Systematic review and meta-analysis of deep venous reflux correction in chronic venous insufficiency.

OBJECTIVE: The aim of this study was to investigate the technical feasibility, operative techniques, safety, and efficacy outcomes of procedures aimed at correcting deep venous reflux, in patients with chronic venous insufficiency. METHODS: We performed systematic literature searches in PubMed, Embase, and Web of Science from databases' inception to February 2022. We included systematic reviews, randomized controlled trials, and observational studies describing surgical procedures to treat patients with deep reflux due to primary and secondary incompetence, post-thrombotic syndrome (PTS). Proportion meta-analyses were performed for all the efficacy and safety outcomes. RESULTS: We included 57 studies in the quantitative synthesis: three randomized controlled trials including 252 patients and 54 case series including 4004 patients. Studies included a median of 38 patients, with a mean age of 51 years; 52% of them were males. Forty percent of studies included 2291 patients with primary incompetence, 29% of studies included 595 patients with PTS, and 31% of studies included 1118 patients with both diseases. As for primary incompetence, pooled estimates for all procedures showed an 89% (95% confidence interval [CI], 82%-94%) of ulcer healing, 10% (95% CI, 4%-18%) ulcer recurrence, 98% (95% CI, 93%-100%) valve patency, 84% (95% CI, 78%-90%) valve competence, 0.05% (1/1904 patients) pulmonary embolism, 1% (95% CI, 0%-3%) wound infections, 5% (95% CI, 1%-9%) hematoma, 2% (95% CI, 0%-6%) lymphocele, 2% (95% CI, 1%-4%) thrombosis, 85% (95% CI, 74%-94%) pain improvement, 89% (95% CI, 65%-100%) edema improvement, and 85% (95% CI, 73%-93%) lipodermatosclerosis improvement. Patients with PTS showed less favorable outcomes: 82% (95% CI, 71%-91%) of ulcer healing, 18% (95% CI, 5%-36%) ulcer recurrence, 88% (95% CI, 78%-96%) valve patency, 78% (95% CI, 66%-88%) valve competence, no pulmonary embolism, 6% (95% CI, 0%-22%) wound infections, 6% (95% CI, 3%-10%) hematoma, 5% (95% CI, 1%-12%) lymphocele, 7% (95% CI, 1%-16%) thrombosis, 79% (95% CI, 59%-94%) pain improvement, 75% (95% CI, 61%-88%) edema improvement, and 64% (95% CI, 9%-100%) lipodermatosclerosis improvement. CONCLUSIONS: The number of studies included in each meta-analysis are limited, and knowing how this element can affect the statistical power, as well as the absence of comparative control groups, it is not possible to draw definitive conclusions. Nevertheless, deep venous reconstructive surgery for reflux may increase the probability of clinical improvement in patients affected by chronic venous insufficiency. Outcomes appear to be satisfactory even if possible adjunctive procedures may be required over the course of the patient's lifetime. Consequently, a strict follow-up protocol is required to maintain outcomes. Further studies are required to evaluate deep venous reconstructive surgery for reflux particularly as to how it compares with the more recently introduced endovenous approaches.

Time-Driven Activity-Based Costing for Capturing the Complexity of Healthcare Processes: The Case of Deep Vein Thrombosis and Leg Ulcers.

Time-driven activity-based costing (TDABC) is suggested to assess costs within the value-based healthcare approach, but there is a paucity of applications in chronic diseases such as deep vein thrombosis (DVT) and leg ulcers. In this context, we applied TDABC in a cost-effectiveness analysis comparing venous stenting to compression ± anticoagulation (standard of care-SOC) from both hospital and societal perspectives in Italy. TDABC was applied to both treatments to assess costs that were included in a cost-effectiveness model. Clinical inputs were retrieved from the literature and integrated with real-world data. The Incremental Cost Utility Ratio (ICUR) of stenting compared to SOC was EUR 10,270/QALY and EUR 8962/QALY for hospital and societal perspectives, respectively. The mean cost per patient for venous stenting of EUR 5082 was higher than the Diagnosis-Related Group (DRG) reimbursement (EUR 4742). For SOC, an ulcer healing in 3 months costs EUR 1892, of which EUR 302 (16%) is borne by the patient versus a reimbursement of EUR 1132. TDABC showed that venous stenting may be cost-effective compared with SOC but that reimbursement rates may not completely cover the real costs, which are partially sustained by the patients. A more efficient policy for covering the real costs may be beneficial for both clinical centers and patients.

