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Venous ulcers

Summary

Venous Leg Ulcers (VLU) are relatively common, affecting 1% of the population in the U.S. [1].   VLU can be defined as an open skin lesion of the leg or foot that occurs in an area affected by venous hypertension SVS. It is a chronic condition and recurrence rate within 3 months after wound closure is as high as 70%. [1]. Thirty-five percent of people with VLU experience four or more episodes  [2] [3].

History: Qualified professional multidisciplinary team should perform a complete assessment of the patient. Risk factors for chronic venous insufficiency (CVI) and VLU recurrence or delayed healing should be assessed. 

Physical Examination: Location: generally between area mid-calf and approximately 1 inch below the malleolus [4], Check signs of chronic venous disease such as varicosities, telangiectasia, varicose veins, edema, etc. Wound characteristics: VLU generally have irregular margins, can be superficial to deep, have fibrin and granulation tissue, have frequent, moderate to heavy exudate. 

Diagnosis: Predominantly clinical, but peripheral arterial disease (PAD) needs to be ruled out with evaluation of ankle brachial index ratio and venous disease should be documented with duplex ultrasound. Other tests can be ordered when necessary

Differential diagnosis: Arterial ulcers, neuropathic ulcers, pressure ulcers are most common.

Documentation: Documentation should be done at least weekly to assess wound healing progress, and include number and position of ulcers on the leg. Wound measurements should be made for each VLU, including area, perimeter, and depth, description of wound edge, peri-wound area, wound base quality, amount and type of drainage, and infection, history of debridement. 

Treatment plan summary 

  • Clinicians should aim for 30% decrease in size in the first 4 weeks of treatment with standard care (local wound care, peri-wound care, specific care, ancillary measures) If VLU does not reach this target, it has a 68% probability of failing to heal within 24 weeks [4] [5] [6].
  • 1BThe first-line treatment for VLUs is compression therapy in the form of bandages, stockings or mechanical devices [7](Grade 1B), but 32%-45% of people have unhealed ulcers after 24 weeks of treatment with adequate compression [8].
  • 1C
    VLU debridement is recommended at initial assessment and as needed (Grade 1C)
  • Dressings are generally applied underneath compression to manage wound exudate and maintain wound bed moist (Grade 2B). Dressings are equally effective.
  • It is important that peri-wound skin be protected from exudate and other irritants
  • 2C
    It is better that antimicrobials (topic and systemic) be used only in case of clinical infection (Grade 2C)
  • 1B
    Pentoxifylline should be considered as an aid in VLU healing (Grade 1B)
  • Venous surgery can help heal or prevent VLU recurrence in patients with incompetent superficial veins and/or perforators, deep venous reflux or proximal chronic venous obstruction/stenosis.
  • No consensus exists about which second-line treatment works best [9]. If VLU does not decrease by 30% after 4 weeks of standard care, patient and treatment plan needs to be re-evaluated, and only then should adjunctive therapy be considered.
  • Among adjunctive therapies, clinicians might opt for wound coverage with autologous tissue (e.g., skin grafting, flaps) or cellular and/or tissue based products (CTP).
    2B
    Among CTP, single-layered dermal replacement (allogeneic matrix) and bilayered bioengineered skin (composite matrix) with compression have shown some effectiveness in treating recalcitrant VLU (Grade 2B).
    2C
    Negative pressure wound therapy can be used to promote increase of granulation tissue prior to skin grafting (Grade 2C). Diosmin/hesperidin (MPFF) might be used to increase VLU healing (Grade 2C).
  • Patient education is key in increasing adherence to treatment. 

When to refer to specialists

  • Vascular surgeon: Abnormal ankle brachial index ratio, duplex ultrasound results with any indications for vascular surgery
  • Nutritionist at initial evaluation
  • Respective specialists if associated metabolic, hematologic, autoimmune, oncologic diseases are suspected
  • Plastic surgeon for surgical wound coverage procedures

Coding

First select ICD-10 for underlying pathology:

  • Chronic venous hypertension with ulcer (I87.31-, I87.33-)
  • Post-phlebitic syndrome with ulcer (I87.01-, I87.03-)
  • Post-thrombotic syndrome with ulcer (I87.01-, I87.03-)
  • Varicose ulcer (I83.0-, I.83.2-)

Then for VLU severity:

  • Non-pressure chronic ulcer of the calf (L.97.2-)

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Introduction

Background

Venous Leg Ulcers (VLUs) are a relatively common, complex type of wound that have a negative impact on people’s lives and incur high costs for health services  [8]. VLU can be defined as an open skin lesion of the leg or foot that occurs in an area affected by venous hypertension [5]. VLUs can result in pain, unpleasant odor, reduced mobility, sleep disturbance, reduced psychological well-being and social isolation  [8]. In severe cases and when associated with arterial insufficiency, VLUs can lead to limb amputation [10] [11]

Venous ulcers are often recurrent, and open ulcers can persist from weeks to many years. It is estimated that 93% of VLUs will heal in 12 months, and 7% remain unhealed after five years. The recurrence rate within 3 months after wound closure is as high as 70%. [1]. Thirty-five percent of people with VLU experience four or more episodes [2] [3]

The first-line treatment for VLUs is compression therapy, but 32%-45% of people have unhealed ulcers after 24 weeks of treatment with adequate compression [8] [12]. Since these figures were extracted from randomized controlled trials, the percentage of unhealed ulcers in the real world are probably higher.

Despite the relatively low prevalence, VLUs represent a significant financial burden to the healthcare system in the U.S., estimated to be between US$ 2 and 2.5 billion per year [5] [13]. One study estimated the overall burden to Medicare and private insurers due to VLU in the U.S. (excluding out-of-pocket payments and other indirect costs such as lost productivity) to be of US$14.9 billion (in 2012 US$ ). [14] In the U.K., estimated costs to treat a person with open leg ulcer is around GBP 1700 (US$ 2122) per year at 2012 prices, mostly related to nursing time  [15].  

Etiology

Venous ulcers are the final stage of chronic venous insufficiency (CVI)  [8]. It is not infrequent for leg ulcers to be associated with CVI and arterial vascular disease, in which case, these ulcers are said to be of “mixed etiology.” The term chronic venous disease is generally applied to the full spectrum of chronic venous disease (CEAP C0-6), whereas chronic venous insufficiency is reserved for more severe presentations (CEAP C4-6) [16].

Risk Factors   

  • Risk factors for CVI: older age, obesity, previous leg injuries, deep venous thrombosis, and phlebitis [13] [17]
  • Risk factors for delayed VLU healing or recurrence: Initial wound area and VLU duration (a VLU that is smaller than 10cm2 and has a duration shorter than 12 months at first visit has a 70% change of healing by the 24th week of care, whereas a VLU larger than 10cm2 and with a duration longer than 12 months has only 22% chance of healing by the 24th week of care  [8] [18]. Other risk factors include post thrombotic syndrome or venous insufficiency in superficial and/or deep vein systems and/or the perforating venous systems, history of vascular surgery, trauma, repeat intimal venous damage or varicosities, family history of VLU, male gender, obesity, increasing age > 50 years of age [19].

Pathophysiology

  • CVI results in venous hypertension (ambulatory venous pressures of up to 60 to 90 mmHg, as opposed to the normal levels of 20 to 30 mmHg), which can happen due to obstruction to venous flow, dysfunction of venous valves, and/or failure of the "venous pump." Venous hypertension and hemodynamic abnormalities lead to inflammatory alterations with microcirculatory changes that can result in venous stasis and VLU. [20]
  • The pathophysiology of VLU is complex and healing is delayed in many patients due to a chronic inflammatory condition. [21] Patient risk factors predispose individuals to chronic venous diseases including VLU. Changes in shear stress to the vein walls are likely initiating events, leading to activation of adhesion molecules on endothelial cells, and leukocyte activation with attachment and migration into vein wall, microcirculation, and in the interstitial space. Multiple chemokines, cytokines, growth factors, proteases and matrix metalloproteinases are produced. The pathology of VLU involves an imbalance of inflammation, inflammatory modulators, oxidative stress, and proteinase activity [21]

Epidemiology

Prevalence

  • Prevalence of ulcers of venous etiology only the UK is about 2.9 cases per 10,000 people [8] [22], whereas mixed arterial/venous leg ulcers have a prevalence of 1.1 per 10,000 people [5].
  • Approximately 1% of the population in the United States, 3% of people over 80 years of age in westernized countries  [1]. Prevalence is increasing, coinciding with an ageing population. In the U.S., VLUs affect between 500,000 to 2 million people per year [9].
  • More prevalent among women, but this gender discrepancy decreases with age  [17].
  • Most common type of leg ulcer (~ 80% of  leg ulcers) [13]

Incidence  

  • The overall incidence rate is 0.76 (95% CI, 0.71, 0.83) for men and 1.42 (1.35, 1.48) per 100 person-years for women. [23]

Assessment

History

  • Qualified professional multidisciplinary team should evaluate and perform a complete assessment of the patient. Patients with VLU frequently present with other co-morbidities.
  • It is important to obtain a comprehensive patient history of the patient’s current condition, recurrence and treatment if any, medical and surgical history including past deep vein thrombosis (DVT), pulmonary embolism or malignancy, medications, and other risk factors related to VLU, CVI or non-healing leg wounds  [5] [19] [24].
  • Symptoms potentially related to chronic venous disease should be identified. Those include: extremity pain, burning aching, throbbing, cramps, heaviness, itching, tiredness, fatigue, and restless legs [5] [13] [19]. Venous symptoms are usually exacerbated when the patient is standing and relieved by rest or limb elevation (as opposed to pain of peripheral artery disease, which worsens with walking or that is relieved by rest, or which worsens with limb elevation). Pain is localized to the affected veins, skin changes or ulcer and does not irradiate.
  • Extremity swelling due to chronic venous disease can be present in 25-75% of patients, worsens with prolonged standing and improves with leg elevation and walking. In women, symptoms exacerbate with menses or pregnancy.  
  • Severe complications include cellulitis, osteomyelitis, and malignant change. [13]

Physical Examination

VLUs commonly present in between area mid-calf and approximately 1 inch below the malleolus  [4]. The recurrence of an ulcer in the same area is highly suggestive of venous ulcer  [13]. Physical examination for signs of venous disease should include  [5]:

    • Inspection for: active or healed ulcers, varicosities, telangiectasia, varicose veins, edema, chronic venous skin changes and dermatitis, such as skin discoloration, inflammation, eczema, hyperpigmentation, malleolar flair, corona phlebectatica (venous starburst of veins radiating distally from the medial malleolus), atrophie blanche (capillaries are virtually absent in areas of fibrotic scars, also known as livedoid vasculopathy) (Figure 1), lipodermatosclerosis (severe fibrosing panniculitis of the subcutaneous tissue, area of indurated inflammatory tissue that binds the skin down to the subcutaneous tissue)
    • Palpation for: varicosity, palpable venous cord, tenderness, induration, edema, and pulses
    • Auscultation for bruit and reflux
    • Evaluation of ankle mobility
    • Assessment of foot temperature, measurement of the ankle brachial pressure index, testing for peripheral neuropathy, to look for signs of associated diseases such as arterial disease or diabetes mellitus  [4].               

    Figure 1. Atrophie blanche and livedoid vasculopathy

      Wound Characteristics

      • Margins: irregular  
      • Depth:  superficial-to-deep
      • Wound bed: granulation tissue and fibrin often present, minimal to moderate aching pain at borders and middle of the wound bed
      • Exudate: Frequent, moderate to heavy
      • Anatomic location: often at the medial distal lower extremity and ankle, at the malleolar area


      Figure 2. Venous ulcer and stasis
      dermatitis on right lower leg

      Figure 3. Superficial venous ulcer
      with irregular margins   

                            Figure 4. Venous ulcers on

                    right and left lower extremities

      Figure 5. Venous ulcer: indurated margins,
      red granulation tissue 

      Figure 6. Highly exudative venous ulcer
      with fibrin tissue

      Figure 7. Venous stasis


      Diagnosis

      The diagnosis of VLU is predominantly clinical, however peripheral arterial disease (PAD) needs to be ruled out with evaluation of ankle brachial index ratio and venous disease should be documented with duplex ultrasound. Other tests can be ordered when necessary.

      • Ankle Brachial index ratio for all patients with VLU:
        • Rationale: to rule out peripheral arterial disease (PAD), which can be present in up to 25% of VLU patients [2] [3] , normal ABI is between 0.9 and 1.30  [4] [25]. The typical cutoff point for diagnosis of PAD is ABI< or =0.90 at rest  [5], indices <0.8 signify some arterial disease and may be associated with intermittent claudication  [4], ABI<=0.50 usually corresponding to critical limb ischemia  [4] [5]. ABI>1.4 is strongly correlated with cardiovascular disease  [26]. The current standard for detection of significant PAD is an ABI<0.8  [4] [27] [28]. However, the Society for Vascular Surgery recommends referral to a vascular specialist if ABI<0.9, for further workup [5]. See “Compression” for more on compression options for ischemic extremities.
      • Comprehensive venous duplex ultrasound for all patients with suspected VLU [4] [5] [24]
        • Rationale: For a leg ulcer to be classified as a VLU, there needs to be objective documented evidence of venous disease [5] . The correct method/type of ultrasound should be ordered to decrease chances of inconclusive results. Evaluation for both obstructive and reflux patterns of venous disease with comprehensive color flow venous duplex ultrasound including B-mode gray-scale imaging, pulsed Doppler sampling, and color flow analysis, in supine and standing positions is considered first-line [4] [5] . Common findings in limbs with VLU are venous reflux (superficial and/or deep) and outward flow in perforators  [29]. Referral to vascular surgeon is recommended in cases with significant superficial junctional venous reflux (saphenofemoral or saphenopopliteal junction reflux >0.5 s) [24] or superficial reflux directed to the ulcer bed [5], deep vein incompetence/obstruction  [5] [24], or perforator incompetence (outward flow of >500 ms duration, with a diameter of >3.5mm located beneath or associated with the ulcer bed) [5] [24] or past history of venous surgery [24](See indications for vascular surgery)
      • Venous plethysmography for routine initial evaluation of VLU is discouraged unless results of venous duplex ultrasound are inconclusive, or if patient has recurrent or recalcitrant VLU [5].
        • Rationale: Plethysmography can identify hemodynamic obstruction patterns Blecken. If venous refill time measured with below-knee tourniquet and photoplethysmography is greater than 20 mmHg after vein surgery, result is a good predictor of VLU healing and non-recurrence  [19].  Clinicians can measure toe pressure by placing a small toe cuff around the great toe and attaching a plethysmography probe at the pulp of great toe tip. The cut-off values of toe pressure and TBI are arbitrary and vary in the literature. In general, a toe pressure of 70 to 110 mmHg or TBI > 0.5 to 0.75 is considered normal and anything below is diagnostic of PAD. A toe pressure lower than 30 mmHg or TBI 0.2 is considered severely ischemic and diagnostic of critical limb ischemia (CLI). Wound healing potential drops as TBI decreases from the normal values.[30]
      • Routine use of microcirculation assessment prior to primary therapy is discouraged by the Society for Vascular Surgery (SVS) but it can be used when concomitant arterial etiology is suspected, if there is concern for adequate microcirculation related to other conditions affecting microcirculation, or for monitoring of advanced wound therapy [5]. Transcutaneous oxygen tension (TCPO2) near VLU: if >= 30mmHg, rules out arterial disease and predicts VLU healing  [19].
      • Laboratory evaluation for thrombophilia for patients with a history of recurrent or recalcitrant VLU or thrombosis: patients with VLU have a higher prevalence of thrombophilia, which is associated with recurrent and recalcitrant ulcers [5]. Laboratory evaluation includes inherited hypercoagulable factors (anti- thrombin deficiency, protein C and protein S deficiencies), factor V Leiden (resulting in activated protein C resistance), prothrombin G20210A, plasminogen activator inhibitor type 1 mutations, hyperhomocysteinemia, antiphospholipid antibodies (anticardiolipin and lupus anticoagulant), and cryoglobulins and cryoagglutinins [5].  Factor VIII related antigen, von Willerbrand factor (VWF), D-dimer and factor V Leiden: if indicative of hypercoagulation tendency, pose a risk factor for post-thrombotic syndrome  [19].
      • Routine wound culture is not advised. Instead, guidelines suggest wound culture only when VLU shows clinical signs of infection. See “Wound culture”
      • Wound biopsy is indicated in VLU that fail standard therapy after 4 weeks of treatment or for differentiation of other possible non-venous causes for leg ulcer  [4] [5]. See “Wound biopsy”

