CLINICAL CASE 5. Timing of superficial and deep vein endovascular interventions for the treatment of venous leg ulcers
Nadelin Nikolov, MD, PhD
Department of Vascular Surgery,
National Heart Hospital, Sofia,
Bulgaria
We present a case of a 66-year-old female with a recurrent venous leg ulcer (VLU) in the left medial malleolus. The patient had suffered iliofemoral deep venous thrombosis (DVT) 10 years ago. She was treated with oral anticoagulation for 2 years and venoactive drugs but no compression stockings. Since then, she has complained of visible varicose veins, swelling, and discomfort in her left leg. Five years after the index DVT, she developed a small VLU in the area of the left medial malleolus, which became bigger over time. The ulcer was treated with various kinds of dressings but never healed completely.
We performed duplex ultrasound and found concomitant vein pathology: both reflux and obstruction. The great saphenous vein (GSV) was 9 mm in diameter with reflux. Also, chronic occlusion of the left common iliac vein was detected.
Our treatment plan was to intervene in both pathologies. First, we performed radiofrequency ablation of the GSV trunk from the calf’s middle third. After the procedure, we added a knee-length compression stocking with a pressure of 30 to 40 mm Hg at the ankle. One week later, we performed endovascular intervention of the deep veins. Under ultrasound guidance, we punctured the left common femoral vein. Left common iliac vein occlusion was verified and crossed with a stiff hydrophilic guidewire supported by a Berenstein catheter. Predilatation with a 10-mm balloon catheter and afterward dilatation with a 14-mm noncompliant balloon was performed. We used intravascular ultrasound (IVUS) to determine the length of the occlusion and external iliac vein diameter. It was found to be 11 mm, so we decided to implant a 14/90-mm Wallstent. After the postdilatation with a 14-mm balloon, we noted brisk flow in the inferior vena cava and disappearing of the collaterals. The patient was discharged on prolonged antithrombotic, venoactive drug, and compression therapy the next day. We achieved complete ulcer healing after 1 month.
Discussion
obstruction impact venous ulcer healing?
Dr Geroulakos. The presence of iliac vein obstruction decreases the healing rate of venous leg ulcers (VLUs) treated with compression and superficial venous reflux elimination and increases the recurrence rate. Raju S et al have reported cumulative rates of limbs with healed ulcers and freedom of ulcer recurrence in legs with healed ulcers (C5) at 5 years to be 54% and 88%, respectively.1
Dr Kan. VLUs account for 70% to 80% of ulcers assessed and treated in clinics, with a prevalence of up to 2% of the population. VLU healing involves coordinated processes, including hemostasis, inflammation, proliferation, and remodeling, and the contribution of different cells, including leukocytes, platelets, fibroblasts, vascular smooth muscle cells, endothelial cells, and keratinocytes, as well as the release of various biomolecules, including transforming growth factor, cytokines, chemokines, matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), elastase, urokinase plasminogen activator, fibrin, collagen, and albumin. With good wound care and compression therapy, VLU usually heals within 6 months.2
The combination of chronic iliocaval obstruction and VLUs in patients can be very complex and a barrier to healing. As shown by Ruiz CS et al, patients with successful venous stent placement had significantly higher wound healing rates at 12 months than the persistent occlusion group (79.3% vs 22.6%; P<0.001).3 Venous stent intervention is recommended to promote wound healing.
