Treatment of chronic venous disease of the lower extremities: what’s new in guidelines?

Download this issue Back to summary
Anthony J. COMEROTA

Guidelines for patient care offer recommendations to physicians for diagnosis and management of common diseases that generally apply to the typical patient. This manuscript addresses some of the newer guidelines to help clinicians manage patients with chronic venous disease of the lower extremities. The two important documents, “Management of Chronic Venous Disorders of the Lower Limbs: Guidelines According to Scientific Evidence”1 prepared by an international consensus group under the auspices of the leading societies for venous disease, and, “Antithrombotic Therapy for Venous Thromboembolic Disease,”2 as part of the American College of Chest Physicians (ACCP) 8th consensus conference, have recently been published to help physicians care for patients with venous disease. While there is broad overlap of these two documents, the recent ACCP guidelines have made specific changes with recommendations and suggestions linked to objective grades, which form the basis of this discussion.

The method of determining the strength and quality of the recommendations deserves mention. Recommendations are generally accompanied by a number, which refers to the strength of the recommendation, and a letter, which refers to the quality of the evidence supporting the recommendation. The guidelines for chronic venous disorders use three levels of strength: Grade I is a strong recommendation, Grade II a moderate, and Grade III a weak recommendation. The recent ACCP guidelines use only two levels for the strength of their recommendations: Grade 1 for strong and Grade 2 for weak.3 They further indicate that statements accompanied by a Grade 1 level are “recommendations” and statements accompanied by a Grade 2 level are “suggestions.”

The quality of evidence upon which the strength of the recommendation is based ranges from “A” for high quality, which is consistent evidence from randomized trials, to “B” for moderate quality, which is evidence from nonrandomized trials or inconsistent evidence from randomized trials. Level “C” is low quality, which is suggestive evidence from nonrandomized trials, observational reports, or expert opinion. Guideline-writing committees are becoming increasingly aware of costs of care and patient values and preferences, as are physicians. It stands to reason that a clear-thinking, well-informed patient will agree with treatment recommendations that follow strong guidelines (Grades 1A), whereas when physicians are faced with atypical clinical circumstances or weak guideline recommendations (ie, suggestions), cost of care and patient values and preferences should be considered in addition to the risks and benefits of the treatment.

MAGNITUDE OF THE PROBLEM

Venous disease is one of the most common disorders afflicting the populations of developed and developing countries. New studies show that acute venous thrombosis resulting in fatal pulmonary embolism kills more people than acute myocardial infarction or acute stroke.4 Over one million people per year will suffer acute deep venous thrombosis (DVT) in the United States alone. The postthrombotic morbidity that follows is substantial and is proportional to the extent of venous thrombosis.5-7

Chronic venous disease is a common condition with major socioeconomic impact due to its high prevalence. The cost of chronic venous disease includes its investigation, its treatment, and the loss of working days by the afflicted patients.8, 9 Mild forms of venous disease, such as reticular veins and telangiactasias, are present in 80-85% of the population, varicose veins are present in 40% of men and 60% of women, and ankle edema is found in 7% of men and 16% of women.10 Venous ulceration will occur in 0.3% of the population on an annual basis and approximately 1% of the population in Western countries will have either an active or healed venous ulcer.9-11

The prevalence of chronic venous disease increases with age. Age can be considered a “dose-related risk factor.” 9, 10 However, the most impressive risk of chronic venous disease is a history of DVT. DVT increases the odds ratio of chronic venous disease by a factor of 25.12

The proportion of patients presenting with chronic venous symptoms increases linearly with the Clinical scale of the CEAP classification.13

Quality-of-life studies have shown that chronic venous disease is associated with increased pain, reduced physical function and mobility, and increased feelings of depression and social isolation.14 The quality-of-life (QOL) assessment is directly associated with the severity of venous disease.15 Patients who have or have had venous ulcers report a QOL similar to patients suffering with congestive heart failure.16 Acute DVT often leads to chronic postthrombotic morbidity, and the severity of postthrombotic venous disease correlates directly with the extent of the acute DVT. Treatment of acute DVT is relevant to this discussion, because extensive DVT results in severe chronic morbidity unless patients are treated to eliminate the acute clot.