New Perspectives on Micronised Purified Flavonoid Fraction in Chronic Venous Disease: From Microvalves to Clinical Effectiveness.

The importance of chronic venous disease (CVD), as a cause of reduced quality of life and increased costs to healthcare systems, is expected to rise in parallel with population aging and the increasing prevalence of obesity. Venoactive drugs (VADs) are frequently used to treat the symptoms and signs of CVD. The most commonly used and widely studied VAD, micronised purified flavonoid fraction (MPFF), is effective at all stages of CVD, and has been shown to significantly reduce leg pain, leg heaviness and swelling, as well as ankle oedema and functional discomfort, in clinical trials. Recently, experiments employing animal models of CVD have demonstrated that MPFF has anti-inflammatory and venotonic effects at the microvalve level, and a pilot clinical study in patients with CVD has provided support for these findings. Collectively, these results suggest that early initiation of MPFF treatment may have the potential to favourably alter the clinical course of the disease, although further clinical data are required to confirm these findings. International guidelines on CVD management strongly recommend MPFF to reduce symptoms and improve quality of life. Studies are now needed to investigate the impact of long-term treatment on disease progression.

Extended anticoagulation for venous thromboembolism: A survey of the American Venous Forum and the European Venous Forum.

OBJECTIVE: Extended anticoagulation therapy should always be considered after standard treatment of an unprovoked episode of venous thromboembolism (VTE). It can also be considered for selected patients with provoked VTE. However, the evidence-based protocols suggested by some clinical guidelines and risk assessment tools to guide this practice are limited and ambiguous. The goal of the present survey research was to analyze current practices in applying extended anticoagulation therapy for patients with VTE among members of the American Venous Forum (AVF) and European Venous Forum (EVF). METHODS: An online survey was created by the AVF Research Committee. The survey consisted of 16 questions to identify the country of practice, specialty, experience of the participating physicians, and their clinical practice patterns in applying extended anticoagulation therapy for VTE patients. The survey was distributed via e-mail to the members of the AVF and EVF. RESULTS: A total of 144 practitioners, 48 AVF members (33%) and 96 EVF members (66%), participated in the survey. Most of the respondents identified themselves as vascular specialists with primary certification in vascular surgery (70%), vascular medicine or angiology (9%), and venous disease or phlebology (3%). Of the 144 respondents, 72% believed that the risk of VTE recurrence will generally overweigh the risk of bleeding for patients with unprovoked VTE. Extended anticoagulation therapy might be used by 97% of providers. Different patterns in real world clinical practice were identified. More than one half of the practitioners estimated the VTE recurrence and bleeding risk subjectively. The antithrombotic drugs most commonly used for secondary prophylaxis were rivaroxaban, apixaban, warfarin, dabigatran, and aspirin, in decreasing order of frequency. Among the reasons selected for not regularly considering extended anticoagulation therapy were the lack of specific clinical practice guidelines (24%), lack of reported evidence (9%), and absence of valid VTE and/or bleeding risk prediction calculators (8%). Twelve participants (8%) stated that extended anticoagulation therapy would not be beneficial for most patients with VTE. Ten participants (7%) indicated that prescribing extended anticoagulation therapy was outside the scope of their specialty. CONCLUSIONS: Different practice patterns exist regarding extending anticoagulation therapy beyond the standard treatment for patients with VTE. Major gaps in knowledge remain a serious challenge at least partially explaining the inaccuracy and inconsistency in long-term VTE management. Appropriately designed studies are needed to evaluate risk stratification tools when contemporary best medical therapy is used, accurately predict VTE recurrence and its long-term outcomes, and tailor safe and effective secondary prophylaxis.