Patients with VLU should be evaluated for venous outflow obstruction; if present, restoration of blood flow with stent placement may improve wound healing. After venous intervention and stenting to remove the obstruction, healing time is shortened, and ulcer-free time is increased.3
Dr Josnin. Restoring a harmonious venous flow associated with venous compression guarantees effective healing and reduced ulcer recurrence. To my knowledge, the study by Ruiz CS et al is the one that best demonstrates this.3
Dr Lobastov. The prevalence of nonthrombotic and postthrombotic iliocaval obstruction of >50% in patients with active or healed VLU has been reported as 28% to 37%, whereas more severe obstruction of >80% was found in 23%.4,5
In another study, the combination of iliocaval obstruction of >50% and superficial venous reflux was found in 32% of C5-6 patients.6 The presence of venous obstruction may delay ulcer healing and make it recalcitrant to standard conservative treatment even after ablation of superficial reflux.3,7-9
Dr Nikolov. VLUs are a widespread, debilitating problem with high recurrence rates. First-line conservative treatment with graduated compression stockings is not always enough and has a high recurrence rate. Current guidelines for treating chronic venous disease recommend compression therapy and eradication of superficial reflux. Still, the pathophysiological mechanism seems to be more complex, especially in the presence of deep vein pathology.10 We do not have clear guidelines for treating reflux and obstruction patients. Which intervention should be first? Should we treat and wait? Should we perform a staged or concomitant procedure?
Dr Lobastov. According to the systematic reviews, venous stenting is associated with ulcer healing in 73% to 80% of patients with postthrombotic obstruction, irrespective of superficial reflux.11-13 Individual studies show that adjunctive ablation of superficial veins does not improve outcomes of venous stenting, including ulcer healing.14,15 Others suggest that intervention on superficial veins in addition to venous stenting may improve outcomes in C4-6 patients.16 However, all these trials are nonrandomized and do not allow the drawing of any strong conclusion.
Dr Nikolov. Venous ulcers are caused by a complex cascade of events initiated by venous hypertension resulting from venous reflux, venous obstruction, or both. When we have mixed pathology, it is not clear which to treat first or whether we have to treat both. There is evidence in both directions. Some researchers present data suggesting that correction of iliac vein obstruction dramatically improves superficial reflux.17,18 Nowadays, there is no doubt that deep vein stenting is the first-line treatment for iliac vein obstruction (thrombotic and nonthrombotic lesions) that proves to be safe and effective. Furthermore, it is more cost-effective than standard medical and compression therapy alone.19 It is the same for the ablation techniques for treating superficial reflux. My practice in patients who present with VLU and superficial reflux is to correct it first with wound care and compression therapy. Despite this complex care, up to 32% do not heal, and the reason for that, in most cases, is unaddressed iliac vein obstruction.8
Dr Geroulakos. In most patients, ablation of the superficial venous reflux is safe in the presence of iliac vein obstruction.
Dr Josnin. The treatment of superficial venous reflux remains safe and effective as long as the treated segment is not vicarious. Any indication for treatment in these patients must therefore make the practitioner pay particular attention to the deep venous network and the causes that led to this venous thrombosis, which may impact the type of treatment that would be chosen.
Dr Kan. The development of deep venous segmental reflux may occur primarily or may result from damage to the valves by the thrombotic process. In general, two-thirds of patients may develop valvular insufficiency 1 year after their deep venous thrombosis (DVT) events. Iliofemoral DVT and May-Thurner syndrome can lead to deep venous reflux, which then delivers hydrostatic pressure peripherally, possibly leading to clinically significant superficial venous reflux. These central venous lesions and reflux may exacerbate superficial venous insufficiency in patients with chronic venous insufficiency (CVI). When asking about superficial venous reflux, presentations of deep venous reflux are common and may be a sign of more severe CVI.20 How to properly treat these patients is an important issue.
The retrospective cohort study by Li et al may provide clues in answering whether superficial reflux ablation is effective and safe in the presence of iliac vein obstruction. Their results showed that superficial vein surgery was safe and effective in patients with deep venous reflux, improving clinical and patient-reported outcomes compared with patients without deep vein reflux. Furthermore, they highlight that patients with and without deep vein reflux significantly improved their clinical scores and patient-reported outcomes after superficial vein treatment.20 Deep vein reflux alone is not associated with poorer outcomes after superficial vein treatment and should not prevent intervention.