CLASSIFICATION AND SEVERITY SCORING OF CHRONIC VENOUS DISEASE

There is a broad range of signs and symptoms associated with chronic venous disease. A number of classification systems have been proposed. A widely accepted, objective, and standardized classification system is crucial for accurate and reproducible description of patients. Lack of precision in diagnosis and description leads to conflicting reports of disease distribution and a poor understanding of the management of specific venous pathology. A standardized classification facilitates improved precision of communication and serves as a foundation for accurate reporting of the severity of disease and response to treatment. The CEAP classification (Clinical, Etiology, Anatomy, Pathology) was proposed and subsequently adopted worldwide as a basis for improved patient description.17 This is a pointin- time assessment which includes the clinical assessment (C), an etiologic assessment of the patient’s disease (E), an anatomic assessment of location of the pathology (A), and the pathophysiologic basis for the underlying disease (P). The CEAP classification provides a broad-based, objective, anatomic, and physiologic basis for classification of venous disease. This has improved standardization, communication, decision making, and reporting of venous disease.

The Villalta classification is a clinical scale using subjective scores of 0 (absence) to 3 (severe) for symptoms of pain, cramps, itching, and physical findings of edema, pigmentation, venous ectasia, erythema, and induration. This has been used specifically for patients with postthrombotic syndrome. Studies have reported good interobserver agreement and the ability to differentiate moderate versus severe disease.18 This instrument is limited by its subjective rather than objective scoring for the clinical features mentioned and appears to have been applied only to patients with postthrombotic syndrome.

The Venous Clinical Severity Score (VCSS) includes nine attributes which are graded from 0 to 3. Attributes include pain, varicose veins, edema, pigmentation, inflammation, induration, active ulcers and size, and compression therapy. The use of a properly designed disease severity scoring system allows patients with similar degrees of chronic venous disease to be selected for entry into clinical trials and to have their outcomes assessed objectively following treatment. Properly applied, a venous severity scoring system is a valuable tool in venous outcome assessment.

The VCSS has been studied and shown to be valid in that its scores increase in a linear fashion with CEAP clinical class.19 The VCSS is reliable as demonstrated in tests of intraobserver variability.20-25 Therefore, a change in score of this instrument can be used as an outcome measure assessing treatment. Unfortunately, responsiveness of the VCSS has not been adequately evaluated; therefore, it cannot be used as yet to calculate sample sizes for clinical trials.26

PATHOPHYSIOLOGY OF CHRONIC VENOUS DISEASE

Understanding the pathophysiology of a disease state is basic to effective treatment. Results from studies that demonstrate treatment efficacy lead to guideline recommendations. The apparently simple concept of venous hypertension being responsible for chronic venous disease belies the complex cellular and molecular processes set into motion by the abnormal venous hemodynamics. Ambulatory venous hypertension is the hemodynamic pathology, with its underlying components being venous valvular incompetence, luminal obstruction, and failure of the calf muscle pump. Calf muscle pump failure is generally the consequence of obesity or other immobilization, often a reflection of high central venous pressures. A progressive increase in soft tissue findings and skin damage has been reported with increasing exercise venous pressures. In patients with chronic venous disease with ambulatory venous pressures <30 mm Hg, no ulcers were observed.27 However, nearly all patients with exercising venous pressures of >90 mm Hg experienced venous ulceration. The consequence of venous hypertension is relative stasis with marked reduction in shear stress at the vein wall. Vein distension and reflux allow venous flow reversal. The reduced shear stress, structural changes in vein walls, and areas of disturbed and turbulent flow establish an environment to initiate and maintain inflammation. Shear stress governs leukocyte behavior and endothelial cell function. The resulting changes in endothelial cell signaling through a variety of pathways alter gene expression and the production and release of cytokines, proteases, and other factors that impact inflammation.28