      Differential Diagnosis

      • Arterial ulcers: typically painful, and punched out or stellate in appearance. The surrounding skin is red and taut. Some arterial ulcers are pale; others may have a black or yellow eschar.
      • Neuropathic ulcers: Usually occurs on plantar aspect of feet in patients with diabetes, neurologic disorders, or Hansen disease. The extremity and the ulcer are usually insensitive.
      • Pressure ulcers: Located over bony prominences; risk factors include excessive moisture and altered mental status
      • Metabolic: e.g., diabetes mellitus, gout, Gaucher disease, etc
      • Hematologic: e.g., Sickle cell anemia, thalassemia, polycythemia vera, leucemia
      • Autoimmune: e.g. Rheumatoid arthritis, leukocytoclastic vasculitis, polyarteritis nodosa
      • Exogenous
      • Neoplasia
      • Infection
      • Medication
      • Skin disorders: e.g., Pyoderma gangrenosum, necrobiosis lipoidica, sarcoidosis, acute contact dermatitis

      Documentation

      • Documentation of VLU is important to assess healing rates, as they determine whether a treatment plan should be continued or not. VLU progress should be recorded weekly or sooner if significant change.
      • All wound care services provided need to be documented in a way that supports the Medical Necessity requirements for the evaluation and subsequent care of wounds that are refractory to healing or have complicated healing cycles either because of the nature of the wound itself or because of complicating metabolic and/or physiological factors.  
      • Documentation should include number and position of ulcers on the leg. Wound measurements should be made for each VLU, including area, perimeter, and depth, description of wound edge, peri-wound area, wound base quality, amount and type of drainage, and infection, history of debridement [5].

      Signs of Improvement

      • Reimbursement for Wound Care services on a continuing basis for a particular wound in a patient requires documentation in the patient's record that the wound is improving in response to the Wound Care being provided. 
      • It is not medically reasonable or necessary to continue a given type of Wound Care if evidence of wound improvement cannot be shown. 
      • Medicare expects that with appropriate care, wound volume or surface dimension should decrease by at least 10 percent per month or wounds will demonstrate margin advancement of no less than 1 mm/week. 
      • Medicare expects the wound-care treatment plan to be modified in the event that appropriate healing is not achieved.
      • Such evidence must be documented with each date of service provided.
      • Evidence of improvement includes measurable changes (decreases) of some of the following: 
        • Drainage 
        • Inflammation
        • Swelling
        • Pain
        • Wound dimensions (diameter, depth) 
        • Necrotic tissue/slough 

      Wound Reference Wound Exam Tool and others

      • Tools that facilitate standardized assessment should be used:
        • Wound Reference Wound Exam Notes Generator creates notes to help support medical necessity according to Medicare that can be transferred to electronic medical records

        • Wound measurement methods include manually measuring length and width (the longest length with the greatest width at right angles), manual tracing, digital photography, and software programs that calculate wound dimensions from a photograph of the lesion. Wound tracings that calculate the area via digital software are slightly better than linear measurement [4].

        Treatment

        Treatment Goal

          • In general, the goals of treatment are to reduce edema, improve ulcer healing, and prevent recurrence.
          • Clinicians should aim for 30% decrease in size in the first 4 weeks of treatment with standard care (local wound care, peri-wound care, specific care, ancillary measures) If VLU does not reach this target, it has a 68% probability of failing to heal within 24 weeks  [6] [31] [32].
          • VLUs that fail to reach a 30% decrease in size after 4 weeks of treatment with standard therapy should be reassessed (See Plan Reassessment) and be considered for adjunctive treatment options (see Adjunctive Treatment[4] [5] [19] [28]. Many adjunctive therapies are only covered by Medicare and other private insurers if VLUs fail to show evidence of healing with standard therapy for 4 weeks  [33].

            Local Wound Care

            Cleanser

            Debridement

            • 2C
              We recommend debridement (vs. no debridement) at initial assessment and as needed at subsequent visits in VU patients covered by Medicare part B or other health insurance plans that only covers surgical dressings for wounds that are surgically created or have been debrided (Grade 1C).
                • Rationale: Although there is consensus in the wound care literature that debridement is necessary to promote wound healing  [37] [38] [39], current evidence [5][19][28][34]  [40] [41] is limited (level C) and does not allow one to conclude with confidence that debridement improves healing of non-infected VU, or if wounds that are healing debride themselves [40]. Nevertheless, studies suggest that active debridement removes obvious necrotic tissue and excessive bacterial burden, which can slow down healing process, increase risk of osteomyelitis, and sepsis [42] [43]. Furthermore, Medicare part B will only cover surgical dressings for ulcers that have been debrided or surgically created [33].
                • Current studies do not provide sufficient evidence to conclude with confidence which method of debridement is most effective in promoting VU healing [5][19][28][34][40], so other factors need to be considered when choosing a debridement method for a specific situation. (For insurance coverage, see Debridement – section on Coding, Coverage and Reimbursement).
                • 2C
                  When choosing debridement methods for VU patients, we suggest clinicians consider factors such as status of the wound, capability of health care provider, overall condition of the patient, professional licensing restrictions, patient preference and insurance coverage (Grade 2C), as follows:
                • Surgical debridement: for patients with VLU with large necrotic areas or associated cellulitis/ osteomyelitis, with no significant clotting disorders, not on active anticoagulant therapy, and with no other contraindications for general/regional anesthesia if needed. Surgical debridement is rapid and highly selective, but is resource intensive (needs operating room and personnel, in the U.S., must be performed by a physician or qualified non-physician practitioner), may cause excessive bleeding, transient bacteremia, damage to tendons and nerves, and add risks associated with general/regional anesthesia if anesthesia is needed [40]
                • Sharp debridement with scissors, scalpel, and forceps: for VLU patients with necrotic areas or signs of infection, no significant clotting disorders, not on active anticoagulant therapy, who are not surgical candidates, or when resources needed for surgical debridement are not available (Figures 8, 9, 10). It must be performed by trained, licensed health care practitioners (not necessarily a physician or qualified non-physician practitioner), and it is often performed at bedside or in a procedure room. It has been termed the “gold standard” of wound debridement [40] [44], and is the preferred method by the Society for Vascular Surgery [5]. This method does not have the extra risks associated with general/regional anesthesia and costs of OR and OR personnel. It is less aggressive than surgical debridement and is fast, but it is also imprecise and may carry the greatest risk of tissue damage of any of the debridement methods [42]. Debridement is a painful procedure [45] and patients often ask clinicians to stop before completion  [46], therefore pain needs to be managed [5].  EMLA (5%) applied for 30 to 45 minutes in a dose of 1 g to 2 g/ 10 cm² significantly reduces the pain from sharp debridement and decreases post-debridement pain in patients with VU  [47]. However, in certain countries EMLA is not approved to be applied directly to wounds.
                • High pressure jet debridement: for VLU patients with same indication and contraindications as sharp debridement, when sharp/surgical debridement or other forms of debridement are not available. Low-quality RCTs do not show any difference on VU healing when compared with sharp debridement  [48] [49]. Cost of the device is another constraint.
                • Autolytic debridement (e.g., hydrocolloid): for patients with exudative VU [50], with no signs or potential for infection (e.g, ischemia of the limb or digit) [40] [50] [51], and when sharp or surgical debridement is not available or not an option. Autolytic debridement is done by occluding the wound with a dressing that traps exudate in the wound, allowing endogenous proteolytic enzymes produced by macrophages present in exudate to selectively liquefy necrotic tissue [40]. This method is slow and needs exudate but it is highly selective, painless and requires only minimal clinical training [42].
                • Enzymatic debridement (e.g, collagenase): for VLU patients with no signs of infection, when sharp or surgical debridement is not available or not an option. Topical application on normal tissue can cause irritation in the peri-wound skin [42].
                • Biological debridement (e.g, maggots): for VLU patients with no personal bias against maggots, when sharp or surgical debridement is not available or not an option [5]. Can be painful  [52].
                • Mechanical debridement (e.g, whirpool, wet-to-dry dressings): for VLU patients with no signs of infection, when sharp or surgical debridement is not available or not an option. This form of debridement is non-selective, slow, and often painful  [50] [51]. Wet-to-dry dressings can increase potential for infection in large wounds with extensive necrosis  [53].


                Figure 8. Venous ulcer with fibrin and necrotic tissue pre-debridement

                Figure 9. Venous ulcer immediately post sharp debridement        

                Figure 10. Venous ulcer after sharp debridement,primary dressings and compression


                Topical primary dressing

                Antimicrobial topical agents:

                • Cadexomer iodine: for patients with infected VU, clinicians might opt to use cadexomer iodine with compression to promote wound healing. Low-quality evidence (level C) suggests that cadexomer iodine is more effective than standard care in healing VU [58]. Cadexomer iodine products can also absorb exudate and promote debridement. Cases of hyperthyroidism after treatment of VU have been reported [61].
                • Silver-based preparations: current evidence does not support use of silver-based products for VU patients, as it is unclear whether silver increases rate of healing of VU, compared with no silver [58]. Also, a rigorous cost-effectiveness analysis concluded that silver-impregnated dressings were unlikely to be cost-effective when compared with non-antimicrobial dressings in patients with VU  [62].
                • Honey-based preparations: current evidence of low quality (evidence level C) does not support use of honey-based products for VU patients as it is unclear whether honey increases rate of healing of VU, compared with no honey [58] [63]. One of these trials conducted a rigorous cost-effectiveness analysis in parallel with the RCT and concluded that honey was unlikely to be cost-effective in promoting VU healing  [64].
                • Povidone-iodine: current evidence of low quality (evidence level C) suggests that there is no difference in VU healing when povidone-iodine preparations are used compared with other interventions (dextranomer, hydrocolloid dressing, paraffin gauze dressing, foam dressing) [58].  
                • Other topical antimicrobials: current evidence is of poor quality and does not allow one to make definite conclusions about the effectiveness of peroxide-based preparations, ethacridine lactate, chloramphenicol, framycetin, mupirocin, ethacridine or chlorhexidine in healing VU [54][58]

                Skin grafts and skin equivalents:

                • Skin grafting should be considered as primary therapy only for large wounds (i.e., >25 cm2), in which healing is unlikely without grafting [5]. See “Skin grafts and skin equivalents”.

                Peri-wound Care

                Skin maceration

                • 2C
                  For patients with VLU whose peri-wound skin is likely to be in contact with exudate, we suggest application of a skin protectant, also known as topical barrier, on the peri-wound skin to prevent skin maceration and enlargement of wound (Grade 2C).
                  • Rationale: Skin maceration is primarily caused by excess exudate, which can enlarge the wound and impede healing [28].  The mainstay of treatment and prevention of skin maceration is management of excess exudate (See “Exudate management”). There is low-quality evidence showing that skin protectant is more effective than no skin barrier on peri-wound skin in promoting healing of VLU  [65]. Different types of skin protectants seem to be equally effective in promoting wound healing, but some might be removed/applied more easily than others  [66]. Skin protectants are however, not covered by Medicare and most insurance plans, so cost is an important factor to be considered.

                Stasis dermatitis

                • 1A
                  For VLU patients with stasis dermatitis and dry, flakey peri-wound skin, we recommend use of daily moisturizers to alleviate symptoms and dermatitis flares underneath compression (Grade 1A).
                  • Rationale: Patients with VLU often have stasis dermatitis (stasis eczema), which manifests as dry, itchy skin, erythema, hemosiderin deposition, and scaling [67] [68]. If left untreated, symptomatic stasis dermatitis can lead to scratching and fissuring, which can delay VLU healing and contribute towards development of new ulcers. Stasis dermatitis is a result of venous hypertension [69] [70] and thus, compression is considered the main treatment for stasis dermatitis. Topical local treatment is also essential and consists mainly of emollients and steroids. There is high-quality evidence that supports use of moisturizers on eczematous skin to improve symptoms, and decrease the amount of topical corticosteroids needed to achieve similar reductions in eczema severity [19] [71]. There is no reliable evidence that one moisturizer is better than another. Moisturizers are however, not covered by Medicare and most insurance plans, so cost is important when choosing moisturizers.
                • For VLU patients with stasis dermatitis and dry, lightly reddened, itchy, inflamed skin, we suggest short courses of topical mid-potency steroids, such as triamcinolone 0.1% or betamethasone valerate 0.12% foam (twice a day for 4 weeks) (Grade 2C) [5] [70] [72]. Clinicians might also opt to change underlying padding to pure cotton cast padding [6] Alternative interventions include treatment with oral doxycycline 100 mg with topical tacrolimus 0.1% for four weeks (evidence level C)  [73], but tacrolimus is currently FDA-approved only for atopic dermatitis and not for other types of dermatitis.
                • For VU patients with stasis dermatitis and dry, itching, burning skin, clinicians might also opt to use zinc or calamine impregnated rolled gauze wrap as first layer [6], besides interventions listed above.

                Contact dermatitis

                • 2C
                  Skin moisturizers with no lanolin underneath compression can also help reduce contact dermatitis (Grade 2C) [5].
                  • Rationale: Peri-wound skin of VU patients seems to be more susceptible to contact dermatitis, and care must be taken to avoid irritants agents, sensitizing allergens such as bacitracin, sulfa, lanolin (a component of some moisturizers)  [74], and trauma on peri-wound skin due to repetitive removal of dressings  [75].