Dr Nikolov. The next big question is which pathology to treat first—reflux or obstruction. Although superficial vein ablation is the recommended treatment for reflux, there are no randomized controlled trials (RCTs) for using it in the setting of deep vein obstruction. Most physicians would say removing reflux means eliminating a potentially significant collateral network. It is, however, known that the involvement of the saphenous vein in collateral compensation of outflow obstruction will be relatively minor.21-23 A recent systematic review by Benfor et al found that the available data are limited but suggests that ablation of superficial vein reflux is safe in patients with proximal deep vein obstruction.24 They also found that combining ablation with stenting further improves venous ulcer healing.
Dr Lobastov. A recent systematic review addressed the question of superficial vein ablation in the presence of deep vein obstruction and concluded that it may be safe.24 Authors combined studies with nonthrombotic and postthrombotic venous obstructions predominantly of proximal localization. In fact, only one trial by Raju S et al assessed saphenous stripping in the presence of infrainguinal obstruction, which was supplemented by the repair of deep venous valves in 81%.25 Authors found clinical and functional improvement in all patients irrespective of deep vein status. All other studies dealt with patients having iliocaval obstruction and investigated superficial ablation and stenting in different combinations and sequences. So, it is possible to conclude the safety of superficial venous ablation in proximal deep vein obstruction when saphenous veins and their tributaries rarely provide collateral outflow. Moreover, even in the presence of a suprapubic bypass through an epigastric vein, great saphenous vein (GSV) could be easily ablated with preservations of collaterals. In contrast, data on superficial vein ablation in the presence of infrainguinal deep vein obstruction, when saphenous veins could provide significant collateral outflow, is limited. With regard to the efficacy of superficial vein ablation in the presence of proximal deep vein obstruction, the results of analyzed studies are conflicting. However, adjunctive venous stenting seems to improve outcomes of superficial vein ablation but not vice versa.7,14,15,26
In terms of VLU healing, individual RCTs that enrolled a limited number of patients with previous DVT (7%-9%), without deep vein obstruction, and with deep vein reflux in 32% to 38% showed an increased chance for ulcer healing and decreased risk of ulcer recurrence when ablation of superficial reflux by open surgery (ESCHAR study [Effect of Surgery and Compression on Healing And Recurrence]) for endovenous interventions (EVRA study [Early Venous Reflux Ablation]) supplemented standard conservative care.27,28 However, due to the exclusion of patients with deep venous obstruction, these results could not be extrapolated to the current clinical case.
Dr Geroulakos. In the absence of active or healed leg ulcers, dealing with superficial venous reflux with endovenous thermal ablation and phlebectomy may be sufficient for the management of the patient.
Dr Josnin. I have no experience in this regard, and it would seem to me that performing both procedures simultaneously would be an entirely feasible option unless reflux is suspected to have a more significant impact on ulceration. In such case, given the need for anticoagulation after stenting and a more cumbersome procedure, I would leave open the possibility of an evaluation that includes ulcer healing, the severity of venous disease, and quality of life (QOL) prior to performing the recanalization.
Dr Kan. Stent-first, ablation-first, or simultaneous surgery may be surgical options for patients with both superficial and deep venous diseases. According to the findings of Alsheekh A et al, there appears to be no significant difference, so it’s unclear whether vein ablation or stenting should be performed first.29 Also, about 16% of patients in that study said neither approach helped. I prefer to do the stent or simultaneous procedures to avoid dirty wound contamination issues.
Dr Lobastov. The current evidence does not clarify what to do first in patients with proximal venous obstruction and superficial reflux: stenting or ablation. The decision may be based on the preferences of the patient and physician, institutional capacity, and clinical features. In any case, if the first approach did not lead to ulcer healing, the second one should be utilized. However, another question can arise: if the first approach was effective, is it necessary to make a supplementary treatment? Further robust RCTs should be focused on these questions.