The seminal role of leukocyte activation as a result of venous hypertension was recognized following basic animal experiments and human research. Animal models of venous hypertension demonstrated increased numbers of leukocytes in the skin of extremities with venous hypertension.29,30 Both humans and animals have shown increased macrophages, mast cells, and T-lymphocytes in the skin affected by chronic venous disease.29,30 When leukocytes are activated as a result of venous hypertension, they shed L-selectin and produce other integrins which bind to intracellular adhesion molecules (ICAMs). This permits endothelial cell adhesion of leukocytes and initiates their migration through the vessel wall into the extravascular tissues, leading to degranulation. Studies of induced venous hypertension (standing for 30 minutes) in humans have demonstrated reduced levels of L-selectin and CD11b on the leukocyte membrane, while at the same time plasma levels of L-selectin increased.31 Interestingly, patients with chronic venous disease show a systemic increase in leukocyte adhesion. Plasma from patients with chronic venous disease induces more leukocyte activation of otherwise normal white cells than plasma from normal patients.32 Activated neutrophils produce and stimulate the production of proteolytic enzymes such as matrix metalloproteinases (MMPs) and other serine proteases. Inhibitors of MMPs are also produced, often in greater proportion, which leads to the accumulation of extracellular matrix material, resulting in the characteristic lipodermatosclerosis of chronic venous disease.

Increased production of transforming growth factor beta (TGF-_1) and fibroblast growth factor beta (FGF-_1) also occurs. TGF-_1 stimulates collagen synthesis and further increases tissue inhibitor of MMP production, whereas FGF-_1 is a stimulus for smooth muscle cell migration.33,34 The sum of these events also results in increased soft tissue sclerosis.

Limb blood flow is altered in patients with chronic venous disease.35 Plasma levels of vascular endothelial growth factor (VEGF) are increased in patients with chronic venous disease who have skin changes compared with patients with normal skin.36 VEGF may promote the growth of capillaries which are observed in patients with lipodermatosclerosis and further promote the extravasation of fluid into the interstitial space by increasing permeability. The fibrin cuff around capillaries in damaged skin also contains collagen, laminin, fibronectin, and tenascin,37 which reflects the altered cellular metabolic functions previously discussed.

This brief overview of the pathophysiology of chronic venous disease should improve understanding of treatment modalities which have shown efficacy and have therefore led to guideline recommendations.

WHAT’S NEW IN GUIDELINES

Treatment of iliofemoral venous thrombosis
The writing committee for Antithrombotic Therapy for Venous Thromboembolic Disease of the 2008 ACCP guidelines recognized the excess morbidity of this particular distribution of disease. It is important to understand the anatomy of lower extremity venous drainage, which functionally resembles a funnel, with distal veins draining into larger but progressively fewer veins as blood moves cephalad. The common femoral and iliac veins represent the spout of the funnel, which is the single common channel of lower extremity venous drainage. If this channel is obstructed, it will affect the entire leg, with adverse functional consequences on all distal veins.The greatest change in guidelines is the recommendation for consideration of a strategy of thrombus removal in patients with iliofemoral DVT. This is a reversal of the statements from guidelines published in 2004.38

Venous thrombectomy
The 2008 ACCP guidelines recommend considering venous thrombectomy for acute iliofemoral DVT in patients with symptoms for <7 days, good functional status, and a life expectancy >1 year.

Rationale: This is based upon level 1 data emanating from a large randomized study by Plate et al.39-41 Patients were followed up and reported at 6 months, 5 years, and 10 years following randomization to venous thrombectomy or anticoagulation. Patients randomized to thrombectomy showed improved patency, lower venous pressures, less leg swelling, and fewer postthrombotic symptoms than patients treated with anticoagulation alone. Other, nonrandomized series also reported favorable outcomes of contemporary venous thrombectomy. Long-term observational results from 10 reports with the mean of 41 months of follow-up demonstrated a 76% patency, with 8 reports demonstrating functional venous valves in the femoropopliteal segment in 63%.42

Since venous thrombectomy is infrequently performed, the committee suggested that “catheter-directed thrombolysis is usually preferable to operative venous thrombectomy” (Grade 2C).

Catheter-directed thrombolysis
The recommendation for catheter-directed thrombolysis (CDT) for acute iliofemoral DVT in patients with a low risk of bleeding, symptoms <14 days, good functional status, and a life expectancy >1 year is also proposed to reduce acute symptoms and postthrombotic morbidity.