                Skin Infection

                • See “Check for VLU infection” and “Antimicrobial topical agents

                Specific Care - Compression

                Compression therapy plays a crucial role in the treatment of patients with venous leg ulcers and remains the cornerstone of VLU care [9]. Compression therapy with standard care has the potential to heal approximately 50% -75% of VLUs [76] [77].

                Types of compression can be:

                • Static
                  • Compression bandages (multi or single-layered)
                    • Elastic
                    • Inelastic
                    • Multicomponent
                  • Tubular dressings (bandages)
                    • Elastic
                    • Inelastic
                  • Gradient compression stockings
                    • Elastic
                  • Gradient compression wrap
                    • Inelastic
                  • Dynamic or intermittent
                    • Intermittent pneumatic compression
                  • Contraindications to compression therapy in VLU patients include patients with arterial disease, cellulitis and acute deep venous thrombosis.
                    • Rationale: The latter two conditions should be properly treated before compression therapy is initiated. Cellulitis is a relative contraindication – compression may be used, as long as antibiotic therapy has been implemented. All VLU patients should be screened for arterial disease using Doppler measurement or ankle-brachial pressure index (ABPI) by trained staff before receiving compression therapy [7]. Compression on a limb compromised by arterial disease can lead to ischemic sequelae and tissue necrosis [5]. Arterial disease manifested by ABI below 0.8 is often considered clinically significant. Patients with VLU who have ABI between 0.5 and 0.7 may be eligible to receive modified (reduced) compression (30 mmHg at the ankle) [23], pending consultation and indication by a vascular specialist [7] [78]
                    • Patients with ABI at or below 0.5, ankle pressure <60 mmHg or toe pressure <30 mmHg should not receive compression [5] [78]
                  • 1B
                    For VLU patients with no contraindications, we recommend compression over no compression therapy to promote wound healing (Grade 1B)
                    .
                  • Rationale: Clinical guidelines recommend this intervention [19] [28]  [39]  [79], which is supported by at least moderate quality evidence (level B) (81,84). Compression is the gold standard for VLU treatment, however, issues such as patient adherence and clinicians’ skills may interfere with its effectiveness. Many patients cannot tolerate, or do not adhere to, compression bandaging therapy  [80]. Also, achieving the desired pressure with bandages can be difficult, as correct application is operator-dependent. As a result, many patients do not receive adequate compression therapy [81] [82] [83].  Skills can be improved by training professionals [82] [84] (See  application techniques in section ‘How to use’ in “Compression Bandages”, “Tubular Dressings (Bandages)”, “Gradient Compression Stockings” and “Dynamic or Intermittent Compression” “Compression”, section “How to”) and adherence can be improved by educating patients on the importance of compression therapy [85]. As for costs, compression bandages and certain gradient compression stockings are covered by Medicare part B as long as used on patients with active VLU. Multilayered compression systems with elastic components have been shown to be more cost-effective than usual care [86] [87]
                  • 2B
                    As for initial choice of compression therapy, we suggest multilayered compression bandages over single layered compression bandages (Grade 2B), and multilayered bandages with an elastic layer (e.g, 4LB) over those composed mainly of inelastic layers (e.g, SSB) (Grade 2B).
                    • Rationale: Clinical guidelines and evidence from systematic reviews of at least moderate quality support use of multicomponent systems over single-component systems, and systems with elastic components over those without [19][39][7][79][88]. However, when choosing the type of compression therapy, clinicians should consider factors such as availability of resources, clinicians’ experience and level of expertise, size of the ulcer, exudate level, dressing change frequency, level of pain, support from caregivers. Ultimately, the main goal is to deliver high-strength compression [28]. However, Of note, staff familiarity with different types of compression systems can greatly influence compression effectiveness. Meta-analyses mostly based on data from countries that routinely use 4-component systems with an elastic component (4LB) have indicated that 4LB was more effective than short-stretch bandages (SSB) in VLU healing [7]. However, in comparing 4LB with SSB in countries where the medical staff is familiar with applying SSB (eg, Netherlands, Austria, Canada), there is no significant difference among VLU healing rates [5][7]. Two‐component bandage systems with an elastic layer appear to perform as well as the four-layer bandage (4LB) [7].  In terms of insurance coverage, as long as used to treat VU, compression bandages and gradient compression stockings (30-40mmHg) are covered by Medicare Part B and most insurance plans. As for costs, multilayered compression systems with elastic components are generally more expensive than single-layered ones when considering product costs only. However, clinicians need to consider not only material costs, but also other types of costs, such as nursing time and frequency of change, and effectiveness. In terms of cost-effectiveness, multilayered compression systems with elastic components are more cost-effective than usual care [86] [87] and than multicomponent systems with an inelastic component (e.g., short stretch bandages) [12] [89]. Inelastic compression (e.g., Unna’s Boot) can be useful in the initial phases of edema reduction, when frequent dressing changes are needed due to weeping.
                  • 2B
                    Two-layer gradient compression stockings (HH) that deliver 40 mmHg pressure at the ankle can be considered an effective alternative to multilayered compression systems (4LB) (Grade 2B).
                    • Rationale: Based on results on a large RCT, two-layer compression stockings (HH) is as effective in healing VU as 4LB, and it seems to have the additional benefit reducing recurrence rates and being more cost-effective. HH is not suitable for all patients - it might be hard to apply and remove them, and they may not be tolerated by patients with morbid obesity, lipodermatoesclerosis or severe edema. In the trial, patients that used HH had a higher rate of change of compression modality mid-treatment [15] [90].
                  • 2C
                    Intermittent pneumatic compression (IPC) therapy can be used when all other compression therapy methods have failed or on patients that do not tolerate multilayered compression systems or high compression gradient stockings (Grade 2C).
                    • Rationale: IPC uses an air pump to inflate and deflate an airtight bag wrapped around the leg, and it is considered better than no compression in promoting VU healing, but currently there is little evidence to support that addition of IPC to compression therapy offers any benefit [79] [91]. Medicare will cover IPC for patients for with refractory edema from chronic venous insufficiency with significant ulceration of the lower extremities that have received standard therapy but have failed to heal after 6 months of continuous treatment  [92].
                  • 2C
                    To decrease risk of ulcer recurrence in patients with a healed VLU, we suggest compression therapy with gradient compression stockings at the highest pressure patients can tolerate (Grade 2C).
                    • Rationale: VLU treatments generally do not eliminate the underlying venous hypertension that caused VLU in the first place, so a degree of compression seems to be necessary long term [28]. Although clinical guidelines for VLU recommend lifelong use of gradient compression stockings to decrease risk of recurrence [19][28][39][79], current evidence supporting this intervention is considered limited and of low quality by systematic meta-analyses [88][93]. As such, one cannot determine with certainty that compression therapy is effective in reducing risk of recurrence, but one cannot refute this possibility either. As for level of compression, results from one trial suggest that recurrence is lower in high-compression hosiery than in medium-compression hosiery [93]. Patient adherence to treatment can be problematic, but patient education on the importance of long-term compression can help improve adherence [85]. Another complicating factor is the fact that Medicare part B and most insurance plans do not cover compression therapy (including gradient compression stockings) for prevention of VLU once it has healed, which can also impact on patient adherence if financial resources are an issue. If patient has indications and is a surgical candidate, underlying vascular pathology should be surgically addressed to reduce risk of recurrence (see ‘Vascular Surgical Interventions’).
                  Practice Tip:

                  Ancillary Measures

                  Physical exercise

                  Leg elevation

                  Nutrition

                  • Clinical guidelines recommend nutritional assessment for patients with VLU as a best practice.
                    • Rationale: Poor nutrition may be a risk factor for delayed VLU healing [99]. There are very few studies on the effects of nutritional supplementation on VLU healing. However, a formal nutritional assessment for VLU patients is considered best practice  [5] [28]  [100]. Patients with VLUs are commonly overweight and also have a relative nutritional deficiency that needs to be addressed  [4] [101]. Protein intake must be adequate to support the growth of granulation tissue [5][28], and protein deficiency has been shown to be associated with increase in VLU area [102]. Nutritional support is required if an individual is undernourished [28][79]. Oral zinc does not appear to aid in VLU healing  [103].

                  Pentoxifylline

                  Lymphatic drainage

                  • 2C
                    We suggest against adjunctive lymphatic drainage for healing of VLU (Grade 2C).
                    • Rationale: There are no data linking manual lymphatic drainage to wound healing [17], and thus, this intervention for VLU patients is discouraged by the Society for Vascular Surgery [5]

                  Vascular Surgical Interventions

                  Surgical treatment of lower extremity chronic venous disease is not described here. Below are suggestions and recommendations on vascular surgery interventions to treat or prevent VLU by the Society for Vascular Surgery and American Vascular Forum (SVS) [5].

                  • 2C
                    For patients with active, history or at risk of VLU, who have incompetent superficial veins with axial reflux directed to the bed of the ulcer, with or without deep vein disease, the SVS suggests ablation of superficial incompetent veins in addition to standard compression therapy to: help heal an active VLU (Grade 2C), prevent recurrence of VLU in patients with active ulcers (Grade 1B), prevent recurrence of VLU in patients with healed ulcers (Grade 1C), and prevent ulceration in patients at risk for VLU (Grade 2C).
                  • 2C
                    For patients with active, history or at risk of VLU, who have incompetent superficial veins that have reflux to the ulcer bed in addition to pathologic perforating veins (outward flow of >500 ms duration, with a diameter of >3.5 mm) located beneath or associated with the healed ulcer bed, with or without deep venous disease, the SVS suggests ablation of superficial and perforator incompetent veins in addition to standard compression therapy to: aid in healing and prevent recurrence of VLU in patients with active ulcers (Grade 2C), prevent development of ulcers in patients at risk for VLU (Grade 2C), and prevent recurrence of VLU in patients with healed ulcers (Grade 2C).
                  • 1C
                    For patients with active or healed VLU, with isolated pathologic perforator veins (outward flow of >500 ms duration, with a diameter of >3.5 mm) located beneath or associated with the healed or active ulcer bed regardless of the status of the deep veins, the SVS suggests ablation of the “pathologic” perforating veins in addition to standard compression therapy to: aid healing and prevent recurrence of VLU (Grade 2C).
                  • 1C
                    For those patients who would benefit from pathologic perforator vein ablation, the SVS recommends treatment by percutaneous techniques that include ultrasound-guided sclerotherapy or endovenous thermal ablation (radiofrequency or laser) over open venous perforator surgery to eliminate the need for incisions in areas of compromised skin (Grade 1C).
                  • 2C
                    In a patient with active, history or at risk of VLU, with infrainguinal deep venous obstruction the SVS suggests autogenous venous bypass or endophlebectomy in addition to standard compression therapy to aid in venous ulcer healing and to prevent recurrence (Grade 2C)
                  • 2C
                    In order to aid healing or prevent recurrence of VLU in patients with active, history or at risk of VLU with deep venous reflux, in addition to compression therapy the SVS suggests: against ligation of femoral or popliteal veins (Grade 2C), individual valve repair for those who have axial reflux with structurally preserved deep venous valves (Grade 2C), valve transposition or transplantation for those with absence of structurally preserved axial deep venous valves when competent outflow venous pathways are anatomically appropriate for surgical anastomosis (Grade 2C), autogenous valve substitutes by surgeons experienced in these techniques (Grade 2C)
                  • 2C
                    In order to aid healing or prevent recurrence of VLU in patients with active, history or at risk of VLU with proximal chronic venous obstruction/severe stenosis, in addition to compression therapy the SVS recommends venous angioplasty and stent recanalization (Grade 1C), or open surgical bypass in case of failure of endovascular treatment (Grade 2C).

                  Plan Reassessment

                  VLUs that fail to reach a 30% decrease in size after 4 weeks of treatment with standard therapy (See local care, peri-wound care, specific care and ancillary measures, pentoxyfiline) should be reassessed. Re-evaluation of the patient and wound should be performed before the use of adjuvant therapies to ensure that compression has achieved edema control, bio-burden is well controlled, and exudate is not excessive. Differential diagnosis should be considered as well.

                  Edema control with adequate compression

                  • Check if desired pressure is being delivered through the bandages or compression method of choice (See “Compression”, section “How to”)
                  • Check patient’s adherence. Adherence can be improved by educating patients on the importance of compression therapy [85]. (See “Patient Education”)

                  Check for VLU infection:

                  • Wound culture: If infection is suspected in a VLU, a specimen should be obtained from the wound surface or wound drainage with a validated quantitative bacteriology swab method and sent for microbiological analysis. Guidelines suggest against routine culture of VU [5][28]. Infection in VLU can manifest as fever, leukocytosis, worsening pain, cellulitis, purulence, increased exudate, malodor, discolored friable granulation tissue, biofilm, tissue necrosis [5] .
                  • 2C
                    Antibiotics: We suggest systemic antibiotics be administered only to patients with VLU with clinical signs of infection that have more than 1 million colony-forming units per gram of tissue (1 x 10^6 CFU/g of tissue) and not to VLU patients with wounds that are just colonized by bacteria (Grade 2C). At present, no evidence is available to support the routine use of systemic antibiotics in promoting healing of clinically infected venous leg ulcers [58]. However, the studies had a small sample size and an unclear risk of bias with potential limitations that can affect the results of the studies (evidence level C) [58]. As a result, authors could not recommend the discontinuation of any of the agents reviewed either. Nevertheless, clinical guidelines are in agreement that systemic and topic antimicrobial agents should be used only in cases of clinical infection and not bacterial colonization, due to the increasing problem of bacterial resistance to antibiotics (5,19,61). Overuse of antimicrobials is an emergent public health problem, and it is linked to the development of resistant organisms and iatrogenic disease, such as Clostridium difficile colitis, and increased health care costs [9]. The choice of systemic antibiotics systemic antibiotics should be guided by sensitivities performed on wound culture. Oral antibiotics for 2 weeks is preferred as initial treatment [5].
                  • For patients with clinically infected VLU whose bacteriological analysis shows virulent or difficult to eradicate bacteria (such as beta-hemolytic streptococci, pseudomonas, and resistant staphylococcal species), antimicrobial therapy can be initiated even at lower levels of colony-forming units per gram of tissue [5][28]
                  • Cellulitis surrounding the venous ulcer are usually caused by streptococci or staphylococci and should be treated with systemic gram-positive bactericidal antibiotics, reserving broad coverage for unresponsiveness [5][28].
                  • Topical antimicrobial preparations also may be considered in patients with clinical signs of VLU infection.