Residual volume fraction during walking using wireless air plethysmography in patients with chronic deep venous disease.

OBJECTIVE: Traditional air plethysmography (APG) provides a quantitative measure of the residual volume fraction (RVF) after 10 tiptoe movements. The recent development of a wireless Bluetooth (Bluetooth SIG, Inc, Kirkland, Wash) APG device, the PicoFlow (Microlab Elettronica, Padua, Italy), enabled us to measure RVF during normal walking. The aim of our study was to compare the RVF obtained during tiptoeing with RVF obtained during normal walking in patients with deep venous pathology (ie, reflux and/or obstruction). METHODS: A total of 61 consecutive symptomatic patients (27 women and 34 men; median age, 46 years; range, 18-79 years) with chronic venous disease due to deep venous pathology (venous reflux or obstruction, or both) before treatment or persisting after intervention were included in the present study. Of the 122 total limbs examined, 79 were affected by deep chronic venous disease and 43 contralateral limbs were normal with normal deep veins and acted as controls. The APG examination was performed using the PicoFlow device using the standard examination technique. The RVF was calculated from the residual volume at the end of 10 tiptoe movements and also during normal walking. RESULTS: At the end of the 10 tiptoe movements, the mean ± standard deviation RVF was 27.0% ± 13.2% in the limbs with normal deep veins and 38.8% ± 16.9% in the limbs with deep chronic venous disease (P < .001). During walking, when a steady state in volume was reached, the RVF was 26.3% ± 17.8% in the limbs with normal deep veins and 43.1% ± 18.6% in limbs with deep venous disease (P < 0.001). A significant difference was found between limbs with normal deep veins and limbs with deep venous reflux, irrespective of which exercise was performed. However, the mean RVF between the limbs with normal deep veins and those with outflow obstruction in the absence of reflux was significant during walking (P = .012) but not during tiptoeing (P = .212). The mean RVF was higher in the C3 to C6 limbs than in the C0 to C2 limbs with tiptoeing (29.9% ± 14.5% vs 38.3% ± 17.0%; P < .006). Similar results were obtained with walking (29.2% ± 18.0% vs 42.4% ± 18.8%; P < .004). CONCLUSIONS: In limbs with normal deep veins and deep veins with reflux, the RVF measured during walking with wireless APG was similar to the RVF obtained during tiptoeing. However, in the limbs with outflow obstruction in the absence of reflux, the RVF during walking was higher than the RVF after tiptoeing. Our results have shown that the evaluation of RVF during walking is feasible and practical.

An estimate of the economic burden of venous leg ulcers associated with deep venous disease.

INTRODUCTION: Venous leg ulcers (VLU) embody the most severe stage of the broad spectrum of chronic venous disease. Approximately 40% of patients with VLU present with the underlying deep venous disease (DVD). Although the data are scarce, these deep venous disease-related VLU (DRV) are thought to have higher recurrence rates and a substantial economic burden. The objective of this study was to assess the economic burden of DRV across Australia, France, Germany, Italy, Spain, the UK, and the USA. METHODS: A comprehensive literature review was undertaken to identify publications documenting the incidence and prevalence of VLU and DRV, medical resource utilization, and associated costs of DRV. Findings from this literature review were used to estimate the economic burden of illness, including direct medical costs over a 12-month interval following initial presentation of a newly formed DRV. RESULTS: Total annual incidence of new or recurrent DRV in Australia, France, Germany, Italy, Spain, UK, and the US are estimated at 122,000, 263,000, 345,000, 253,000, 85,000, 230,000, and 643,000 events, respectively, in 2019. Incidence ranges from 0.73 to 3.12 per 1000 persons per year. The estimated annual direct medical costs for patients managed conservatively in these geographies total ~ $10.73 billion (USD) or $5527 per person per year. CONCLUSION: The availability of published data on the costs of VLU care varies widely across countries considered in this analysis. Although country-specific VLU practice patterns vary, there is a uniform pattern of high-cost care.