Rationale: A small randomized trial of catheterdirected lytic therapy versus anticoagulation demonstrated significantly better patency and preservation of valve function in patients treated with CDT versus anticoagulation.43 Large single-center series and multicenter venous registries demonstrate an 80-90% success rate, with progressively lower bleeding complications over time.44-46 A casecontrolled cohort study, which followed the National Venous Registry, demonstrated significantly improved QOL in patients with iliofemoral DVT treated with CDT compared with those treated with anticoagulation.47 The improved QOL was directly related to lytic success.

The committee suggested correction of underlying venous lesions using balloon angioplasty and stents (Grade 2C). While there are no objective data supporting this statement, the collective clinical observations and expert opinion suggest that residual (uncorrected) venous lesions increase the likelihood of rethrombosis. Alternatively, correction of focal lesions in the proximal system is associated with good long-term outcome. This suggestion applies to both venous thrombectomy and CDT.

The committee recommends the same intensity and duration of anticoagulation following thrombectomy and CDT as patients who do not undergo these treatments (Grade 1C). This is a uniformly strong opinion by the experts, which underscores the need to avoid recurrence, although proper trials of intensity and duration of anticoagulation following interventional therapy have not been performed.

Early ambulation and compression
Early ambulation in patients with acute DVT is now recommended in preference to initial bed rest (Grade 1A).

Rationale: Randomized trials of early ambulation and leg compression have demonstrated reduced pain, edema, and postthrombotic morbidity compared with patients treated with bed rest and anticoagulation.48-52

For patients who have symptomatic proximal DVT, elastic compression stockings of 30-40 mm Hg are recommended (Grade 1A).

Rationale: Two randomized trials treating patients after a first episode of acute symptomatic proximal DVT demonstrated significant reduction (50%) of postthrombotic symptoms in patients wearing compression stockings compared with those treated without compression.53,54 A Cochrane review of compression following acute DVT also concluded that compression stockings substantially reduced the incidence of the postthrombotic syndrome after two years.55

The early application of a snug wrap from the base of the toes to the upper thigh combined with ambulation and anticoagulation is the method described by Partsch et al,56 which has been shown to be effective in the early management of patients with acute proximal DVT.

Intermittent pneumatic compression
For patients with severe edema of the leg due to postthrombotic syndrome, a course of intermittent pneumatic compression (IPC) is suggested (Grade 2B).

Rationale: In a crossover study57 in patients with severe postthrombotic syndrome, IPC of 40 mm Hg proved more effective than placebo pressures. Patients uniformly preferred therapeutic pressures to placebo.

In patients with venous ulcers resistant to healing with wound care and standard compression, the addition of IPC is suggested (Grade 2B).

Rationale: IPC has been shown to increase venous velocity, reduce edema, increase TcPO2, increase popliteal artery blood flow, and increase endothelial nitric oxide synthase. These basic effects of IPC have translated into improved healing of venous leg ulcers in clinical trials. Randomized trials in patients with persistent venous ulcers have demonstrated significantly increased healing58,59 and more rapid healing of venous leg ulcers when IPC was used in addition to standard wound care and compression wraps. Compression pressures and cycles have varied in the studies reported; therefore, IPC prescription for the treatment of postthrombotic syndrome and venous ulcers has not been standardized.

Pentoxifylline
Pentoxifylline at a dose of 400 mg PO TID in addition to local care and compression and/or IPC is recommended in patients with venous leg ulcers.

Rationale: The pharmacologic effect of pentoxifylline improves the rheology of blood flow in the microcirculation by altering the stiffness of the red blood cell membrane.60 Eight randomized studies were tabulated by a Cochrane review evaluating pentoxifylline versus placebo in patients with venous leg ulcers, using objective measurements of wound healing.61 There was uniform observation that pentoxifylline improved wound healing.

Micronized Purified Flavonoid Fraction or Sulodexide
In patients with persistent venous ulcers, rutosides, in the form of micronized purified flavonoid fraction (MPFF) given orally, or sulodexide, administered intramuscularly and then orally, is suggested to be added to local care and compression.

Rationale: Five studies (three published, two unpublished) have been performed using MPFF in the management of patients with venous ulcers.62-66 Two studies were placebo-controlled. A meta-analysis of these five studies has been reported.67 Ulcer healing occurred in 61% of the MPFF patients at 6 months compared with 48% of controls (P=0.03). The benefit of MPFF appeared greatest in ulcers >5 square cm and those existing >six months.