Dr Nikolov. A large study by Lawrence et al looked at the impact of the 3 treatment modalities on venous ulcer healing: superficial vein ablation, perforator vein ablation, and deep venous stenting.15 Data came from 11 centers in the USA and included 832 patients. The main findings of this study are that ablation of truncal and perforating vein reflux, as well as stenting of deep vein obstruction, all contribute to the healing of venous ulceration. Patients with chronic venous ulcers should have truncal and perforator reflux treated to improve wound healing. Furthermore, patients who fail to heal with superficial and perforator vein ablation should undergo an examination of the iliocaval veins. Significant deep venous obstruction, as well as incompetent truncal veins, should be treated to improve and accelerate wound healing. It is noteworthy that patients who underwent deep venous stenting heal faster than those with untreated deep vein obstruction.
We look forward to the results from another interesting study—the DEVELOP trial (DEep VEin Lesion OPtimization).30 Patients will be randomized to undergo either truncal ablation and compression therapy or truncal ablation, simultaneous with iliac interrogation with IVUS and stenting of significant (>50%) iliac vein lesions plus compression therapy. The primary feasibility outcome will be the rate of eligible patient participation, whereas the primary clinical outcomes will be ulcer healing and procedural safety.
In summary, our treatment strategy and preference in patients with complex pathology (both reflux and obstruction) are staged procedures. First, we correct the reflux, and there are several reasons for that. Ablation is faster and easier and is a safe intervention and can be done in an outpatient setting. Another reason is that if we perform stenting first, we should leave the patient on prolonged anticoagulation. There is much evidence that ablation in patients on anticoagulation is safe, but if we could minimize the risk of bleeding complications, we should do so.31,32 Venous stenting is safe and cost effective but requires much more skill and resources.
Dr Geroulakos. According to the International Delphi consensus, anticoagulation is the preferred treatment for a compressive iliac vein lesion during the first 6 to 12 months after venous stenting. Low molecular weight heparin (LMWH) is the antithrombotic agent of choice during the first 2 to 6 weeks. Lifelong anticoagulation is recommended after multiple DVTs. Discontinuation of anticoagulation after 6 to 12 months is advised after venous stenting for a single acute DVT. There is no consensus regarding the role of long-term antiplatelet therapy.33
Dr Kan. In comparison with bypass surgery, endovascular therapy in patients with chronic outflow obstruction is considered a good option for symptom control owing to its relative simplicity, low risk, and its being a day surgery, as conservative compression therapy may fail later. In this era of increasing use of deep vein stenting, there is currently no consensus on postoperative antithrombotic therapy regarding the duration and type of anticoagulation after chronic recanalization. However, as a general rule, thrombotic venous disease requires more aggressive medical management after surgery than a nonthrombotic disease because of the higher rate of rethrombosis in the former.
A typical treatment regimen will include an enoxaparin bridge to warfarin. Practitioners increasingly consider the direct oral anticoagulants (DOACs; rivaroxaban) as an alternative to warfarin; however, data on its efficacy after recanalization and stenting are scarce. Furthermore, patient adherence to oral anticoagulants is critical during postoperative care to avoid significant skipping of medications. Many practitioners use antiplatelet drugs such as aspirin and clopidogrel after venous stent placement, but this practice is based on arterial data and physiology.
Dr Lobastov. Stenting of postthrombotic venous obstruction is associated with the lowest primary and secondary patency compared with nonthrombotic lesions and DVT.13,34 The reason for stent occlusion include mechanical, clinical, and therapeutic factors.35 The recent systematic review revealed a high heterogeneity of different antithrombotic approaches that did not affect stent patency.36 The type and duration of therapy seem to depend on the characteristics of the primary thrombotic event and the severity of venous obstruction. In postthrombotic lesions, prolonged anticoagulation is usually indicated and sometimes in combination with antiplatelets, especially in recurrent DVT and after reinterventions.33 In case of total and extended postthrombotic occlusion, initial therapy with LMWH may be beneficial.37 Compared with vitamin K antagonist (VKA), rivaroxaban appeared more effective after stenting postthrombotic obstructions, regarding primary patency, in-stent stenosis, symptom recurrence, and ulcer healing.38
So, treatment after stenting of postthrombotic deep venous obstruction therapy with LMWH for 2 to 6 weeks, followed by rivaroxaban for 6 to 12 months with a further decision about prolonged anticoagulation made on an individual basis, is advocated. Anticoagulation for an indefinite period may be suggested for all patients except those with index DVT provoked by major transient risk factors.39-41 Additional use of antiplatelets may be suggested after reinterventions in individuals with low bleeding risk.