Chronic venous disease and diabetic microangiopathy: pathophysiology and commonalities.

Chronic venous disease and diabetes mellitus are highly prevalent and debilitating conditions affecting millions of individuals globally. Although these conditions are typically considered as separate entities, they often co-exist which may be important in both understanding their pathophysiology and determining the best treatment strategy. Diabetes mellitus is twice as common in patients with chronic venous disease compared with the general population. Notably, a large proportion of patients with diabetes mellitus present with venous disorders, although this is often overlooked. The etiology of chronic venous disease is multifactorial, involving hemodynamic, genetic, and environmental factors which result in changes to the venous endothelium and structural wall as well as inflammation. Inflammation, endothelial dysfunction and hyperfiltration or leakage, are commonly observed in diabetes mellitus and cause various diabetic microvascular complications. Both diseases are also influenced by the increased expression of adhesion molecules, chemokines, and cytokines, and are characterized by the presence of vessel hypertension. Consequently, despite differences in etiology, the pathophysiology of both chronic venous disease and diabetic microangiopathy appears to be driven by endothelial dysfunction and inflammation. Treatment strategies should take the co-existence of chronic venous disease and diabetic microangiopathy into account. Compression therapy is recommended in inflammatory conditions that have an edema component as seen in both chronic venous disease and diabetes mellitus. Lifestyle changes like weight loss and exercise, will improve metabolic state and lower inflammation and should be promoted in these patients. Additionally, both patient populations may benefit from venoactive drugs.

Clinical guidelines versus current clinical practice for the management of deep vein thrombosis.

BACKGROUND: Deep vein thrombosis (DVT) is one of the major health problems worldwide with potentially serious outcomes related to mortality and morbidity. We provide a current view on how patients with DVT are managed in routine practice compared with the recommendations of published clinical guidelines. METHODS: A literature review was conducted on studies reporting diagnostic and treatment patterns for acute DVT. Four dimensions were evaluated to compare the differences between clinical practice and clinical guidelines recommendations: diagnostic pathway, prescription of pharmacologic treatment and related duration, and prescription of compression therapy. For each aspect, the agreement with the corresponding guideline has been estimated as a percentage ranging from 0% (no agreement) to 100% (full agreement). RESULTS: Sixteen studies reported clinical practices in 10 countries. Among them, Japan showed the highest agreement with guidelines, followed by the UK and Switzerland. Hong Kong showed the highest agreement with diagnosis guidelines, Spain for drug treatment, UK for treatment duration, and France for compression therapy. Conversely, Germany reported a complete disagreement with guidelines for diagnosis, followed by low agreement level by UK and Italy, and Switzerland reported a lower agreement level with prescription of compression therapy. CONCLUSIONS: The implementation of clinical guidelines for the management of patients with DVT varies among countries from strict adherence to a complete lack of adherence. In this context, registries may be a useful tool to analyze clinical practice and produce findings that may be generalizable across populations.

Post-thrombotic syndrome.

Post-thrombotic syndrome (PTS) is a chronic venous insufficiency manifestation following an episode of deep-vein thrombosis (DVT). It is an important and frequent long-term adverse event of proximal DVT affecting 20-50% of patients. This position paper integrates data guiding clinicians in deciding PTS diagnosis, treatment and follow-up.

Venous stenting for patients with outflow obstruction and leg ulcers: cost-effectiveness and budget impact analyses.