The mechanism of benefit of MPFF is likely related to increased venous tone68,69 and improved lymphatic flow,70-72 resulting in diminished capillary hyper – permeability and increased capillary resistance,73,74 which results in decreased edema.

The importance of leukocyte activation as part of the cellular pathophysiology of venous disease was previously discussed. MPFF has been shown to reduce neutrophil adhesion in the post-capillary venules75 and inhibit leukocyte adhesion and migration in the microcirculation.76,77

The glycosaminoglycan sulodexide, when given intramuscularly and orally, improved venous leg ulcer healing as demonstrated in a placebo-controlled trial.78 There did not appear to be adverse side affects.

SUMMARY

The recent ACCP guidelines have added important new recommendations and suggestions for the management of patients with acute and chronic venous disease. The recommendations regarding acute DVT will have a major impact on reducing the frequency and virulence of postthrombotic chronic venous disease.

The physical and pharmacologic measures recommended will substantially improve the care of patients with chronic venous disease. These measures are consistent with the international guidelines published in International Angiology and the revised and updated UIP guidelines currently under development.

REFERENCES

1. Nicolaides AN, Allegra C, Bergan J, Bradbury A, Cairols M, Carpentier P, et al. Management of chronic venous disorders of the lower limbs: guidelines according to scientific evidence. Int Angiol 2008;27(1):1-59.
2. Kearon C, Kahn SR, Agnelli G, Goldhaber SZ, Raskob G, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: ACCP evidence-based clinical practice guidelines (8th ed). Chest 2008;133(6):454S-545S.
3. Guyatt G, Gutterman D, Baumann MH, ddrizzo-Harris D, Hylek EM, Phillips B, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest 2006;129(1):174-81.
4. Heit JA, Cohen AT, Anderson FA, Jr., on Behalf of the VTE Impact Assessment Group. Estimated annual number of incident and recurrent, nonfatal and fatal venous thromboembolism (VTE) events in the US. ASH Annual Meeting Abstracts 2005;106(11):910.
5. Strandness DE, Jr., Langlois Y, Cramer M, Randlett A, Thiele BL. Long-term sequelae of acute venous thrombosis. JAMA 1983;250(10):1289-92.
6. Beyth RJ, Cohen AM, Landefeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med 1995;155(10):1031-7.
7. Delis KT, Bountouroglou D, Mansfield AO. Venous claudication in iliofemoral thrombosis: long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004;239(1):118-26.
8. Abenhaim L, Clement D, Norgren L. The management of chronic venous disorders of the leg: an evidence-based report of an international Task Force. Phlebology 1999;14:1-126.
9. Kurz X, Kahn SR, Abenhaim L, Clement D, Norgren L, Baccaglini U, et al. Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management. Summary of an evidence-based report of the VEINES task force. Venous Insufficiency Epidemiologic and Economic Studies. Int Angiol 1999;18(2):83-102.
10. Evans CJ, Fowkes FG, Ruckley CV, Lee AJ. Prevalence of varicose veins and chronic venous insufficiency in men and women in the general population: Edinburgh Vein Study. J Epidemiol Community Health 1999;53(3):149-53.
11. Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med 1997;12(6):374-83.
12. Scott TE, LaMorte WW, Gorin DR, Menzoian JO. Risk factors for chronic venous insufficiency: a dual casecontrol study. J Vasc Surg 1995;22(5):622-8.
13. Eklof B, Rutherford RB, Bergan JJ, Carpentier PH, Gloviczki P, Kistner RL, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004;40(6):1248-52.
14. van Korlaar, I, Vossen C, Rosendaal F, Cameron L, Bovill E, Kaptein A. Quality of life in venous disease. Thromb Haemost 2003;90(1):27-35.