Dr Geroulakos. Micronized purified flavonoid fraction (MPFF) counteracts the pathophysiologic mechanisms of chronic venous disease (CVD) and ulceration and has proven to be an effective adjunct to compression therapy in patients with large and chronic VLUs.
Dr Josnin. In international guidelines, MPFF has a special place in the treatment of ulcers. It was recommended in 2011 by the Society for Vascular Surgery and the American Venous Forum and in 2015 by the European Society for Vascular Surgery (ESVS) for use in healing primary venous ulcers as an adjunct to compression therapy (Class IIa, level A). Then, in 2018, it was recommended by the International Union of Phlebology and the International Union of Angiology (Grade A) and in 2022, by the ESVS (class IIa, level A).10,42-44
Dr Kan. MPFF has the ability to improve venous tone and capillary permeability, but the exact mechanism of action of the drug remains unclear. MPFF has anti-inflammatory, antioxidant, and powerful free-radical scavenging properties. MPFF decreases the expression of adhesion molecules by neutrophils and monocytes in patients with CVD. Based on the experimental results, MPFF usage in chronic venous hypertension prevented capillary rarefaction and the venous inflammatory cascade initiation.45
From the perspective of the mechanism of action, it would appear that MPFF treatment can promote the healing of venous ulcers. However, its role may be limited to adjuvant therapy. To treat venous ulcer wounds, it is still necessary to eradicate the cause, improve the lifestyle, and assist with compression therapy.
Dr Tazi Mezalek. VLU is the final stage of CVI and is the most common leg ulcer type. The ulcers are often painful and exudative, and the recurrence rates can reach 56%, especially in those who are not adherent to compression stocking therapy.46 This cycle of healing and recurrence considerably impacts individuals’ health and QOL, health care, and socioeconomic costs. Low-stretch compression is the primary treatment for VLU, which assists by reducing venous hypertension and peripheral edema and enhancing venous return. However, studies show that issues with adherence to compression therapy may be the principal cause of healing failure. Pharmacological treatment that suppresses inflammation would be an invaluable intervention to complement compression treatments. MPFF has venotonic properties and acts on leukocytes and endothelium, which results in decreased inflammation and permeability. A meta-analysis of randomized prospective studies found that MPFF accelerated the healing of leg ulcers.47
Dr Lobastov. According to the latest Cochrane meta-analysis, venoactive drugs (VADs) may have little or no effect on ulcer healing (risk ratio [RR] 0.94; 95% CI, 0.79-1.13).48 However, the authors of this report combined data on different drugs, including rutosides, hidrosmine and diosmine, without separation of MPFF, aminaftone, and calcium dobesilate. The recent umbrella review found 3 systematic reviews, including the above mentioned, suggesting the efficacy of MPFF (RR, 1.36; 95% CI, 1.07-1.74) and rutosides (RR, 1.7; 95% CI, 1.24-2.34) in addition to standard compression and topical therapy for ulcer healing.49 The individual meta-analysis of 5 RCTs with MPFF use in addition to standard compression therapy and local care found a significant 32% (95% CI, 3%-70%) increase in chance for ulcer healing and a 5-week reduction in time to heal.47 It is important that the treatment course duration in all trials was 6 months. It could sometimes be prolonged for 12 months without increasing the risk of adverse events but with further reduced symptoms.50 So, treatment duration with MPFF is essential to achieve individual benefit.
Conclusion
• In patients with VLUs, nonthrombotic and postthrombotic iliocaval venous obstruction is prevalent and often associated with superficial venous reflux.