                  Check for exudate control

                  • See “Topical primary dressings

                  Consider differential diagnoses

                  • Wound biopsy: is recommended for VLU that do not improve with standard care after 4 weeks of treatment and for all ulcers with atypical features  [4] [5]. Preferably, biopsies should be punch or elliptical biopsy specimens, taken from the edge of the ulcer to compare the ulcerated area with the surrounding skin [4], and central provisional matrix [5]. Additional tissue analysis to include inflammatory cytokines and MMP are still under investigation and does not have clinical applicability [5] [106]. H&E is widely used in wound histopathology analysis, but other special stains can be used depending on the differential diagnosis [4].The specimen taken from the center of the wound should also be sent for culture [4].
                  • Laboratory evaluation for thrombophilia
                  • Referral to other specialists if autoimmune/micro-occlusive disorders, other vascular diseases, dermatologic conditions, metabolic, hematologic disorders are suspected.

                  Re-evaluate need for vascular intervention

                  • See “Vascular Surgical Interventions

                  Adjunctive Therapy

                  Adjunctive therapies for the healing of VLU should only be considered if VLU does not decrease by 30% after 4 weeks of comprehensive care including compression therapy, debridement, control of bio-burden, wound moisture balance, and pentoxifylline [5][9][28][94]. Evidence supporting these potentially costly interventions are not sufficiently strong to justify them as primary therapy. Re-evaluation of the patient and wound (See “Plan reassessment”) should be performed prior to initiating adjunctive therapy [5].

                  Platelet-rich Plasma (PRP) and Growth factors

                  Skin grafts, flaps and skin equivalents

                  Skin grafts and flaps
                  • For patients with VLU that fail to achieve 30-40% size reduction in 4-6 weeks of standard treatment, clinical guidelines suggest skin grafting accompanied with proper compression [5][28][94]. Skin grafting should be considered as primary therapy only for large wounds (i.e., >25 cm2), in which healing is unlikely without grafting [5].
                    • Rationale: Autografts, allografts, human skin equivalents and other methods can be used to achieve wound coverage as an adjunctive intervention, which may result in healing rates of up to 73%  [113]. Also, skin grafting can result in better quality of life for VLU patients, when compared with standard care [114]. It is important to note that wound coverage will not address the underlying cause of VLU, and thus continued use of compression therapy is essential [28].
                  • Prior to any wound coverage procedure, clinical guidelines recommend that the wound bed be prepared adequately, by removing slough, debris, necrotic tissue and management of bioburden levels, preferably to 10^5 CFU/g of tissue, with no beta hemolytic streptococci in the venous ulcer (5,28)
                  • 2C
                    Split-thickness skin graft: for patients with VLU that failed to decrease in size by 30% in 4 weeks of standard therapy, we suggest split-thickness autologous skin graft accompanied with compression over continuation of standard care, as an alternative for wound coverage (Grade 2C).
                    • Rationale: Although available literature cannot provide firm evidence of benefit in VLU healing [28][94][115], most surgeons have experience with this procedure, and it might be most accessible than other types of wound coverage alternatives. This procedure is generally done at a surgical facility, and requires some sort of anesthesia, exposing patients to inherent risks. Another disadvantage is the need to create other wounds (donor areas, which increase recovery time, and create cosmetic concerns).
                  • Free flaps: For patients with recalcitrant VLU with severe lipodermatosclerosis, the Wound Healing Society guideline suggests free flap transfer [28].
                    • Rationale: Wide excision of diseased tissue and replacement with uninjured tissue and venous valves can help in the treatment of VLU. Microsurgical flaps are performed by specialists, require hospitalization and specialized healthcare staff.
                  • Pedicled and perforator flaps: For patients with recalcitrant VLU with severe lipodermatosclerosis, when resources needed for free flaps are not available, clinicians might opt to cover VLU with pedicled or perforator flaps[116].
                    • Rationale: Free flaps are still preferred as they avoid additional scarring in surrounding area, commonly seen when local flaps are used and primary closure is not possible due to excessive tension and tissue that is not affected by chronic venous insufficiency is brought to replace injured areas. Pedicled flaps, such as reverse sural flap sacrifice major vascular supply to the foot. Local transposition flaps can be used to cover small defects, but their greatest limitation is size  [116]. Coverage failure rate when free flaps are used to cover distal thirds defects of lower extremely are comparable to that of local transposition flaps like propeller flaps  [117].
                  Skin equivalents
                    • 2C
                      Autologous bioengineered skin or cultured epidermal autografts (CEA): We suggest against use of autologous bioengineered skin or cultured epidermal autografts (CEA) for coverage of non-healing VLU (Grade 2C).
                      • Rationale: Low quality evidence support the use of CEA or split-thickness cultured autografts to promote healing of VLU that failed to achieve size reduction with standard therapy [118] [119] [120] [121][122]. The Wound Healing Society clinical guideline suggests against use of CEA[5]. Some disadvantages of these wound coverage methods are the need for patient to undergo a biopsy to retrieve skin, followed by a wait period of weeks for the cells to be cultivated [115]. The FDA approved some commercial products as a humanitarian-use device (HUD). Medicare and private insurers in the U.S. do not cover these products routinely.
                    • Cellular and/or Tissue Based Products (CTPs): CTPs allow patients with VLUs that have failed to show signs of improvement in 4-6 weeks the chance to receive wound coverage without problems inherent with autografts (e.g., autograft harvesting, hospital stay, anesthesia risks, donor area) [115]. Generally, CTPs can be applied in an outpatient setting. The choice of which CTP to use relies heavily on physician/patient preference, costs, availability of resources, accessibility to CTPs. CTPs that are not considered drugs and/or biological products can be categorized in one of the categories below [33]and may be covered by Medicare and private insurers if all requirements are met – See “Coding, coverage and reimbursement” section in “Cellular and/or Tissue Based Products
                    • 2C
                      Human skin allografts: Clinicians might opt to use human skin allografts and compression therapy for patients with non-healing VLU if resources are available (Grade 2C).
                      • Rationale: Studies have shown that treatment with human skin allografts resulted in a higher healing rate of VLUs when compared to standard care, but evidence is considered of low quality [115].
                    • 2B
                      Allogeneic matrix: For VLU that do not respond to standard therapy but have less than 12 months in duration, clinicians might consider single-layered dermal replacement associated with compression therapy (Grade 2B).
                      • Rationale: There is moderate quality evidence that show that single-layered dermal replacement (e.g. Dermagraft), a type of allogeneic matrix, helps VLU heal faster than standard care only. Another type of allogeneic matrix for recalcitrant VLU is dehydrated human amnion/chorion membrane allograft (e.g., EpiFix) associated with compression therapy (Grade 2C). Evidence supporting use of dehydrated human amnion/chorion membrane for VLU healing is currently considered of low quality [115] [123] [124] [125] [126] [127].
                    • 2B
                      Composite matrix: Clinicians might consider bilayered bioengineered skin and compression over standard therapy for non-healing VLU (Grade 2B).
                      • Rationale: Evidence is drawn mainly from 2 trials that compared a bilayered skin equivalent (e.g., Apligraf) with standard care of foam or a dressing made to look like the skin equivalent [115][128] [129], on which many clinical guidelines base their recommendation for this intervention [5][19][28]. Bilayered bioengineered skin has been shown to be more cost-effective than Unna’s boot by a study that received part of its funds from the industry [129]. However, it might not be easily accessible and shelf life is usually a few days long (e.g.,15 days for Apligraf).
                    • 2C
                      Acellular matrix: Non-healing VLU can also be treated with acellular collagen matrix derived from porcine intestinal mucosa and compression therapy (Grade 2C).
                      • Rationale: There is low quality evidence that supports use of acellular porcine matrix (e.g, Oasis Wound Matrix) to treat recalcitrant VLU [55][115][130][131]. An industry-sponsored cost-effectiveness study concluded that acellular porcine matrix is more cost-effective than bilayered bioengineered skin or single-layered dermal replacement, but was more effective and more costly than standard care only  [132]. Shelf life of this acellular matrix is generally about 2 years. Hyaluronic matrix dressings are also categorized as acellular matrices, and currently there is no robust evidence that it can perform better than other types of dressings in VLU healing  [133] [54].
                    • 2B
                      Drugs/biologics: We suggest against use of cultured epithelial allografts or growth-arrested human keratinocytes and fibroblasts (HP802-247) as adjunctive therapy for VLU (Grade 2B).
                      • Rationale: It has been shown that difference of VLU healing outcomes between experimental groups using these modalities and control groups were not statistically significant [28][115]

                    Systemic Pharmaceutical Agents

                    • Rationale: Current evidence, albeit of low quality, suggests that oral zinc does not improve VLU healing in patients without a deficient total body zinc reservoir [28][103]

                    Biophysical Interventions

                    • 2C
                      Clinical guidelines do not support use of other therapies such as whirlpool, laser therapy, phototherapy with UV light, or warming to treat VLU (Grade 2C).
                    • Rationale: Current evidence is not strong enough to support these interventions to promote healing or prevent recurrence of VLU[5][19][28].

                    Patient Education - for Clinicians

                    VLU are a chronic, long-term problem, with recurrence rates are as high as 70%. Therefore, long-term maintenance must be addressed even for healed ulcers [28]. Patient adherence to treatment can be problematic, but patient education on the importance of long-term compression and lifestyle changes can help improve adherence [85]. We recommend sharing our patient education materials with VLU patients.

                    • Compression therapy (handout)
                    • Gradient Compression Stockings for Patients
                    • Chronic wounds
                    • Basic principles of wound care
                    • Debridement
                    • Edema control
                    • Help VLU healing

                    Patient education to prevent VLU for the first time

                    • For patients with chronic venous disease who have never developed a VLU (C1-4), clinical guidelines suggest regular exercise, leg elevation when at rest, careful skin care, weight control, and appropriately fitting foot wear[5][19].
                    • For patients with chronic venous disease who have never developed a VLU and have varicose veins and swelling or venous stasis skin changes (C3-4) due to primary valvular reflux, guidelines suggest compression compression, 20 to 30 mm Hg, knee or thigh high  [5].

                    Patient education for VLU healing

                    • Compression, supervised calf muscle exercise, smoking cessation and adequate nutrition are recommended (see “Ancillary measures”)

                    Patient education to prevent VLU recurrence

                    • Compression therapy with gradient compression stockings at the highest pressure patients can tolerate   [4] [5][19] [81], moisturizer to prevent skin breakdown [19], supervised calf muscle exercise [5][19] [96], smoking cessation [19] are recommended (See “Ancillary measures”)
                    • Leg elevation can be suggested, although current evidence to support this intervention in prevention of VLU recurrence is of low quality [96].
                    • Community-based clinics to promote adherence to compression therapy or prevent recurrence can be suggested to patients, although evidence on the effectiveness of such clinics is still unclear [81]

                    Coding and Documentation

                    Coding and documentation related to VLU

                    • Identify and document first any documented underlying condition (ICD-10-CM documentation)  
                    • Red arrows indicate non-billable code, Green arrows are billable codes
                    • Specify laterality
                      • Right, left or unspecified
                    • Specify ulcer severity
                      • Limited to breakdown of skin
                      • With fat layer exposed
                      • With necrosis of muscle
                      • With necrosis of bone
                      • Unspecified severity

                    Select code for non-pressure chronic ulcer of the calf [148]

                    Quality Measures

                    The Quality Payment Program (QPP) has two tracks eligible providers can choose  [149]:

                    • Advanced Alternative Payment Models (APMs) or
                    • The Merit-based Incentive Payment System (MIPS)

                    Quality is one of the 4 categories of MIPS, which Replaces the Physician Quality Reporting System (PQRS).

                    Under MIPS- Quality, eligible providers need to:

                    • Most participants: Report up to 6 quality measures, including an outcome measure, for a minimum of 90 days.
                    • Groups using the web interface: Report 15 quality measures for a full year.
                    • Groups in APMs qualifying for special scoring under MIPS, such as Shared Savings Track 1 APM or the Oncology Care Model one-sided risk APM: Report quality measures through your APM. You do not need to do anything additional for MIPS quality.

                    Measures are issued by QPP or by Qualified Clinical Data Registries (QCDR). Measures issued by QCDR are also known as non-MIPS or non-QPP measures.

                    Below are measures that are directly related to VLU. For a comprehensive list of wound care related measures, see “Wound Care Quality Measures”.

                    MIPS currently does not have VLU-specific measures. Listed below are VLU-specific measures issued by two QCDR: US Wound Registry and CECity Wound Collaborative [150] [151]. QCDR measures can only be reported through respective QCDR.

                    QCDR

                    Title

                    Description

                    ID

                    Measure Type

                    Wound Care Quality Improvement Collaborative CECity (WCQIC)

                    Non-Invasive Arterial Testing in Patients with Lower Extremity Ulcer(s)

                    During patient visit 1 or 2, the

                    practitioner orders non-invasive arterial testing

                    2

                    Efficiency

                    WCQIC

                    Nutritional Screening and Intervention

                    Nutritional nutritional screening with a

                    assessment or

                    Plan in Patients with Chronic Wounds and Ulcers

                    The percentage of patients aged 18 years and older with a diagnosis of a wound or ulcer of any type who undergo nutritional screening with a validated tool (such as the Nestle MNA) within the 12 month reporting period, and for whom an appropriate nutritional intervention was ordered based on the results of the tool

                    5

                    Efficiency

                    WCQIC

                    Efficacy of human amnion/chorion membrane allograft

                    Time in days from first application of EpiFix to complete wound healing. Number of EpiFix applications from first application to complete wound healing

                    6

                    Efficiency

                    US Wound Registry (USWR)

                    Adequate Compression at each visit for Patients with VLUs

                    Percentage of venous leg ulcer visits of patients aged 18 years and older that received adequate compression within the 12-month reporting period.

                    5

                    Process

                    US Wound Registry (USWR)

                    VLU Healing or Closure

                    Percentage of venous leg ulcers among patients age 18 or older that have achieved healing or closure within 12 months, stratified by the Wound Healing Index.

                    6

                    Outcome

                    US Wound Registry (USWR)

                    Plan of Care for VLU Patients not Achieving 30% Closure at 4 Weeks

                    Percentage of patients aged 18 years or older with a diagnosis of venous leg ulcer for whom a plan of care was not created if they failed to achieve 30% of wound closure within 4 weeks

                    7

                    Process

                    US Wound Registry (USWR)

                    Appropriate use of Cellular or Tissue Based Products (CTP) for Patients aged 18 Years or Older with DFU or VLU

                    Percent of patients 18 or older with venous or diabetic foot ulcer who receive cellular and/or tissue derived products appropriately as demonstrated by meeting all of the numerator targets of this problem and patient level composite measure: venous ulcer or diabetic foot ulcer did not achieve 30% closure within 4 weeks, patient underwent vascular screening, wound bed preparation with debridement of necrotic tissue, venous ulcer had adequate compression at each visit and diabetic foot ulcer had adequate off-loading at each visit.