15. Kaplan RM, Criqui MH, Denenberg JO, Bergan J, Fronek A. Quality of life in patients with chronic venous disease: San Diego population study. J Vasc Surg 2003;37(5):1047-53.
16. Andreozzi GM, Cordova RM, Scomparin A, Martini R, D’Eri A, Andreozzi F. Quality of life in chronic venous insufficiency. An Italian pilot study of the Triveneto Region. Int Angiol 2005;24(3):272-7.
17. Rutherford RB, Padberg FT, Jr., Comerota AJ, Kistner RL, Meissner MH, Moneta GL. Venous severity scoring: An adjunct to venous outcome assessment. J Vasc Surg 2000;31(6):1307-12.
18. Villalta S, Bagatella P, Piccioli A, Lensing AW, Prins M, Prandoni P. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome [Abstract]. Haemostasis 1994;24:158a.
19. Meissner MH, Natiello C, Nicholls SC. Performance characteristics of the venous clinical severity score. J Vasc Surg 2002;36(5):889-95.
20. Norman GR. Issues in the use of change scores in randomized trials. J Clin Epidemiol 1989;42(11):1097-105.
21. Kirshner B, Guyatt G. A methodological framework for assessing health indices. J Chronic Dis 1985;38(1):27-36.
22. Guyatt GH, Feeny DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med 1993;118(8):622-9.
23. Norusis MJ. Repeated measures analysis of variance: more on procedure MANOVA. SPSS Advanced Statistics User’s Guide. Chicago: SPSS Inc.; 1990. p. 121-49.
24. Fleiss JL. The measurement of interrater agreement. Statistical methods for Rates and Proportions. 2nd ed. New York: John Wiley and Sons; 1981. p. 212-36.
25. Uhl JF, Cornu-Thenard A, Carpentier PH, Schadeck M, Parpex P, Chleir F. Reproducibility of the “C” classes of the CEAP Classification. J Phlebology 2001;1:39-48.
26. Guyatt G, Walter S, Norman G. Measuring change over time: assessing the usefulness of evaluative instruments. J Chronic Dis 1987;40(2):171-8.
27. Nicolaides AN, Schull K, Fernandes E. Ambulatory venous pressure: new information. In: Nicolaides AN, Yao JS, editors. Investigation of Vascular Disorders. New York: Churchill Livingstone; 1981. p. 488-94.
28. Ohura N, Yamamoto K, Ichioka S, Sokabe T, Nakatsuka H, Baba A, et al. Global analysis of shear stressresponsive genes in vascular endothelial cells. J Atheroscler Thromb 2003;10(5):304-13.
29. Lalka SG, Unthank JL, Nixon JC. Elevated cutaneous leukocyte concentration in a rodent model of acute venous hypertension. J Surg Res 1998;74(1):59-63.
30. Hahn TL, Unthank JL, Lalka SG. Increased hindlimb leukocyte concentration in a chronic rodent model of venous hypertension. J Surg Res 1999;81(1):38-41.
31. Saharay M, Shields DA, Porter JB, Scurr JH, Coleridge Smith PD. Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease. J Vasc Surg 1997;26(2):265-73.
32. Takase S, Schmid-Schonbein G, Bergan JJ. Leukocyte activation in patients with venous insufficiency. J Vasc Surg 1999;30(1):148-56.
33. Badier-Commander C, Couvelard A, Henin D, Verbeuren T, Michel JB, Jacob MP. Smooth muscle cell modulation and cytokine overproduction in varicose veins. An in situ study. J Pathol 2001;193(3):398-407.
34. Lindner V, Reidy MA. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc Natl Acad Sci U S A 1991;88(9):3739-43.
35. Paolini DJ, Comerota AJ, Jones LS. Lower extremity arterial inflow is adversely affected in patients with venous disease. J Vasc Surg 2008;48(4):960-4.
36. Shoab SS, Scurr JH, Coleridge-Smith PD. Increased plasma vascular endothelial growth factor among patients with chronic venous disease. J Vasc Surg 1998;28(3):535-40.
37. Coleridge-Smith P. Inappropriate leukocyte activation in venous disease. In: Bergan J, editor. The Vein Book. Philadelphia: Elsevier; 2006. p.57-65.
38. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):401S-28S.