• In patients with a combination of deep venous obstruction and superficial venous reflux, venous stenting and superficial ablation are often indicated together. There is conflicting evidence that superficial reflux ablation in the presence of deep venous obstruction is safe and effective or can improve outcomes in adjunct with venous stenting.
• The decision to perform ablation and stenting and the sequence of interventions should be made on an individual basis considering the preferences of the patient and physician and institutional capacities.
• After stenting of postthrombotic venous obstruction, prolonged anticoagulation with LMWH switched to DOACs is indicated for 6 to 12 months or longer after individual assessment of risks and benefits considering the nature of primary DVT, technical aspects of venous stenting, and individual bleeding risk. Additional antiplatelet therapy may be suggested in recurrent DVT and after reinterventions.
• MPFF can improve venous ulcer healing in addition to standard conservative treatment. The duration of the therapy with MPFF of ≥6 months is essential to achieve maximal benefits.
CORRESPONDING AUTHOR
Nadelin Nikolov
Department of Vascular Surgery and
Angiology, National Heart Hospital
Ulitsa Konyovitsa 65, 1309 Sofia,
Bulgaria
email: nadelin.nikolov@gmail.com
References
1. Raju S, Darcey R, Neglen P. Unexpected major role for venous stenting in deep reflux disease. J Vasc Surg. 2010;51(2):401-408; discussion 8.
2. Raffetto JD, Ligi D, Maniscalco R, Khalil RA, Mannello F. Why venous leg ulcers have difficulty healing: overview on pathophysiology, clinical consequences, and treatment. J Clin Med. 2020;10(1):29.
3. Ruiz CS, Hamrick MF, McGinigle KL, Marston WA. Iliac vein recanalisation and stenting accelerate healing of venous leg ulcers associated with severe venous outflow obstruction. Wound Repair Regen. 2023;31(2):193-198.
4. Marston W, Fish D, Unger J, Keagy B. Incidence of and risk factors for iliocaval venous obstruction in patients with active or healed venous leg ulcers. J Vasc Surg. 2011;53(5):1303-1308.
5. Sermsathanasawadi N, Pruekprasert K, Pitaksantayothin W, et al. Prevalence, risk factors, and evaluation of iliocaval obstruction in advanced chronic venous insufficiency. J Vasc Surg Venous Lymphat Disord. 2019;7(3):441-447.
6. Chinchalongporn W, Tanmit P, Pruekprasert K, et al. Prevalence and predictors of combined >50% iliocaval venous obstruction and superficial venous reflux in chronic venous insufficiency patients with healed or active venous leg ulcer. J Vasc Surg Venous Lymphat Disord. 2023;11(3):502-509.
7. Yang X, Wu X, Peng Z, Yin M, Lu X, Ye K. Outcomes of endovenous laser ablation with additional iliac vein stenting of nonthrombotic lesions in patients presenting with active venous ulcers. J Vasc Surg Venous Lymphat Disord. 2021;9(6):1517-1525.
8. Mousa AY, Broce M, Yacoub M, AbuRahma AF. Iliac vein interrogation augments venous ulcer healing in patients who have failed standard compression therapy along with pathological venous closure. Ann Vasc Surg. 2016;34:144-151.
9. George R, Verma H, Ram B, Tripathi R. The effect of deep venous stenting on healing of lower limb venous ulcers. Eur J Vasc Endovasc Surg. 2014;48(3):330-336.
10. De Maeseneer MG, Kakkos SK, Aherne T, et al. Editor’s choice – European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs. Eur J Vasc Endovasc Surg. 2022;63(2):184-267.
11. Qiu P, Zha B, Xu A, et al. Systematic review and meta-analysis of iliofemoral stenting for post-thrombotic syndrome. Eur J Vasc Endovasc Surg. 2019;57(3):407-416.