                    9

                    (not listed on website)

                    Clinical Guidelines

                    • Society for Vascular Surgery and the American Venous Forum
                      • Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery ® and the American Venous Forum. Journal of Vascular Surgery (2014) [5]
                    • Wound, Ostomy and Continence Nurses Society (WOCN)
                      • Guideline for Management of Wounds in Patients With Lower-Extremity Arterial Disease (LEAD): An Executive Summary (2014) [78]
                    • Wound Healing Society
                      • Wound Healing Society 2015 update on guidelines for venous ulcers (2015) [28]
                    • Association for Advancement of Wound Healing
                      •  Venous Ulcer Guideline (2010)  [19] 

                    Summary of Evidence

                    Summary of Evidence – Cleansers   (Back to text)

                    • The 2006 Wound Healing Society guideline, updated in 2015, suggested that wounds be cleansed with a neutral, nonirritating, nontoxic solution such as sterile saline or water initially and at each dressing change, and that routine wound cleansing be accomplished with a minimum of chemical and/or mechanical trauma. Their suggestion was based on low-quality evidence (Evidence level C) from on 1 literature review, 1 clinical case series, and 2 experimental studies, and based on principles that irrigating and cleansing the wound removes loose impediments to wound healing [28][34]
                    • The 2014 American Society for Vascular Surgery guideline suggested that venous leg ulcers be cleansed initially and at each dressing change with a neutral, nonirritating, nontoxic solution, performed with a minimum of chemical or mechanical trauma (Grade 2C). Their suggestion was based on low-quality evidence (Evidence level C), from on 1 literature review, 1 RCT with high risk of bias and imprecision, and 1 clinical case series, and assuming that most patients with VUs present with significant wound exudate and other debris in and around the wound area that must be cleansed routinely before dressing application. [5]
                    • The 2010 AAWC guideline recommends that VU be cleansed gently at low pressure (4-15psi) with safe, non-antimicrobial cleanser, based on 1 RCT at high risk of bias/imprecision, 1 literature review, and 1 study that validated the clinical efficacy and cost effectiveness of multidisciplinary guidelines for the diagnosis and treatment of venous leg ulcer, and was not specific to cleansers in wound care. Although authors classified evidence as high-quality (evidence level A), according to the GRADE methodology, we would classify evidence as low-quality (evidence level C) due to high risk of bias/ imprecision. [19]

                    Summary of Evidence – Debridement (Back to text)


                    • A 2011 analysis of 14 guidelines for VLU found that debridement was suggested in 86% of the guidelines, but only one-third suggested at the strong level [39].
                    • A 2015 Cochrane systematic review that evaluated 10 RCT (715 participants) recognized that there is consensus in the wound care literature that debridement is necessary to promote wound healing [37] [38] [39], however authors found only minimal evidence to support active debridement of VLU to promote wound healing. Most studies had unclear risk of bias or were at high risk of bias. The smallness of the evidence base means that one cannot conclude with confidence that debridement improves healing, or which method of debridement, or duration of debridement confers most benefit in the healing of venous ulcers. RCTs that met inclusion criteria in this review evaluated only autolytic and enzymatic debridement methods, and none of the included RCTs evaluated surgical, sharp or mechanical methods of debridement, or debridement versus no debridement [40].
                    • The 2014 Society for Vascular Surgery[5], the 2015 Wound Healing Society [28][34], and the 2010 Association for Advancement of Wound Care (AAWC) [19] guidelines support VLU debridement of VLU to promote wound healing, although the levels of evidence assigned by these societies differed from each other, possibly due to different evidence grading methodologies and different studies from which evidence was drawn (SVS uses GRADE framework).

                    Intervention for VLU

                    Society for Vascular Surgery, 2014

                    AAWC, 2010

                    Wound Healing Society, 2015

                    VLU debridement at initial evaluation vs. no debridement

                    Grade 1B (strong recommendation, moderate quality evidence)

                    A (high quality evidence)

                    Level II (moderate quality evidence)

                    Additional maintenance debridement of VLU

                    Grade 2B (weak recommendation, moderate quality evidence)

                    n/a

                    Level II (moderate quality evidence)

                    Surgical debridement for VLU with slough, nonviable tissue, or eschar.

                    Grade 1B (strong recommendation, moderate quality evidence)

                    C2

                    n/a

                    Hydrosurgical debridement

                    Grade 2B (weak suggestion, moderate quality evidence, as an alternative to surgical debridement)

                    n/a

                    n/a

                    Ultrasonic debridement

                    Grade 2C (weak suggestion not to use intervention vs.  surgical debridement, low quality evidence)

                    A (high quality evidence) for high-frequency

                    n/a

                    Enzymatic Debridement

                    Grade 2C (weak suggestion, low quality evidence, as an alternative to surgical debridement)

                    A (high quality evidence)

                    n/a

                    Biological debridement

                    Grade 2B ((weak suggestion, moderate quality evidence, as an alternative to surgical debridement)

                    A (high quality evidence)

                    n/a

                    Mechanical debridement

                    n/a

                    C (low quality evidence)

                    n/a

                    Autolytic

                    n/a

                    A (high quality evidence)

                    n/a

                    • We reviewed the Cochrane systematic review and the studies that the three guidelines used to grade quality of evidence and strength of recommendation (when applicable) for each of intervention above.  Applying the GRADE framework to the combined body of evidence, we found that:
                      • Evidence that support the recommendation to perform debridement at initial evaluation and for maintenance to promote VU healing compared to no debridement was of low quality (evidence level C), provided mainly by observational studies. Conclusions of other studies cited by guidelines were not directly relevant in supporting this intervention in VU, as they primarily compared effectiveness of different debridement methods, or assessed effectiveness of debridement in other types of wounds (e.g., pressure injuries, diabetic foot ulcers), which may have a different response to debridement compared to VU. Other studies were not directly relevant, as they did not evaluate effect of debridement as an intervention in VU healing as an outcome.
                      • Current studies do not provide sufficient evidence to conclude with confidence which method of debridement confers most benefit in the healing of venous ulcers. Studies that concluded that one method was superior than other had important methodological limitations (level C). Other studies included in the guidelines were not directly relevant, as they compared effectiveness of methods of debridement in other types of wounds (e.g, pressure ulcers), or did not evaluate VU healing as an outcome.

                    Summary of Evidence – Exudate management, moist wound bed  (Back to Text)


                    • The 2014 Society for Vascular Surgery (SVS)[5], the 2015 Wound Healing Society (WHS)[28][34], and the 2010 Association for Advancement of Wound Care (AAWC)[35] guidelines support managing VLU exudate and maintaining a moist wound bed, although the levels of evidence assigned by these societies differed from each other, possibly due to different evidence grading methodologies and different studies from which evidence was drawn (SVS uses GRADE framework).

                    Intervention

                    for VLU

                    Society for Vascular Surgery, 2014

                    Wound Healing Society, 2015

                    AAWC, 2010

                    Manage venous leg ulcer exudate and protect peri-wound skin

                    Grade 2B (weak recommendation, moderate quality evidence)

                    Level I (high quality evidence)

                    A (high quality evidence)

                    Maintain a moist wound bed

                    Grade 2C (weak recommendation, low quality evidence)

                    Level I (high quality evidence)

                    A (high quality evidence)

                    • We reviewed the studies that the three guidelines used to grade quality of evidence and strength of recommendation for each of intervention above and found that:
                      • The recommendation to maintain a moist wound bed is supported by moderate quality evidence (evidence level B), provided mainly by experimental studies that demonstrated that moist environments promote faster wound healing. Conclusions of other studies cited by guidelines were not directly relevant in supporting this intervention, as they primarily compared effectiveness of different dressings in VU healing, and did not necessarily evaluate effect of moist vs. non-moist environment in wound healing.
                      • The recommendation to manage venous leg ulcer exudate and protect peri-wound skin is supported by moderate quality evidence (evidence level B), provided mainly by experimental studies that demonstrated that exudate has higher levels of MMP and suggested that the presence of excessive levels of MMP at the wound surface of pressure ulcers may impede the healing of these wounds. Conclusions of other studies cited by guidelines were not directly relevant in supporting this intervention, as they primarily compared effectiveness of different dressings in VU healing, and did not necessarily evaluate effect of VLU exudate and MMP in wound healing and peri-wound skin integrity.

                    Summary of Evidence - Topical Dressings (Back to text)


                    Alginate: Low-quality evidence (Evidence level C due to high risk of bias) suggests that when associated with compression, alginate dressings, hydrocolloid and plain non-adherent dressings are equally effective in healing venous ulcers

                    • A 2016 systematic review evaluated the same RCTs (295 participants) and arrived at the same conclusion as the authors of the Cochrane review.  [152]
                    • A 2015 Cochrane systematic review that evaluated 5 RCTs (295 participants). All studies were industry funded. 1 compared different brands of alginate, 3 compared alginate with hydrocolloid, 1 with plain non-adherent dressing. Most participants received the dressing and four-layer bandage. No statistically significant between-group differences were detected for any comparison, for any healing outcome. Meta-analysis was feasible for one comparison (alginate and hydrocolloid dressings) with data from two RCTs (84 participants) pooled for complete healing at six weeks: risk ratio 0.42 (95% confidence interval 0.14 to 1.21). Adverse event profiles were generally similar between groups (not assessed for alginate versus plain non-adherent dressings. Authors concluded that the current evidence base is of low quality, mainly due to mostly uncertain risk of bias. Evidence does not suggest that alginate dressings are more or less effective in the healing of venous leg ulcers than hydrocolloid or plain non-adherent dressings, and there is no evidence to indicate a difference between different proprietary alginate dressings. It is possible that dressing performance, in terms of ease of removal, is better for hydrocolloid dressings than alginate. [153]

                    Hydrogel: Low-quality evidence (Evidence level C due to high risk of bias) suggests that when associated with compression, low-adherent dressings, different brands of hydrogel or miscellaneous dressings are equally effective and present no difference in adverse effects in healing venous ulcers

                    • 2 systematic reviews identified 5 RCTs (379 participants) that compared hydrogel dressings with either low adherent dressings (2 RCTs), another brand of hydrogel (2 RCTs) and miscellaneous dressings (1 RCT). Evidence from RCTs was of low or uncertain quality due to risk of bias, but in none of the comparisons was there evidence that any one dressing type was better than others in terms of number of ulcers healed. [133]

                    Foam: Low-quality evidence (Evidence level C, due to high risk of bias) suggests that when associated with compression, foam dressings, hydrocolloid, paraffin gauze, hydrocapillary, knitted viscose, and protease modulating matrix dressings are equally effective and present no difference in adverse effects in healing venous ulcers

                    • A 2016 systematic review concluded that the venous leg ulcer pairwise comparisons of alginate vs. low-adherent dressings, alginate vs. hydrocolloid, alginate vs. hydrofiber, foam vs. low-adherent dressings, foam vs. hydrocolloid, and hydrocolloid vs. low-adherent dressings included in our meta-analysis revealed moderate-quality level B evidence that there were no statistically significant differences in ulcer healing efficacies between the two interventions examined in each comparison [152]
                    • A 2014 AHRQ systematic review also concluded that based on the low quality   evidence available, there are no data to support superiority of specific dressings in venous ulcer healing or adverse effects [9]
                    • A 2013 Cochrane systematic review that evaluated 12 RCTs (1023 participants) that compared foam to another dressing found no statistically significant difference in wound healing or adverse events for any comparison. [154]Studies: 3 RCTs compared hydrocellular foam dressings and polyurethane foam dressings. 5 RCTs compared foam dressings and hydrocolloid dressings. 2 compared foam dressings with paraffin gauze, 1 with hydrocapillary dressing, 1 with knitted viscose dressing, and 1 with protease modulating matrix. Most participants received the dressing and four-layer bandage. Most studies were industry funded. Authors concluded that at present there is no evidence to suggest that foam dressings are better or worse than any other primary wound contact dressing for the healing of venous leg ulcers when applied beneath compression devices. However, the current evidence base is mainly of low quality, mainly due to high/uncertain risk of bias.

                    Hydrocolloid: Low-quality evidence (Evidence level C, due to high risk of bias) suggests that when associated with compression and compared to non-adherent dressings, foam, alginate, different brands of hydrocolloid, gauze, lyophilized collagen dressing and magnesium sulfate paste and gauze, hydrocolloid dressings showed equivalent dressing effectiveness in promoting complete ulcer healing.

                    • A 2011 review of systematic reviews analyzed 3 systematic reviews (search date 1997, 16 RCTs; search date 2003, 15 RCTs; and search date 2006, 27 RCTs). The first systematic review identified 9 RCTs, the second review identified 8 RCTs, and the third review identified 9 RCTs comparing hydrocolloid dressings versus simple dressings in the presence of compression. Conclusion: Compared with simple dressings Hydrocolloid dressings are no more effective than simple low-adherent dressings at increasing ulcer healing rates in people receiving compression (author classifies evidence of high-quality evidence). However underlying systematic reviews describe quality of evidence as uncertain or low.  [54]
                    • 2016 systematic review: 14 RCTs. 5 RCTs vs. foam (417 participants, 95% CI 1.00 (0.81, 1.22), 8 RCTs vs. low-adherent dressings (746 participants, 95% CI 1.15(1.00, 1.33).  1 RCT vs. alginate (40 participants, 95% CI 0.61, 0.13-2.96) There were no statistically significant differences in ulcer healing efficacies between the two interventions examined in each comparison. Evidence of moderate quality due to high risk of bias. [152]
                    • 2007 systematic review: 22 RCT - 8 RCT vs non-adherent dressing (792 participants, RR=0.98, 0.85 to 1.12), 4 RCT vs foam (311 participants, RR=0.98 (0.79 to 1.22), 2 RCT vs. alginate (80 participants, RR0.72 (0.48 to 1.69), 3 RCTs vs hydrocolloid (98 participants, RR=1.56, 0.67 to 3.63), 2 RCTs vs hydrogel (237 participant, no meta-analysis), 1 RCT vs gauze (28 participants, no meta-analysis), 1 RCT vs lyophilized collagen dressing (93 participants), 1 RCT vs magnesium sulfate paste and gauze (110 participants). No statistically significant difference in ulcer healing and adverse effects. Evidence was of low or uncertain quality due to risk of bias mainly. [133]
                    • A 2015 systematic review of cost-effectiveness analyses identified 1 study (lower-quality, Drummond score < 8) that compared hydrocolloid and Vaseline gauze dressing associated with compression in treatment of venous ulcers and found that hydrocolloid was more cost-effective than Vaseline gauze.

                    Summary of Evidence – Wet-to-dry (Back to text)


                    WHS recommends against using wet-to-dry dressings to promote wound healing (Level I) [28][34]. Among the studies analyzed, there were 2 meta-analyses that showed no significant differences in terms of the proportion of ulcers healed or reduction in wound size in VLU treated with different types of dressings, including continuously moist saline gauze dressings. Authors of the meta-analyses highlighted the fact that studies had important methodological limitations. In reviewing the studies included in the meta-analyses, we confirmed methodological limitations, and in light of the GRADE framework would consider it of low/uncertain quality (evidence level C).