Aim: To perform cost-effectiveness analysis (CEA) and budget impact analysis (BIA) comparing stenting to standard medical treatment (SMT) for the management of deep venous outflow obstruction and leg ulcers from the Italian Healthcare Service perspective. Materials & methods: A Markov model was developed to project costs and quality-adjusted life-years (QALYs) over 3 years, based on data from literature combined with real-world data. Moreover, a BIA was performed comparing the current scenario (100% SMT) with increasing utilization rates of stenting over SMT from 0.5 to 5%, in the next 5 years. Results: Stenting is a cost-effective (incremental cost-utility ratio €12,388/QALY) or dominant option versus SMT, according to in-patient or day-hospital settings, respectively. Increasing use of stenting over SMT, in the next 5 years, is expected to yield additional costs of 39.5 million Euros (in-patient) or savings of 5.1 million Euros (day-hospital). Conclusion: Stenting is a cost-effective option compared with SMT for patients with deep vein occlusion and ulceration in Italy.

CEAP clinical classes C0S-C4: differences, similarities and role of Ruscus + HMC + vitamin C in patients with chronic venous disease.

Since the publication of the CEAP classification, new research has enriched our knowledge; notably on the heritability of CVD and the genetic and environmental factors involved in this condition, as well as the symptoms apparent within the spectrum of the CEAP clinical classes and the benefits of medical treatment. Using the CEAP classification as a special theme, a symposium with the same title as the present paper was held at the annual meeting of the 2019 European Venous Forum. The lectures presented much valuable information, from which some key points can be extracted. The influence of environmental factors was demonstrated, and the fact that a large amount of information can be obtained from comprehensive history taking. There is robust evidence for heritability. Many candidate genes/loci have been identified, potentially offering new targets for treatment. More research is needed, notably using genome-wide association studies and also on microbiota, which may play a role in CVD through the inflammation pathway. Ruscus + HMC + vitamin C acts by increasing venous and lymphatic tone, protecting microcirculation, and reducing inflammation. It improves quality of life in C0S to C3 CVD patients, while a review of clinical studies and a meta-analysis have confirmed its clinical efficacy across a wide spectrum of CVD clinical classes: C0S, C1S, C2, C3 and C4. It has been awarded a Grade 1A recommendation by the international guidelines.

Investigation of non-saphenous veins in C0S patients.

BACKGROUND: C0S patients have symptoms of chronic venous disorders (CVDs), though an anatomical or pathophysiological explanation is lacking. C0 and C1 classified lower limbs can present with valve incompetence from the second to sixth generation of tributaries of saphenous veins despite the absence of a detectable saphenous truncal reflux. We hypothesized that C0S venous symptoms could stem from the second to sixth generation of saphenous tributaries and small veins that are not connected to the saphenous system. The aim was to explore these veins in C0S subjects and compare them with asymptomatic C0A subjects. METHODS: This was an open, controlled study enrolling 36 subjects, where C0S patients (N.=18) were compared with asymptomatic C0A subjects (N.=18). The VAS (visual analog scale) was used to assess leg pain. Veins were assessed using B-flow ultrasound (valve anatomy), continuous-wave (CW) Doppler (flow patterns), biomicroscopy (visualization of nutritional vessels), laser Doppler flowmetry (quantify supine microvascular perfusion) and quantitative digital photo-plethysmography (PPG) (measuring post-exercise venous refilling time [VRT]). RESULTS: There were no significant differences between C0S and C0A subjects in terms of microvascular perfusion (laser-Doppler), nutritional vessels (biomicroscopy) and VRT (PPG). B-flow ultrasound was unable to acquire sufficient data in second generation saphenous tributaries. However, the CW Doppler identified two different flow patterns: uni- and bidirectional. Bidirectional flow was significantly (P=0.05) higher in C0S versus C0A patients. CONCLUSIONS: CW Doppler, using a flat high-sensitivity probe, revealed the presence of a bidirectional flow that was significantly (P=0.05) higher in C0S than in control patients, suggesting the presence of reflux in non axial veins. These data give a new perspective on the management of C0S patients.

Venous hemodynamic changes in lower limb venous disease: the UIP consensus according to scientific evidence.