39. Plate G, Einarsson E, Ohlin P, Jensen R, Qvarfordt P, Eklof B. Thrombectomy with temporary arteriovenous fistula: the treatment of choice in acute iliofemoral venous thrombosis. J Vasc Surg 1984;1(6):867-76.
40. Plate G, Akesson H, Einarsson E, Ohlin P, Eklof B. Long-term results of venous thrombectomy combined with a temporary arterio-venous fistula. Eur J Vasc Surg 1990;4(5):483-9.
41. Plate G, Eklof B, Norgren L, Ohlin P, Dahlstrom JA. Venous thrombectomy for iliofemoral vein thrombosis—10- year results of a prospective randomised study. Eur J Vasc Endovasc Surg 1997;14(5):367-74.
42. Comerota AJ, Gravett MH. Iliofemoral venous thrombosis. J Vasc Surg 2007;46(5):1065-76.
43. Elsharawy M, Elzayat E. Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial. Eur J Vasc Endovasc Surg 2002;24(3):209-14.
44. Bjarnason H, Kruse JR, Asinger DA, Nazarian GK, Dietz CA, Jr., Caldwell MD, et al. Iliofemoral deep venous thrombosis: safety and efficacy outcome during 5 years of catheterdirected thrombolytic therapy. J Vasc Interv Radiol 1997;8(3):405-18.
45. Comerota AJ, Kagan SA. Catheterdirected thrombolysis for the treatment of acute iliofemoral deep venous thrombosis. Phlebology 2000;15:149-55.
46. Mewissen MW, Seabrook GR, Meissner MH, Cynamon J, Labropoulos N, Haughton SH. Catheter-directed thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology 1999;211(1):39-49.
47. Comerota AJ, Throm RC, Mathias SD, Haughton S, Mewissen M. Catheterdirected thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life. J Vasc Surg 2000;32(1):130-7.
48. Aschwanden M, Labs KH, Engel H, Schwob A, Jeanneret C, Mueller-Brand J, et al. Acute deep vein thrombosis: early mobilization does not increase the frequency of pulmonary embolism. Thromb Haemost 2001;85(1):42-6.
49. Blattler W, Partsch H. Leg compression and ambulation is better than bed rest for the treatment of acute deep venous thrombosis. Int Angiol 2003;22(4):393- 400.
50. Junger M, Diehm C, Storiko H, Hach- Wunderle V, Heidrich H, Karasch T, et al. Mobilization versus immobilization in the treatment of acute proximal deep venous thrombosis: a prospective, randomized, open, multicentre trial. Curr Med Res Opin 2006;22(3):593-602.
51. Partsch H, Blattler W. Compression and walking versus bed rest in the treatment of proximal deep venous thrombosis with low molecular weight heparin. J Vasc Surg 2000;32(5):861-9.
52. Schellong SM, Schwarz T, Kropp J, Prescher Y, Beuthien-Baumann B, Daniel WG. Bed rest in deep vein thrombosis and the incidence of scintigraphic pulmonary embolism. Thromb Haemost 1999;82 Suppl 1:127-9.
53. Brandjes DP, Buller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349(9054):759-62.
54. Prandoni P, Lensing AW, Prins MH, Frulla M, Marchiori A, Bernardi E, et al. Below-knee elastic compression stockings to prevent the postthrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004;141(4):249-56.
55. Kolbach DN, Sandbrink MW, Hamulyak K, Neumann HA, Prins MH. Non-pharmaceutical measures for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev 2004;(1):CD004174.
56. Partsch H. Immediate ambulation and leg compression in the treatment of deep vein thrombosis. Dis Mon 2005;51(2-3):135-40.
57. Ginsberg JS, Magier D, Mackinnon B, Gent M, Hirsh J. Intermittent compression units for severe postphlebitic syndrome: a randomized crossover study. CMAJ 1999;160(9):1303-6.
58. Smith PC, Sarin S, Hasty J, Scurr JH. Sequential gradient pneumatic compression enhances venous ulcer healing: a randomized trial. Surgery 1990;108(5):871-5.
59. Kumar S, Samraj K, Nirujogi V, Budnik J, Walker MA. Intermittent pneumatic compression as an adjuvant therapy in venous ulcer disease. J Tissue Viability 2002;12(2):42-4, 46, 48.
60. Martin M. PHLECO: a multicenter study of the fate of 1647 hospital patients treated conservatively without fibrinolysis and surgery. Clin Investig 1993;71(6):471-7.