12. Badesha AS, Bains PRS, Bains BRS, Khan T. A systematic review and meta-analysis of the treatment of obstructive chronic deep venous disease using dedicated venous stents. J Vasc Surg Venous Lymphat Disord. 2022;10(1):267-282.e4.
13. Majeed GM, Lodhia K, Carter J, et al. A systematic review and meta-analysis of 12-month patency after intervention for iliofemoral obstruction using dedicated or non-dedicated venous stents. J Endovasc Ther. 2022;29(3):478-492.
14. Nayak L, Hildebolt CF, Vedantham S. Postthrombotic syndrome: feasibility of a strategy of imaging-guided endovascular intervention. J Vasc Interv Radiol. 2012;23(9):1165-1173.
15. Lawrence PF, Hager ES, Harlander-Locke MP, et al. Treatment of superficial and perforator reflux and deep venous stenosis improves healing of chronic venous leg ulcers. J Vasc Surg Venous Lymphat Disord. 2020;8(4):601-609.
16. Guo Z, Li X, Wang T, Liu J, Chen B, Fan L. Effectiveness of iliac vein stenting combined with high ligation/endovenous laser treatment of the great saphenous veins in patients with clinical, etiology, anatomy, pathophysiology class 4 to 6 chronic venous disease. J Vasc Surg Venous Lymphat Disord. 2020;8(1):74-83.
17. Mousa AY, Yacoub M, Broce M, Hass SM, Abu-Halimah S, AbuRahma AF. IP265. Treatment of iliocaval obstruction may alleviate the need for superficial venous ablation in patients with significant varicose venous disease. J Vasc Surg. 2018;67(6):e156-e157.
18. Chait J, Kibrik P, Kenney K, et al. Bilateral iliac vein stenting reduces great and small saphenous venous reflux. Vascular. 2019;27(6):623-627.
19. Rognoni C, Lugli M, Maleti O, Tarricone R. Venous stenting for patients with outflow obstruction and leg ulcers: cost effectiveness and budget impact analyses. J Comp Eff Res. 2020;9(10):705-720.
20. Li C, Jacobowitz GR, Rockman CB, et al. Superficial venous procedures can be performed safely and effectively in patients with deep venous reflux. J Vasc Surg Venous Lymphat Disord. 2023;11(2):281-292.e1.
21. Raju S, Fredericks R. Venous obstruction: an analysis of one hundred thirty-seven cases with hemodynamic, venographic, and clinical correlations. J Vasc Surg. 1991;14(3):305-313.
22. Raju S, Fountain T, Neglén P, Devidas M. Axial transformation of the profunda femoris vein. J Vasc Surg. 1998;27(4):651-659.
23. Labropoulos N, Volteas N, Leon M, et al. The role of venous outflow obstruction in patients with chronic venous dysfunction. Arch Surg. 1997;132(1):46-51.
24. Benfor B, Peden EK. A systematic review of management of superficial venous reflux in the setting of deep venous obstruction. J Vasc Surg Venous Lymphat Disord. 2022;10(4):945-954.e2.
25. Raju S, Easterwood L, Fountain T, Fredericks RK, Neglen PN, Devidas M. Saphenectomy in the presence of chronic venous obstruction. Surgery. 1998;123(6):637-644.
26. Yin M, Huang X, Cui C, et al. The effect of stent placement for May-Thurner syndrome combined with symptomatic superficial venous reflux disease. J Vasc Surg Venous Lymphat Disord. 2015;3(2):168-172.
27. Barwell JR, Davies CE, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004;363(9424):1854-1859.
28. Gohel MS, Heatley F, Liu X, et al. A randomized trial of early endovenous ablation in venous ulceration. N Engl J Med. 2018;378(22):2105-2114.
29. Alsheekh A, Hingorani A, Ascher E, Marks N, Rizvi SA. IP255. Venous stenting vs venous ablation. J Vasc Surg. 2016;63(6 supplement):134S-135S.
