfortunately, not all subjects completing the 16-month questionnaire completed and returned the 22-month questionnaire. Because of the concern for the potential impact of the loss to follow-up group (dropouts), an analysis was performed comparing patients who dropped out after 16 months with patients who completed the study. Results showed that the less-symptomatic patients were the ones dropping out, and patients with more overall symptoms were more likely to continue their participation. Despite this potential negative bias, the catheter-directed UK group continued to show improved HRQOL at final follow-up. Launois et al 15 developed an HRQOL instrument designed to evaluate chronic venous insufficiency and used it in a large cross-sectional study. They found that psychological functioning, physical functioning, pain, social functioning, and overall quality-of-life were significantly worse for patients with chronic venous insufficiency than for those without chronic disease. Beyth et al 16 examined patients 6 to 8 years after acute DVT. Similar to the observations of Launois et al, they found that patients reporting post-thrombotic symptoms had worse HRQOL, which included worse health perception, impairment in physical functioning, and more severe role limitations attributable to physical health, compared with patients without post-thrombotic symptoms. Both Launois et al 15 and Beyth et al 16 examined patients with chronic venous disease and did not evaluate any effect of treatment.

7 136 Comerota et al July 2000 Koopman et al 17 assessed quality-of-life outcome in a prospective trial comparing intravenous heparin administered in the hospital with subcutaneous low molecular-weight heparin administered at home for treatment of acute proximal DVT. Time affected quality-of-life, with improvement of all indicators in both treatment groups. Patients receiving low molecular-weight heparin, however, had better scores for physical activity and social functioning at the end of the initial treatment (1 to 2 weeks), most likely because most patients were treated as outpatients. No quality-of-life difference was found between treatment groups at 12 to 24 weeks. Because neither form of heparin dissolves clots, the results indicate that patients quality-of-life is better when they are treated as outpatients for acute DVT than when they are treated as inpatients. Patients did not perceive any benefit of either treatment at 12 to 24 weeks. Post-thrombotic symptoms are related to ambulatory venous hypertension, which correlates with venous obstruction and valvular incompetence. 18 A recent natural history study of patients with acute DVT demonstrated that patients with the postthrombotic syndrome were more likely to have the combination of persistent deep venous obstruction and valvular incompetence as part of their ongoing pathophysiology than patients without chronic symptoms. 19 Furthermore, patients treated with anticoagulation who underwent physiologic clot lysis within 3 months of their acute DVT were more likely to retain normal venous valve function than patients with delayed physiologic lysis or persistent thrombosis. 20 In light of these observations, it is not surprising that successful catheter-directed thrombolysis results in a better quality-of-life than failed thrombolysis or standard anticoagulation. In two earlier prospective randomized trials of systemic lytic therapy versus anticoagulation for proximal deep venous thrombosis, patients treated with thrombolytic therapy had fewer post-thrombotic symptoms than patients treated with anticoagulation alone. 4,5 In a 5-year follow-up examination of patients with acute DVT who were initially randomized to thrombolytic therapy or anticoagulation, venous function was significantly better in patients who had successful lysis than in patients who did not. 9 The results after thrombolytic therapy for acute DVT are consistent with those of a large Scandinavian trial comparing venous thrombectomy with anticoagulation for acute iliofemoral DVT. At 6 months, 5 years, and 10 years follow-up, patients treated with venous thrombectomy had better iliac vein patency, improved valvular function, and fewer post-thrombotic symptoms than patients treated with standard anticoagulation. 6,7,21 These observations suggest treatment that successfully removes clots from the deep venous system (especially in patients with extensive DVT) is associated with better patient outcomes than anticoagulation alone. Until now, outcome assessment of the treatment of acute DVT was based on post-thrombotic signs and symptoms, phlebographic findings, and physiologic evaluation of various components of venous function and outflow obstruction. Patients assessments of their HRQOL may be the most meaningful long-term outcome. Now a validated instrument exists that can be used as a means of assessing quality-of-life outcome after acute DVT. The observations from this retrospective study cannot be viewed as conclusive, but rather serve as an hypothesis that catheter-directed thrombolysis with UK for iliofemoral DVT is associated with improved HRQOL, compared with standard anticoagulation. These findings offer a compelling argument for a future randomized trial. All future trials evaluating treatment of acute DVT should include a HRQOL measure as part of outcome analysis. We thank Vicki Curran for her editorial assistance with manuscript preparation and David Pasta for his statistical support in analyzing the data. REFERENCES 1. O Donnell TF, Browse NL, Burnand KG, Lea Thomas M. The socioeconomic effects of an iliofemoral venous thrombosis. J Surg Res 1977;22: Mavor GE, Galloway JMD. Iliofemoral venous thrombosis. Br J Surg 1969;19696;56: Hill SL, Martin D, Evans P. Massive vein thrombosis of the extremities. AM J Surg 1989;158: Arnesen H, Hoiseth A, Ly B. 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8 Volume 32, Number 1 Comerota et al 137 function assessment (abstract No. S20.3). Proceedings of the 2nd International Vascular Symposium; 1989, London, Sept Mewissen MW, Seabrook GR, Meissner MH, Cynamon J, Labropoulous N, Haughton SH. Catheter-directed thrombolysis for lower extremity deep vein thrombosis: report of a national multi-center registry. Radiology 1999;211: Mathias SD, Prebil LA, Putterman CG, Chmiel JJ, Throm RC, Comerota AJ. A health-related quality of life measure in patients with deep vein thrombosis: A validation study. Drug Inf J 1999;33: Ware JE Jr, Kosinski M, Keller SD. SF-12: How to score the SF-12 physical and mental health summary scales. 2nd ed. Boston: The Health Institute, New England Medical Center; Feeny DH, Torrance GW, Furlong WJ. Health utilities index. In: Spilker B, editor. Quality of life and pharmacoeconomics in clinical trials. 2nd ed. Philadelphia: Lippincott-Raven; p Stewart AL, Ware JE Jr, editors. Measuring functioning and well-being. The medical outcomes study approach. Durham: Duke University Press; Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality-of-life questionnaire in chronic lowerlimb venous insufficiency (CIVIQ). Qual Life Res 1996;5: Beyth RJ, Cohen AM, Landesfeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med 1995;155: Koopman MMW, Prandoni P, Pionella F, Ockelford PA, Brandjes DPM, Van Der Meer J, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low molecular weight heparin administered at home. N Engl J Med 1996;334: Shull KC, Nicolaides AN, Fernandes E, Fernandes J. Significance of popliteal reflux in relation to ambulatory venous pressure and ulceration. Arch Surg 1979;114: Johnson BF, Manzo RA, Bergelin RO, Standness DE. Relationship between changes in the deep venous system and the development of the post-thrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one-to six-year follow-up. J Vasc Surg 1995;21: Meissner MH, Manzo RA, Bergelin RO, Markel A, Strandness DE. Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vasc Surg 1993;18: Plate G, Akesson H, Einarsson E, Ohlin P, Eklof B. Longterm results of venous thrombectomy combined with a temporary arterio-venous fistula. Eur J Vasc Surg 1990;4: Submitted Jun 8, 1999; accepted Nov 24, BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the Journal of Vascular Surgery for 1999 are available to subscribers only. They may be purchased from the publisher at a cost of $ for domestic, $ for Canadian, and $ for international subscribers for Vol 29 (January to June) and Vol 30 (July to December). Price includes shipping charges. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby, Subscription Customer Service, 6277 Sea Harbor Dr, Orlando, FL 32887; phone or Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.