61. Jull AB, Waters J, Arroll B. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev 2002;(1):CD001733.
62. Guilhou JJ, Fevrier F, Debure C, Dubeaux D, Gillet-Terver MN, Guillot B, et al. Benefit of a 2-month treatment with a micronized, purified flavonoidic fraction on venous ulcer healing. A randomized, double-blind, controlled versus placebo trial. Int J Microcirc Clin Exp 1997;17 Suppl 1:21-6.
63. Glinski W, Chodynicka B, Roszkiewicz J, Bogdanowski T, Lecewicz-Torun B, Kaszuba A, et al. [Effectiveness of a micronized purified flavonoid fraction (MPFF.in the healing process of lower limb ulcers. An open multicentre study, controlled and randomized]. Minerva Cardioangiol 2001;49(2):107-14.
64. Roztocil K, Stvrtinova V, Strejcek J. Efficacy of a 6-month treatment with Daflon 500 mg in patients with venous leg ulcers associated with chronic venous insufficiency. Int Angiol 2003;22(1):24-31.
65. Rieger H, Zuccarelli F. Clinical report (Lab Servier, France) on the effect of Daflon® 500 mg (2 tablets daily) on venous leg ulcers healing in 160 patients treated over a 6-month period. A multicentre, double-blind, randomised, controlled versus placebo parallel group study. 2009.
66. Saveliev VS, Pokrovsky AV, Kireienko AI, Bogachev VY, Bogdanetz LI, Sapelkin SV. Analysis report (Lab Servier, France) of a randomised, multicentre comparative study of efficiency and safety of Detralex® in complementary treatment of complications of chronic venous insufficiency of lower extremities (trophic ulcers). 2009.
67. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction. Eur J Vasc Endovasc Surg 2005;30(2):198-208.
68. Juteau N, Bakri F, Pomies JP, Foulon C, Rigaudy P, Pillion G, et al. The human saphenous vein in pharmacology: effect of a new micronized flavonoidic fraction (Daflon 500 mg) on norepinephrine induced contraction. Int Angiol 1995;14(3 Suppl 1):8-13.
69. Ibegbuna V, Nicolaides AN, Sowade O, Leon M, Geroulakos G. Venous elasticity after treatment with Daflon 500 mg. Angiology 1997;48(1):45-9.
70. Cotonat A, Cotonat J. Lymphagogue and pulsatile activities of Daflon 500 mg on canine thoracic lymph duct. Int Angiol 1989;8(4 Suppl):15-8.
71. Gargouil YM, Perdrix L, Chapelain B, Gaborieau R. Effects of Daflon 500 mg on bovine vessels contractility. Int Angiol 1989;8(4 Suppl):19-22.
72. McHale NG, Hollywood MA. Control of lymphatic pumping: interest of Daflon 500 mg. Phlebology 1994;9(Suppl 1):23- 5.
73. Behar A, Lagrue G, Cohen-Boulakia F, Baillet J. Study of capillary filtration by double labelling I131-albumin and Tc99m red cells. Application to the pharmacodynamic activity of Daflon 500 mg. Int Angiol 1988;7(2 Suppl):35- 8.
74. Galley P, Thiollet M. A double-blind, placebo-controlled trial of a new venoactive flavonoid fraction (S 5682) in the treatment of symptomatic capillary fragility. Int Angiol 1993;12(1):69-72.
75. Friesenecker B, Tsai AG, Intaglietta M. Cellular basis of inflammation, edema and the activity of Daflon 500 mg. Int J Microcirc Clin Exp 1995;15 Suppl 1:17- 21.
76. Korthuis RJ, Gute DC. Postischemic leukocyte/endothelial cell interactions and microvascular barrier dysfunction in skeletal muscle: cellular mechanisms and effect of Daflon 500 mg. Int J Microcirc Clin Exp 1997;17 Suppl 1:11-7.
77. Bouskela E, Donyo KA. Effects of oral administration of purified micronized flavonoid fraction on increased microvascular permeability induced by various agents and on ischemia/reperfusion in the hamster cheek pouch. Angiology 1997;48(5):391-9.
78. Coccheri S, Scondotto G, Agnelli G, Aloisi D, Palazzini E, Zamboni V. Randomised, double blind, multicentre, placebo controlled study of sulodexide in the treatment of venous leg ulcers. Thromb Haemost 2002;87(6):947-52.