There are excellent guidelines for clinicians to manage venous diseases but few reviews to assess their hemodynamic background. Hemodynamic concepts that evolved in the past have largely remained unchallenged in recent decades, perhaps due to their often complicated nature and in part due to emergence of new diagnostic techniques. Duplex ultrasound scanning and other imaging techniques which evolved in the latter part of the 20th century have dominated investigation. They have greatly improved our understanding of the anatomical patterns of venous reflux and obstruction. However, they do not provide the physiological basis for understanding the hemodynamics of flow, pressure, compliance and resistance. Hemodynamic investigations appear to provide a better correlation with post-treatment clinical outcome and quality of life than ultrasound findings. There is a far better prospect for understanding the complete picture of the patient's disability and response to management by combining ultrasound with hemodynamic studies. Accordingly, at the instigation of Dr Angelo Scuderi, the Union Internationale de Phlebologie (UIP) executive board commissioned a large number of experts to assess all aspects of management for venous disease by evidence-based principles. These included experts from various member societies including the European Venous Forum (EVF), American Venous Forum (AVF), American College of Phlebology (ACP) and Cardiovascular Disease Educational and Research Trust (CDERT). Their aim was to confirm or dispel long-held hemodynamic principles and to provide a comprehensive review of venous hemodynamic concepts underlying the pathophysiology of lower limb venous disorders, their usefulness for investigating patients and the relevant hemodynamic changes associated with various forms of treatment. Chapter 1 is devoted to basic hemodynamic concepts and normal venous physiology. Chapter 2 presents the mechanism and magnitude of hemodynamic changes in acute deep vein thrombosis indicating their pathophysiological and clinical significance. Chapter 3 describes the hemodynamic changes that occur in different classes of chronic venous disease and their relation to the anatomic extent of disease in the macrocirculation and microcirculation. The next four chapters (Chapters 4-7) describe the hemodynamic changes resulting from treatmen by compression using different materials, intermittent compression devices, pharmacological agents and finally surgical or endovenous ablation. Chapter 8 discusses the unique hemodynamic features associated with alternative treatment techniques used by the CHIVA and ASVAL. Chapter 9 describes the hemodynamic effects following treatment to relieve pelvic reflux and obstruction. Finally, Chapter 10 demonstrates that contrary to general belief there is a moderate to good correlation between certain hemodynamic measurements and clinical severity of chronic venous disease. The authors believe that this document will be a timely asset to both clinicians and researchers alike. It is directed towards surgeons and physicians who are anxious to incorporate the conclusions of research into their daily practice. It is also directed to postgraduate trainees, vascular technologists and bioengineers, particularly to help them understand the hemodynamic background to pathophysiology, investigations and treatment of patients with venous disorders. Hopefully it will be a platform for those who would like to embark on new research in the field of venous disease.

Deep venous reconstructive surgery.

Surgical correction of deep venous reflux is a valuable adjunct in treatment of selected patient with lower limb venous ulcer. Deep venous obstruction and superficial reflux is must be corrected first. Sustained venous ulcer healing and reduced ambulatory venous hypertension can be achieved in patients with both primary and secondary deep venous insufficiency. When direct valve repair is possible, valvuloplasty is the best option, but when this is not feasible, other techniques can be used, including femoral vein transposition into the great saphenous vein, vein valve transplant, neovalve construction, or nonautologous artificial venous valve.

The use of an extract of Hypericum perforatum and Azadirachta indica in a neuropathic patient with advanced diabetic foot.

The successful use of an extract of Hypericum flowers (Hypericum perforatum) and nimh oil (Azadirachta indica; Hyperoil) in foot wounds with exposed bone in a patient with bilateral advanced diabetic ulcers, has been reported previously. It was hypothesised that this amelioration was linked with the improved glycaemic control and peripheral microvascular circulation. In this case report, the surprisingly successful outcome of another patient using Hyperoil for infection damaged diabetic foot, without prior use of surgical procedure, is described. The patient had no macrovascular pattern impairment. Diabetic foot healing paralleled with controlled local infection and enhanced glycaemic control. The outcome of this patient suggests that the effectiveness of this inexpensive therapy using Hyperoil for diabetic foot is not only linked with the presence of severe microvascular disorder, but also with the appropriate local treatment for ulcer being a must for its recovery.