30. Aherne TM, Keohane C, Mullins M, et al. DEep VEin Lesion OPtimisation (DEVELOP) trial: protocol for a randomised, assessor blinded feasibility trial of iliac vein intervention for venous leg ulcers. Pilot Feasibility Stud. 2021;7(1):42.
31. Sharifi M, Mehdipour M, Bay C, Emrani F, Sharifi J. Effect of anticoagulation on endothermal ablation of the great saphenous vein. J Vasc Surg. 2011;53(1):147-149.
32. Westin GG, Cayne NS, Lee V, et al. Radiofrequency and laser vein ablation for patients receiving warfarin anticoagulation is safe, effective, and durable. J Vasc Surg Venous Lymphat Disord. 2020;8(4):610-616.
33. Milinis K, Thapar A, Shalhoub J, Davies AH. Antithrombotic therapy following venous stenting: international Delphi consensus. Eur J Vasc Endovasc Surg. 2018;55(4):537-544.
34. Razavi MK, Jaff MR, Miller LE. Safety and effectiveness of stent placement for iliofemoral venous outflow obstruction: systematic review and meta-analysis. Circ Cardiovasc Interv. 2015;8(10):e002772.
35. Drebes AB, Davies NH. Anticoagulation after iliofemoral vein stenting – old versus new. Curr Pharm Des. 2018;24(38):4525- 4533.
36. Notten P, Ten Cate H, Ten Cate-Hoek AJ. Postinterventional antithrombotic management after venous stenting of the iliofemoral tract in acute and chronic thrombosis: a systematic review. J Thromb Haemost. 2021;19(3):753-796.
37. Marston WA, Browder SE, Iles K, Griffith A, McGinigle KL. Early thrombosis after iliac stenting for venous outflow occlusion is related to disease severity and type of anticoagulation. J Vasc Surg Venous Lymphat Disord. 2021;9(6):1399-1407.e1.
38. Zhang X, Huang J, Peng Z, Lu X, Yang X, Ye K. Comparing safety and efficacy of rivaroxaban with warfarin for patients after successful stent placement for chronic iliofemoral occlusion: a retrospective single institution study. Eur J Vasc Endovasc Surg. 2021;61(3):484-489.
39. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603.
40. Kakkos SK, Gohel M, Baekgaard N, et al. Editor’s choice – European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg. 2021;61(1):9-82.
41. Stevens SM, Woller SC, Baumann Kreuziger L, et al. Executive summary: antithrombotic therapy for VTE disease: second update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160(6):2247-2259.
42. Gloviczki P, Comerota AJ, Dalsing MC, et al. The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2011;53(5 suppl):2s-48s.
43. Wittens C, Davies AH, Bækgaard N, et al. Editor’s choice – Management of chronic venous disease: clinical practice guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg. 2015;49(6):678-737.
44. Nicolaides A, Kakkos S, Baekgaard N, et al. Management of chronic venous disorders of the lower limbs. Guidelines according to scientific evidence. Part I. Int Angiol. 2018;37(3):181-254.
45. das Gracas C de Souza, Cyrino FZ, de Carvalho JJ, Blanc-Guillemaud V, Bouskela E. Protective effects of micronized purified flavonoid fraction (MPFF) on a novel experimental model of chronic venous hypertension. Eur J Vasc Endovasc Surg. 2018;55(5):694-702.
46. Vowden KR, Vowden P. Preventing venous ulcer recurrence: a review. Int Wound J. 2006;3(1):11-21.
47. 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.
48. Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, et al. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2020;11(11):CD003229.
49. Mansilha A, Gianesini S, Ulloa JH, et al. Pharmacological treatment for chronic venous disease: an umbrella review of systematic reviews. Int Angiol. 2022;41(3):249-257.
50. Guillot B, Guilhou JJ, de Champvallins M, Mallet C, Moccatti D, Pointel JP. A long term treatment with a venotropic drug. Results on efficacy and safety of Daflon 500 mg in chronic venous insufficiency. Int Angiol. 1989;8(4 suppl):67-71.