                    Summary of Evidence – Topic antimicrobial agents (Back to text)

                    • Cadexomer iodine: A systematic meta-analysis of 4 trials that compared cadexomer iodine with standard care in VU patients receiving compression indicated cadexomer iodine is more effective in promoting VU healing (RR 2.17, 95% CI 1.30 to 3.60) [58]. However, trials had a small sample size, were at high risk or bias or had unclear risk of bias with limitations that might affect the magnitude of effect of the intervention (evidence level C). No difference in VU healing was observed when cadexomer iodine was compared with hydrocolloid dressing, paraffin gauze dressing, dextranomer or silver-impregnated dressings.
                    • Silver-based preparations: A systematic review of 12 RCTs, found no statistically significant difference in VU healing in patients treated with silver preparations compared with usual care, placebo, growth factor, non-adherent dressing, and other antimicrobial dressings [58]. One RCT was large and at low risk of bias, others were small and at unclear risk of bias.
                    • Honey: A meta-analysis of 2 RCT found no statistically significant difference in VU healing in VU treated with honey-based preparations and hydrogel or other non-honey dressings of clinicians’ choice [58]. One RCT was large and at low risk of bias, the other was small and at high risk of bias. The same RCTs were evaluated by another meta-analysis that yielded same results. Evidence was considered of low quality (evidence level C), mainly due to high risk of bias that can affect results of the meta-analysis and imprecision [63].

                    Summary of Evidence – Systemic Antibiotics  (Back to text)


                    • A 2014 Cochrane systematic review that evaluated 5 RCTs (233 participants) that reported 8 comparisons of systemic antibiotics (co-trimoxazole, gentamicin, amikacin, ciprofloxacin, trimethoprim, amoxicillin and levamisole) versus placebo, usual care or another antibiotic. In 1 RCT, more participants healed on levamisole compared to placebo (RR 1.31, 95% CI 1.06 to 1.62). However, the trial had an unclear risk of bias - did not state whether VU were infected or not at baseline, and had a small sample size – results could have happened by chance (evidence level C). Levamisole is unlicensed in the UK, and is only available from ’special order’ suppliers for use in treating roundworm infection, and it was withdrawn from the US market in 1999. Authors of the review concluded that at present, no evidence is available to support the routine use of systemic antibiotics in promoting healing of clinically infected venous leg ulcers. However, the studies had an unclear risk of bias with potential limitations that can affect the results of the studies and sample size was small (evidence level C). Therefore, authors could not recommend the discontinuation of any of the agents reviewed. In light of the increasing problem of bacterial resistance to antibiotics, current prescribing guidelines recommend that antibacterial preparations should be used only in cases of clinical infection, not for bacterial colonization [58].
                    • Clinical guidelines agree that routine culture of the ulcer should not be done.  Culture (preferably quantitative) should be employed only when there was evidence of active infection [39]
                    • The 2014 Society for Vascular Surgery [5], the 2015 Wound Healing Society (28,35), and the 2010 Association for Advancement of Wound Care [35] guidelines support treatment of VU with clinical signs of infection and with more than 1 x 10^6 CFU/g of tissue with antimicrobial therapy, although the levels of evidence assigned by these societies differed from each other, possibly due to different evidence grading methodologies and different studies from which evidence was drawn (SVS uses GRADE framework).

                    Intervention for VLU

                    Society for Vascular Surgery, 2014

                    AAWC, 2010

                    Wound healing Society, 2015

                    Treatment of VU with >1 x 10^6 CFU/g of tissue and clinical evidence of infection with systemic antimicrobial therapy

                    Grade 2C (weak suggestion, low quality evidence)

                    A (high quality evidence)

                    Level II (moderate quality evidence)

                    • We reviewed the Cochrane systematic review and the studies that the three guidelines used to grade quality of evidence and strength of recommendation (when applicable) for each of intervention above.  Applying the GRADE framework to the combined body of evidence, we found that:
                      • Evidence that support the recommendation to treat VU with >1 x 10^6 CFU/g of tissue and clinical evidence of infection with systemic antimicrobial therapy compared with no systemic antimicrobial therapy was of low quality (evidence level C). Authors of the 2014 Cochrane systematic review concluded that at present, no evidence is available to support the routine use of systemic antibiotics in promoting healing of clinically infected venous leg ulcers. However, the studies had an unclear risk of bias with potential limitations that can affect the results of the studies and sample size was small (evidence level C). Conclusions of other studies cited by guidelines were not directly relevant in supporting this intervention in infected VU, as they compared effectiveness of topical antimicrobial agents or did not evaluate effectiveness of systemic antibiotics in VU healing

                    Summary of Evidence – Stasis dermatitis (Back to text)

                    • A 2017 Cochrane systematic review on eczema (not stasis dermatitis specifically, but stasis dermatitis is a form of eczema) evaluated 77 RCT (6603 participants) and concluded that most moisturizers showed some beneficial effects, producing better results when used with active treatment, prolonging time to flare, and reducing the number of flares and amount of topical corticosteroids needed to achieve similar reductions in eczema severity. Authors not find reliable evidence that one moisturizer is better than another  [71].

                    Summary of evidence – Compression (back to text)

                    • Authors of a 2012 Cochrane systematic review concluded that compression increases ulcer healing rates compared with no compression, on the basis of 8 RCT at unclear or high risk of bias [7]. Authors of the review believe overall potential limitations of the studies were likely to lower confidence in the estimate of effect mainly due to uncertainty in whether outcome assessment was blinded (evidence level B).
                    • A more recent 2014 systematic review also found moderate level evidence that compression is better than no compression in promoting VU healing [88].
                    • No robust RCTs with results published after 2014 that compared compression vs. no compression for patients with VU have been found.
                    • Guidelines: All 14 guidelines for venous ulcer evaluated by O’Donnell in 2011 recommend compression for VU healing, and most recommend it at the strongest recommended level [39].
                    • The 2014 Society for Vascular Surgery (SVS)[5], the 2015 Wound Healing Society (WHS)[28][34], and the 2010 Association for Advancement of Wound Care (AAWC)[35] guidelines recommend compression therapy over no compression to promote VU healing.

                    Summary of Evidence – Types of Compression (Back to text)

                    • According to the 2012 Cochrane systematic review on the topic, there is evidence that multi-component compression systems are more effective than single-component systems. Most trials that evaluated this comparison were small and at unclear or high risk of bias and did not find a statistically significant difference in outcome, but one was large and at unclear risk of bias, and found that multi-component system was more effective than single-component [7]. Authors of the review believe that overall potential limitations of the large study are somewhat likely to lower confidence in the estimate of effect mainly due to lack of blinding of outcome assessment (evidence level B). The review also concluded that multi-component systems containing an elastic bandage appear to be more effective than those composed mainly of inelastic constituents, based on 5RCTs pooled data. 4 RCTs were small and at high or unclear risk of bias due to non-blinded outcome assessment, however 1 RCT was large and at low risk of bias. The pooled data of individual patient data or IPD (which allows a more sensitive analysis compared to aggregate data) showed at a statistically significant level that multi-component systems (4 layers bandages, or 4LB) with elastic bandage are more effective than multi-component systems that include an inelastic bandage (short stretch bandage, or SSB). However, authors recognize that staff familiarity with certain compression systems can greatly influence their effectiveness. The difference between 4LB and short-stretch bandages (SSB) in the IPD meta-analysis could be partly explained by skill and experience of bandagers; 3 out of 5 trials (75% of participants) were conducted in the UK, where 4LB is standard  [7].
                    • A more recent 2014 systematic review and meta-analysis [155] performed with aggregate data was unable to identify superiority in VLU healing of one approach in the three comparisons of interest: compression stockings vs compression bandages, 4LB systems vs systems that contain less than four layers, and SSBs vs. long-stretch bandages (LSBs - include 4LB and other elastic systems). It is important to note that the categories of compression compared by this study are different than the ones in the Cochrane review [7] and thus the group of trials representing each comparison differed as well. For instance, even though trials comparing SSB and 4LB are included in the assessment of SSB vs. LSB, the overall result of the meta-analysis is different because other studies that compare other types of LSB and SSB are included in the group of trials. Also, this study included 2 more recent trials that did not identify difference in VLU healing between 4LB and SSB. One of these trials [156] is a large RCT with low risk of bias. Ultimately, authors of this study agreed that: there is at least moderate-quality evidence that compression is superior to no compression and should be the mainstay of treatment for venous ulcers of the lower extremities, that multicomponent systems are superior to single component systems, and that an elastic component is needed [88].
                    • Another systematic review and meta-analysis published in 2014 (Nelson et al) compared 4LB and SSB and found no difference in their effectiveness in VLU healing. This study included a recent trial conducted by the Canadian Bandage Trial team to the body of evidence analyzed by O’Meara in the Cochrane meta-analysis on compression therapy [7]. This RCT had 428 participants and was considered of low risk.
                    • Out of 14 clinical guidelines, four guidelines advocated four-layer bandages and three short stretch garments [39].
                    • Interventions related to compression therapy for VLU recommended by The 2014 Society for Vascular Surgery (SVS)[5], the 2015 Wound Healing Society (WHS)(28,35), and the 2010 Association for Advancement of Wound Care (AAWC)[35] are summarized below.

                    Intervention for VLU

                    Society for Vascular Surgery

                    AAWC

                    Wound healing Society

                    Use compression therapy to promote healing in patients with venous ulcers

                    1A

                    A

                    I

                    Use high compression levels (e.g. 40 mmHg) at the ankle level to promote ulcer healing. High strength compression can be applied successfully using many methods including multilayered elastic compression, Unna's boot, compression stockings, and other

                     n/a

                    A

                    I

                    Choose multicomponent compression bandage over single-component bandages for the treatment of venous leg ulcers.

                    Grade 2B

                    A

                     n/a

                    Choose elastic compression bandage as it heals more than inelastic compression

                     n/a

                    A

                     n/a

                    Two-layer compression improves comfort or quality of life more than 4-layer or short stretch

                     n/a

                    A

                     n/a

                    Elastic compression stockings with moisture retaining dressing improve VU healing, pain and application time compared to short-stretch compression bandages or Unna’s Boot

                     n/a

                    A

                     n/a

                    intermittent pneumatic compression when other compression options are not available, cannot be used, or have failed to aid in venous leg ulcer healing after prolonged compression therapy.

                    Grade 2C

                    n/a

                    n/a

                    Summary of Evidence – Compression to prevent recurrence (Back to Text)

                    • A 2014 systematic review concluded that currently low-quality evidence (based on imprecision and heterogeneity) supports the effect of compression on ulcer recurrence [88]
                    • A 2014 Cochrane systematic review summarized 4 RCTs (979 participants) that evaluated compression in patients with healed ulcers. There is some evidence that compression hosiery might prevent ulcers, but the evidence is of low quality, due to imprecision and heterogeneity. One small trial concluded that compression hosiery reduces VLU recurrence rates compared with no compression. Results from one trial suggest that recurrence is lower in high-compression hosiery than in medium-compression hosiery at three years whilst another trial found no difference at 5 years. Rates of patient intolerance of compression hosiery were high. There is insufficient evidence to aid selection of different types, brands, or lengths of compression hosiery [93].
                    • All but one of the 14 clinical guidelines for VLU analyzed by O’Donnell in 2011 recommended below-knee 20/30-mm Hg compression stockings to prevent ulcer recurrence with a strong grade of recommendation in seven [39]
                    • The 2014 Society for Vascular Surgery (SVS)[5], the 2015 Wound Healing Society (WHS)[28][34], and the 2010 Association for Advancement of Wound Care (AAWC)[35] guidelines recommend compression therapy over no compression to reduce risk of VLU recurrence after VLU has healed.

                    Intervention for VLU

                    Society for Vascular Surgery, 2014

                    AAWC, 2012

                    Wound healing Society, 2015

                    In a patient with a healed venous leg ulcer, we suggest compression therapy to decrease the risk of ulcer recurrence.

                    Grade 2B

                    A

                    Level I


                    • New RCTs since 2014 evaluating use of compression to prevent VLU recurrence were found

                    Summary of Evidence – Exercise (Back to Text)


                    • A 2015 review on the effect of supervised exercise on healing and quality of life of VLU patients found 10 articles (RCTs, cohort studies with small sample sizes) that used physical therapy or exercise for patients with open or healed VLUs. They found that although there is evidence that exercise strengthens the calf muscle pump and improves ankle ROM, few studies have investigated the effect of these interventions on QOL and healing, and few involved the supervision of a physical therapist. Authors concluded that there is currently a lack of evidence that physical therapy-oriented exercise has an effect on wound healing, QOL and ulcer recurrence. [95]
                    • A 2014 review on VLU treatment has found low level of evidence (level C) that support a structured program of calf muscle exercise may improve hemodynamic performance and prevent ulcer recurrence [17]. A physical therapist can be instrumental in helping the patient adhere to this care plan.
                    • Clinical guidelines support exercises to increase calf muscle pump function [5][28][94]. The Wound Healing Society guideline states that this intervention has been demonstrated to be helpful in VLU prevention (level III of evidence) and the Society for Vascular Surgery (SVS) suggests supervised exercise to reduce pain and edema in patients with active VLU (Grade 2B). Of note, studies cited by SVS evaluated effect of exercise on strengthening of calf muscle pump in patients with VLU but did not correlate it with VLU healing or prevention of recurrence [157] [158].
                    • A small RCT (Meagher, 2012) evaluated VLU healing in 40 participants with newly diagnosed VLU in randomized in control group and supervised exercise group. Participants who took more steps per day showed faster venous ulcer healing times when compared with those who took fewer steps (p<0.005) Trial is small and underpowered to detect statistical differences, unclear if outcome assessment was blinded (level C)  [159].

                    Summary of Evidence – leg elevation (back to text)

                    • There are no published clinical trials on effects of leg elevation on VLU healing or recurrence.
                    • In 1994, Abu-Own et al conducted a small study and concluded that limb elevation enhanced the microcirculatory flow velocity in liposclerotic skin of patients with chronic venous insufficiency [97]
                    • In 2004, Xia et al evaluated 10 patients with an echographic image analysis and concluded that Leg elevation is extremely effective in reducing edema, even if only for three to four hours [98] 
                    • In a 2010 review, Collins & Seraj assigned level C to leg elevation to minimize edema in patients with chronic venous insufficiency and as adjunctive therapy for VLU and cited Abu-Own et al. as a reference [13]
                    • The 2012 Association for Advancement of Wound Care guideline assigned level C1 of evidence to leg elevation for VLU healing and prevention of recurrence, and cited the references above [94]

                    Summary of Evidence – Pentoxifylline (Back to Text)

                    A 2012 Cochrane systematic review included 12 RCTs (864 participants) comparing pentoxifylline and compression with placebo or no treatment in people with VLU.  Authors concluded that pentoxifylline 400 mg tablet taken three times a day, is an effective adjunct to compression bandaging for treating venous ulcers and may be effective in the absence of compression. The majority of adverse effects were gastrointestinal disturbances, and were tolerated by participants. Quality of trials was variable (Evidence level B) [105]

                    Summary of Evidence – PRP and Growth Factor (Back to Text)

                    • A 2016 Cochrane systematic meta-analysis on use of autologous platelet-rich plasma (PRP) for chronic wounds evaluated 10 RCTs, 3 of which focused only on VLU. Authors concluded that it is unclear if autologous PRP has an effect on VLU and other types of chronic wounds other than diabetic foot ulcers.  Studies showed no difference in the risk of adverse events in people treated with PRP or standard care. These findings are based on low quality evidence due to the small number of studies and patients included, and their poor methodological quality. Authors mentioned that the very few RCTs evaluating PRP are underpowered to detect treatment effects, if they exist, and are generally at high or unclear risk of bias [111]
                    • As for clinical guidelines, AAWC did not find evidence to support use of PDGF in VLU, and WHS does not support use of growth factors in VLU, although isolated reports suggest potential usefulness (28,99)
                    • Reviews of systematic analyses and meta-analyses included a small trial with 60 participants that compared patients who received GM-CSF 200 mcg or 400 mcg (once a week for 4 weeks). Healing rates of the intervention group was higher at a statistically significant level compared to placebo at 13 weeks [54] [160] [161]. However, the trial was small and underpowered to detect treatment effects.
                    • A few recent studies have evaluated the efficacy and safety of PRGF or epidermal growth factors (EGF) as local treatment for venous ulcers. One small trial with 58 patients compared application of PRGF and standard care and found that the average percentage healed area of the PRGF group was significantly higher than that of the control group (p=0.001). However, the trial was small and at unclear risk of bias [108] . Another study was observational and evaluated efficacy, safety of wound dressing containing epidermal growth factor (EGF) in a collagen-gel matrix on hard-to-heal venous leg ulcers, but there was no control group [109].  
                    • In 2014, Barrientos et al published a review on growth factors for chronic wounds and concluded that the four growth factors that have shown the greatest potential in randomized controlled trials include GM-CSF, PDGF, bFGF and VEGF. Current studies to date are small, and have disparate endpoints and modes of growth factor and cytokine administration. Larger randomized controlled trials are needed to support efficacy, side effect profiles, and long term outcomes. All data should be interpreted with caution and any off-label use of these products for the management of wounds should be used in conjunction with the standard of care for non-healing wounds. Areas for future study include optimal delivery methods for growth factors and use of different combinations of growth factors and other adjuvant therapies in addition to debridement [107].

                    Summary of Evidence – STSG (Back to Text)


                    A 2013 Cochrane systematic meta-analysis evaluated two trials that compared split-thickness autografts with a hydrocolloid dressing in 102 participants  [162] [163]. In Warburg 1994, both groups had vein surgery and authors found no evidence of a significant benefit for autografts over a dressing in this small trial (102 participants) (risk ratio (RR) of healing with autografts 0.89, 95%confidence interval (CI) 0.34 to 2.31). Jankunas 2007 reported a large difference in healing rates (RR of healing 42.93, 95% CI 2.72 to 677.16). Authors of the meta-analysis concluded that these trials provide no firm evidence of benefit rather than firm evidence of lack of benefit. The different results could be due to the fact that at baseline, the Warburg 1994 trial had larger ulcers in the skin graft group, which may have biased the results against grafting, or it may indicate that allocation was subverted as there was no indication whether allocation was concealed [115]


                    Clinical guidelines: The 2014 Society for Vascular Surgery (SVS)[5] and the 2010 Association for Advancement of Wound Care (AAWC)[35] guidelines included different interventions related to autologous skin grafting.


                    Intervention for VLU

                    Society for Vascular Surgery

                    AAWC

                    Wound healing Society

                    Split-thickness skin grafting with continued compression for selected large venous leg ulcers that have failed to show signs of healing with standard care for 4 to 6 weeks.

                    Grade 2B

                    n/a

                    n/a

                    Pinch grafts

                    n/a

                    C2

                    n/a


                    We reviewed the Cochrane systematic review and the studies that the two guidelines used to grade quality of evidence and strength of recommendation (when applicable) for each of intervention above.  Applying the GRADE framework to the combined body of evidence, we found that:

                    • Evidence that support use of autologous split-thickness skin grafting with continued compression for VLU that failed to decrease in size by 30% after 4 weeks compared with standard care is of low quality evidence (evidence level C). Authors of the 2013 Cochrane systematic review concluded that the trials studied provide no firm evidence of benefit rather than firm evidence of lack of benefit. Trials were small and/or at high and unclear risk of bias due to lack of outcome assessment blinding, and had inconsistency of results, probably due to discrepancies of wound size in different groups at baseline in of one of the trials. Studies on autologous skin graft cited by guidelines were not directly related to the use vs. no use of autologous split-thickness grafts to promote healing of VLU, as they compared split-thickness grafting with or without low molecular weight heparin or were retrospective studies on pinch grafts for VLU (28,99).

                    Summary of Evidence – CEA (Back to Text)


                    Recommendations related to this intervention given by the 2014 Society for Vascular Surgery (SVS)[5], the 2010 Association for Advancement of Wound Care (AAWC)[35] and the 2015 Wound Healing Society (WHS)[28][34] are listed below:


                    Intervention for VLU

                    Society for Vascular Surgery

                    AAWC

                    Wound healing Society

                    Cultured epithelial autografts or allografts have not been demonstrated to improve stable healing of venous ulcers

                    n/a

                    n/a

                    I - against use of these interventions

                    Split-thickness cultured autografts

                    n/a

                    C2

                    n/a

                    Cultured epidermal autografts (autologous keratinocytes)

                    n/a

                    B

                    n/a

                    We reviewed the citations that the two guidelines used to grade quality of evidence and strength of recommendation (when applicable) for each of intervention above.  Applying the GRADE framework to the combined body of evidence, we found that:

                    • Use of cultured epidermal autografts to treat recalcitrant VLU is based on low quality evidence (evidence level C). One large RCT cited by the AAWC guideline concluded that cultured autologous keratinocytes in a fibrin vehicle were more effective in promoting VLU healing than standard care [118]. However, this study may be at high risk of bias due to attrition bias (no information on which group patients lost to follow up belonged to, which might affect outcomes), and lack of blinding in outcome assessment. Other observational studies also provide low quality evidence that support this intervention [119][120]. Case series evaluated use of split-thickness cultured autografts and provide low quality evidence to support their use in VLU [121] [122].

                    Summary of Evidence – Skin allograft (Back to Text)

                    A 2013 Cochrane meta-analysis evaluated 5 small trials comparing fresh or frozen allografts for VLU. Authors found a higher healing rate with allografts than standard care, but these small trials were of poor quality and hence they recommended this result be treated with caution (evidence level C). Most of the trials provided insufficient evidence of benefit, rather than firm evidence of lack of benefit - Cochrane

                    The 2012 clinical guideline for VLU published by AAWC categorized use of allografts for VLU as low quality evidence (level C)

                    No new RCTs related to use of human skin allografts published since 2012 have been found. There have been some other non-RCT studies since then, but these do not confer the degree of quality needed for the evidence to be considered relevant.  Austin Pourmoussa


                    Summary of Evidence – Allogeneic Matrix (Back to Text)

                    A 2013 Cochrane systematic review analyzed 2 trials (71 participants) that compared a single-layered dermal replacement (Krishnamoorthy 2003; Omar 2004) with standard care of four-layer compression and a low-adherent dressing. Both trials evaluated Dermagraft (Smith and Nephew), described as a human fibroblast-derived dermal replacement; the origin of the cells being newborn foreskin. There was no evidence of benefit associated with dermal skin replacement (at baseline) compared with standard care. There is therefore insufficient evidence, based on 2 small studies, that single-layered dermal skin replacement heals venous ulcers more quickly than a simple low-adherent dressing [115].

                    A study published in 2013 that was not included in the Cochrane review above (Harding et al)[123] published results of a large RCT with 366 patients that evaluated the efficacy and safety of human fibroblast-derived dermal substitute (Dermagraft) plus four-layer compression therapy compared with compression therapy alone in the treatment of VLU. Authors found that overall, there was no difference in the proportion of patients with completely healed study ulcers by 12 weeks between the interventional and control groups. However, more VLUs with less than 12 months in duration treated with Dermagraft healed at 12 weeks than VLUs with less than 12 months treated with compression only (P = 0·029). This study was industry sponsored, and there was no mention of blinded outcome assessment (moderate quality, evidence level B).

                    In 2014, Serena et al [124] published results of a RCT with 84 participants that evaluated the safety and efficacy of one or two applications of dehydrated human amnion/chorion membrane allograft and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of VLU. At 4 weeks, significantly more VLUs treated with the allograft showed a reduction in size greater than 40% compared with the control group (p=0.005). This trial was industry sponsored, outcome assessment was not blinded and the study end point was a surrogate measure of wound healing (low quality, evidence level C)

                    Other studies are small, retrospective or did not report outcomes of use of membrane products on VLU separately [125][126][127].

                    Summary of Evidence – Composite Matrix (Back to Text)

                    A 2013 Cochrane systematic meta-analysis concluded that bilayer tissue-engineered skin replacement, used with compression, increases the rate of healing of VLU compared with simple dressings used with compression. This conclusion was based on 2 trials (345 participants) that compared a bilayered skin equivalent with standard care of foam or a dressing made to look like the skin equivalent [115][128][129]. Meta-analysis shows that the artificial skin was significantly better in promoting VLU healing compared with simple dressings - 1.51 (95% CI 1.22 to 1.88).  Authors of the meta-analysis mentioned that these 2 trials provide reasonable evidence that a greater proportion of venous ulcers heal with artificial skin than a simple dressing, but that the lack of an intention-to-treat analysis for the Falanga 1998 trial [129] reduces their certainty of the results [115]. Although the trial performed by Falanga et al was large, it was considered by the review’s authors at high risk of bias for attrition and performance biases (loss of patients to follow up and lack of blinding in outcome assessment). The trial performed by Brown-Etris [128] included only 36 participants and was underpowered to detect differences between groups. (level B)

                    Listed below are recommendations regarding this intervention given by the 2014 Society for Vascular Surgery (SVS)[5], the 2010 Association for Advancement of Wound Care (AAWC)[35] and the 2015 Wound Healing Society (WHS)(28,35):


                    Intervention for VLU

                    Society for Vascular Surgery

                    AAWC

                    Wound healing Society

                    Cultured allogeneic bilayer

                    skin replacements - Apligraf (with both epidermal and dermal layers) to increase the chances for healing in patients with difficult to heal venous leg ulcers in addition to compression therapy in patients who have failed to show signs of healing after standard therapy for 4 to 6 weeks.

                    Grade 2A

                    A

                    I

                    No new RCTs on use of bilayered bioengineered skin for VLU since 2012 have been found. One retrospective study with data from 1489 patients found that treatment with bilayered skin increased the probability of VLU healing by 29% compared with porcine SIS dressing (hazard ratio = 1.29 [95% confidence interval 1.06, 1.56], p = 0.01)  [164].

                    Summary of Evidence – Acellular Matrix (Back to Text)

                    Studies on acellular matrices were not included in the 2013 Cochrane review [115] on skin grafts for VLU, as acellular matrices were considered as dressings. However, we grouped acellular matrices under CTPs, according to Medicare categorization of these products.

                    In 2005, Mostow et al [130]published results of a RCT with 120 participants that compared treatment of VLU with acellular porcine matrix and compression vs. standard care. VLU in the interventional group healed more than in the control group at a statistically significant level. There was no significant difference in wound recurrence rates between the two groups. Potential biases of this industry-sponsored study include lack of blinding in outcome assessment, and sample size not large enough to reach statistical power (low quality evidence, level C). The Agency for Healthcare Research and Quality (AHRQ) and authors of a systematic review (Valle et al) considered evidence provided by this trial as low quality [131].

                    Other non-RCT small studies evaluated use of acellular matrices in VLU, and reported positive results [123][165] [166].

                    Hyaluronic acid dressings can also be considered acellular matrices. Evidence on its effectiveness in VLU healing compared to standard care with non-adherent gauze or other types of dressing is of low quality:

                    One RCT (n=170 patients) investigated the efficacy and safety of an hyaluronic acid (HA)-impregnated gauze pad compared with a hydrocolloid (HC) dressing, in patients with leg ulcer of venous or mixed etiology  [167]. The primary endpoint was the difference between the groups regarding the percentages of patients achieving a reduction of at least 40% of the initial wound surface after 56 days of treatment. There was no statistically significant difference in healing rates between the interventional and control groups. Another trial (n=89 patients) investigated the efficacy and safety of a gauze pad containing HA in local treatment of venous leg ulcers, compared with its neutral vehicle. The primary endpoint was the percentage of wound size reduction after 45 days. The number of healed ulcers was significantly higher in the HA group at day 45 and 60 (p<0.05)  [168]. One small cohort study reported positive results for another type of hyaluronic acid dressing [169] and another study compared hyaluronic acid based dressing and compression therapy versus non-adherent gauze and compression therapy, but this study did not report or did have meet baseline comparability, inclusion/exclusion criteria, randomization, blinding, allocation concealment or sample size calculation [133][170].

                    Listed below are recommendations regarding acellular matrix given by the 2014 Society for Vascular Surgery (SVS)[5], the 2010 Association for Advancement of Wound Care (AAWC)[35] and the 2015 Wound Healing Society (WHS)[28][34]:

                    Intervention for VLU

                    Society for Vascular Surgery

                    AAWC

                    Wound healing Society

                    Porcine small intestinal sub-

                    mucosa tissue construct in addition to compression therapy for the treatment of venous leg ulcers that have failed to show signs of healing after standard therapy for 4 to 6 weeks

                    Grade 2B

                    n/a

                    II

                    • We reviewed the citations that the two guidelines used to grade quality of evidence and strength of recommendation (when applicable) for each of intervention above.  Applying the GRADE framework to the combined body of evidence, we found that:
                      • Use of porcine small intestinal submucosa tissue construct to treat recalcitrant VLU is based on low quality evidence (evidence level C). The guidelines also used Mostow’s study  [130] as a reference to their suggestion. As mentioned above, potential biases of this industry-sponsored study include lack of blinding in outcome assessment, and sample size not large enough to reach statistical power (low quality evidence, level C). The Agency for Healthcare Research and Quality (AHRQ) and authors of a systematic review [55] considered evidence provided by this trial as low quality  [131].

                    Summary of Evidence – Drugs/biologics (Back to Text)

                    The 2013 Cochrane systematic review described one trial (Goedkoop 2010) that compared growth-arrested human keratinocytes and fibroblasts (HP802-247) with placebo equivalent in 110 participants. For the purposes of the analysis authors of the review combined the results of the six intervention groups and compared them with the placebo group; there was no statistically significant difference between the two groups at either 12 weeks or 24 weeks (Cochrane, 2013)

                    Listed below are recommendations regarding this intervention given by the 2014 Society for Vascular Surgery (SVS)[5], the 2010 Association for Advancement of Wound Care (AAWC)[35] and the 2015 Wound Healing Society (WHS)[28][34]:

                    Intervention for VLU

                    Society for Vascular Surgery

                    AAWC

                    Wound healing Society

                    Cultured epithelial allografts have not been demonstrated to improve stable healing of venous ulcers

                    n/a

                    n/a

                    I – suggest against

                    Cultured allogeneic keratinocyte lysate

                    n/a

                    C1

                    n/a

                    Summary of Evidence – Phlebotonics (Back to Text)

                    A 2017 systematic review [171] concluded that there is moderate quality evidence supporting the use of MPFF in VLU healing, however it excluded the largest trial that assessed use of MPFF on VLU healing, which was unpublished and showed no difference in VLU healing between control and interventional groups[172]. This trial was included in the 2013 Cochrane systematic meta-analysis [137] described below.

                    A 2016 Cochrane systematic meta-analysis [136] evaluated 6 RCTs (461 participants) that compared efficacy of phlebotonics like aminaftone, diosmine, or rutoside versus placebo on ulcer healing. Pooled results showed no statistically significant differences between phlebotonics and placebo (RR 0.94, 95% CI 0.79 to 1.13; I2 = 5%; 461 participants). Quality of evidence was downgraded due to selective outcome and incomplete outcome data reporting (evidence level C). Authors also evaluated other outcomes related to chronic venous insufficiency and found that moderate-quality evidence shows that phlebotonics may have beneficial effects on edema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. 

                    A 2013 Cochrane systematic meta-analysis [137] evaluated 9 RCTs (1075 participants) that compared efficacy of flavonoids and compression on VLU healing. Five of these trials investigated Micronised Purified Flavonoid Fraction (MPFF), and 4 evaluated hydroxyethylrutosides (HR). Meta-analyses showed that more venous leg ulcers were healed in the MPFF groups than in the control groups (RR 1.36; 95% CI 1.07 to 1.74), and in the HR groups than in the control groups (RR 1.70; 95% CI 1.24 to 2.34). However, most of these trials were poorly reported, and so had an unclear risk of bias for randomization, allocation concealment, blinding and methods for addressing incomplete outcome data. There was also a possibility of publication bias (level of evidence C). The only trial with a low risk of bias, with the largest sample size showed no difference in VLU healing outcomes between patients in the MPFF experimental group and control group[172], and it was unpublished, raising the possibility of publication bias, as its result was not favorable for flavonoids. There is evidence to show that studies that are inadequately concealed and not blinded can lead to overestimation of treatment effects by up to 41% and 17% respectively [137].

                    Summary of Evidence – Aspirin (Back to Text)

                    A 2016 Cochrane systematic review included two RCTs of oral aspirin (300 mg/daily) given to patients with VLU in addition to compression and compared with compression and placebo, or compression alone.  Results of the small trials indicated that aspirin was effective in increasing healing rate, preventing recurrence and healing more VLUs compared with the control groups. However, authors of the review downgraded the evidence due to potential selection bias and imprecision due to the small sample size and concluded that low quality evidence from these two trials indicate that there is currently insufficient evidence for them to draw definitive conclusions about the benefits and harms of oral aspirin on the healing and recurrence of venous leg ulcers[138].

                    Summary of Evidence - Zinc (Back to Text)

                    A 2014 Cochrane systematic review included 6 small RCTs comparing oral zinc sulphate with placebo or no treatment in people with arterial or VLU.  Pooling of these trials indicated no statistically significant difference between the two groups for healing (RR 1.22, 95%CI 0.88 to 1.68). Overall, there is no evidence that oral zinc increases the healing of arterial or venous leg ulcers, however evidence is of low quality due to small size of trials and unclear risk of bias (poor reporting of outcomes) [103].

                    Summary of Evidence - Sulodexide (Back to Text)

                    A 2016 Cochrane systematic review included 4 RCTs (463 participants) comparing sulodexide as an adjuvant to local treatment (including wound care and compression therapy) compared with local treatment alone. Meta-analysis of three RCTs suggests an increase in the proportion of ulcers completely healed with sulodexide as an adjuvant to local treatment compared with local treatment alone (rate of complete healing with sulodexide 49.4% compared with 29.8% with local treatment alone; RR 1.66; 95% CI 1.30 to 2.12). This evidence for sulodexide increasing the rate of complete healing is of low quality due to risk of bias (evidence level C). It is unclear whether sulodexide is associated with any increase in adverse events (4.4% with sulodexide versus 3.1% with no sulodexide; RR 1.44; 95% CI 0.48 to 4.34) (evidence level C) [141]

                    Summary of Evidence – Electrical Stimulation  (Back to Text)

                    Several studies show that electrical stimulation may be useful in treating VLU, however most studies have a small sample size and may be underpowered to detect statistical significance [173] [174]included other types of ulcers and did not report results for each type separately ) [175] [176] [177], or are observational in nature  [178].Treatment parameters and type of electrical stimulation among these studies are controversial.

                    Summary of Evidence – Electrical magnetic (Back to Text)

                    A 2015 Cochrane systematic review [142] included 3 small RCTs (94 participants) that evaluated the use of electromagnetic therapy (EMT) and sham EMT in patients with VLU. Two studies that reported healing rates had conflicting results regarding effectiveness of EMT, and the other study reported significantly greater reductions in ulcer size in the EMT group however this result may have been influenced by differences in the baseline characteristics of the wounds/patients. Authors of the review concluded that at present, there is no high-quality evidence (it is not clear) that EMT speeds the healing of venous leg ulcers. Further research would be needed to answer these questions (evidence level C).

                    Trials cited by the AAWC venous ulcer guideline [19] were the same as the ones evaluated by the Cochrane review described above.

                    Summary of Evidence – Ultrasound therapy (Back to Text)

                    A 2010 Cochrane systematic review included 8 RCTs that evaluated high frequency ultrasound (HFU) and low frequency ultrasound (LFU) for treatment of VLU. All trials were small, of poor-quality and heterogeneous. Authors of the review concluded that there is no reliable evidence that US hastens healing of venous ulcers. There is a small amount of weak evidence of increased healing with US, but this requires confirmation in larger, high-quality RCTs. There is no evidence of a benefit associated with low frequency US  [143].

                    A meta-analysis conducted by Voigt et al in 2011 [179] included 8 RCTs. Results demonstrated that early healing (at ≤5 months) in patients with venous stasis and diabetic foot ulcers was favorably influenced by both high- and low-intensity ultrasound delivered at a low frequency—either via contact or noncontact techniques. However, the quality of the data may be suspect, especially for low-frequency low-intensity noncontact ultrasound because of significant biases. In patients presenting with either venous stasis or diabetic foot ulcers (Wagner classification 1-3), early healing appears to be facilitated by either low-frequency low-intensity noncontact ultrasound or low-frequency high-intensity contact ultrasound.

                    The 2014 Society for Vascular Surgery [5], the 2015 Wound Healing Society [28][34], and the 2010 Association for Advancement of Wound Care [35] guidelines do not support use of ultrasound therapy as primary therapy in the treatment of VLU, although the levels of evidence assigned by these societies differed from each other, possibly due to different evidence grading methodologies and different studies from which evidence was drawn (SVS uses GRADE framework).

                    Intervention for VLU

                    Society for Vascular Surgery

                    AAWC

                    Wound healing Society

                    Ultrasound therapy for wounds that fail to progress after 4 weeks of standard care

                    2B, suggest against ultrasound as primary therapy

                    A

                    III


                    A few recent RCTs evaluated the use of ultrasound in the treatment of VLU. Beheshti et al [144]

                    and Olyaie et al [145] published results of a RCT (90 participants) that compared standard care with HFU and MIST ultrasound therapy on VLU that failed to respond to SC for 4 weeks. Size of ulcer, mean degree of pain and edema in ultrasound therapy was decreased after the 4-month visit in comparison to the standard-treatment group (p = 0.01, p < 0.0001 and p < 0.0001, respectively). However, authors report no blinding in outcome assessment and there is no description of sample size calculation (may be underpowered to detect statistical differences)

                    Watson et al [180] conducted a large RCT with 337 patients with at least one venous leg ulcer of >6 months' duration or >5 cm [2] area and an ankle brachial pressure index of ≥ 0.8, that aimed at  assessing the clinical effectiveness of weekly delivery of low dose, high frequency therapeutic ultrasound in conjunction with standard care for hard to heal VLU. Authors concluded that low dose, high frequency ultrasound administered weekly for 12 weeks during dressing changes in addition to standard care did not increase ulcer healing rates, affect quality of life, or reduce ulcer recurrence. Authors concluded that therapeutic ultrasound does not confer any benefit on the healing of hard to heal venous leg ulcers (that is, >5 cm2 in area or >6 months old, or both). The trial can be considered of good quality (evidence level A)

                    Summary of Evidence – HBOT (Back to Text)

                    A 2015 Cochrane review was able to find only one small RCT that evaluated use of HBOT on VLU healing [146]  [181]. The trial (16 participants with VLU for more than a year) compared treatment with 2.4 ATA for 90 minutes to a total of 30 sessions over six weeks with an air-breathing sham treatment on the same schedule. There was a significant reduction in wound area at six weeks following the administration of HBOT (33%mean difference in area ulcerated, 95%CI 19 to 47), but this effect did not persist to 18 weeks and there was no significant increase in the proportion of ulcers healed at any time (RR 5.00, 95%CI 0.28 to 90.18, P = 0.28). The trial did not report undertaking a sample size calculation and may have been underpowered to detect any statistically significant effect of treatment. Also, it was considered at unclear risk for selection and reporting bias [146].

                    Summary of Evidence – NPWT (Back to Text)

                    A 2015 Cochrane review on the use of negative pressure wound therapy (NPWT) for hard to heal leg ulcers (all types) [147] was able to identify only 1 RCT. The trial was small (n=60) (Vuerstaek 2006)  [182], and compared NPWT followed by a punch skin-graft transplant and further NPWT treatment with standard wound care followed by a punch skin-graft transplant and subsequent standard care. The study found that the median time to healing in the NPWT group was 28 days (95% CI 25.5 to 32.5) compared with 45 days (95% CI 36.2 to 53.8) in the standard care group. The study reported an adjusted hazard ratio of 3.2, 95% CI 1.7 to 6.2 suggesting a higher chance of healing with NPWT. However, this evidence was considered of low quality due to imprecision and indirectness. Authors of the review concluded that there is no RCT evidence on the effectiveness of NPWT as a primary treatment for leg ulcers, and that there is limited evidence regarding the use of negative pressure wound therapy (NPWT) for the treatment of hard-to-heal leg ulcers. Given the current uncertainties, practitioners may elect to consider various characteristics such as costs and symptom management properties when choosing between alternative treatment options for leg ulcers. Cochrane. A recent RCT [183] that compared 2 types of NPWT has not been included in the review as review authors are awaiting clarifications from the study authors.  The paper suggests that people with VLUs were randomized along with people with foot ulcers. However, the paper only reported data for those with VLU - which is a sub-group of the overall population. This might impact on the randomized nature of the study Cochrane.


                    Intervention for VLU

                    Society for Vascular Surgery

                    AAWC

                    Wound healing Society

                    NPWT prior to skin graft/flap

                    n/a

                    C1

                    II

                    NPWT as primary therapy for VLU

                    2C, suggest against

                    n/a

                    n/a

                    ICD-10 Coding

                    Coding Chronic venous hypertension (Back to text)

                    I83 Varicose veins of lower extremities

                      I83.0 Varicose veins of lower extremities with ulcer

                           I83.00 Varicose veins of unspecified lower extremity with ulcer

                                I83.001 …… of thigh

                                I83.002 …… of calf

                                I83.003 …… of ankle

                                I83.004 …… of heel and midfoot

                                I83.005 …… other part of foot

                                I83.008 …… other part of lower leg

                                I83.009 …… of unspecified site

                           I83.01 Varicose veins of right lower extremity with ulcer

                               I83.011 …… of thigh

                               I83.012 …… of calf

                               I83.013 …… of ankle

                               I83.014 …… of heel and midfoot

                               I83.015 …… other part of foot

                               I83.018 …… other part of lower leg

                               I83.019 …… of unspecified site

                           I83.02 Varicose veins of left lower extremity with ulcer

                               I83.021 …… of thigh

                               I83.022 …… of calf

                               I83.023 …… of ankle

                               I83.024 …… of heel and midfoot

                               I83.025 …… other part of foot

                               I83.028 …… other part of lower leg

                               I83.029 …… of unspecified site

                       I83.2 Varicose veins of lower extremities with both ulcer and inflammation

                           I83.20 Varicose veins of unspecified lower extremity with both ulcer and inflammation

                               I83.201 Varicose veins of unspecified lower extremity with both ulcer of thigh and inflammation

                               I83.202 Varicose veins of unspecified lower extremity with both ulcer of calf and inflammation

                               I83.203 Varicose veins of unspecified lower extremity with both ulcer of ankle and inflammation

                               I83.204 Varicose veins of unspecified lower extremity with both ulcer of heel and midfoot and inflammation

                               I83.205 Varicose veins of unspecified lower extremity with both ulcer other part of foot and inflammation

                               I83.208 Varicose veins of unspecified lower extremity with both ulcer of other part of lower extremity and inflammation

                               I83.209 Varicose veins of unspecified lower extremity with both ulcer of unspecified site and inflammation

                           I83.21 Varicose veins of right lower extremity with both ulcer and inflammation

                               I83.211 Varicose veins of right lower extremity with both ulcer of thigh and inflammation

                               I83.212 Varicose veins of right lower extremity with both ulcer of calf and inflammation

                               I83.213 Varicose veins of right lower extremity with both ulcer of ankle and inflammation

                               I83.214 Varicose veins of right lower extremity with both ulcer of heel and midfoot and inflammation

                               I83.215 Varicose veins of right lower extremity with both ulcer other part of foot and inflammation

                               I83.218 Varicose veins of right lower extremity with both ulcer of other part of lower extremity and inflammation

                               I83.219 Varicose veins of right lower extremity with both ulcer of unspecified site and inflammation

                           I83.22 Varicose veins of left lower extremity with both ulcer and inflammation

                               I83.221 Varicose veins of left lower extremity with both ulcer of thigh and inflammation

                               I83.222 Varicose veins of left lower extremity with both ulcer of calf and inflammation

                               I83.223 Varicose veins of left lower extremity with both ulcer of ankle and inflammation

                               I83.224 Varicose veins of left lower extremity with both ulcer of heel and midfoot and inflammation

                               I83.225 Varicose veins of left lower extremity with both ulcer other part of foot and inflammation

                               I83.228 Varicose veins of left lower extremity with both ulcer of other part of lower extremity and inflammation

                               I83.229 Varicose veins of left lower extremity with both ulcer of unspecified site and inflammation

                    Coding – post phlebitic (Back to text)

                           I87.01 Postthrombotic syndrome with ulcer

                               I87.011 …… of right lower extremity

                               I87.012 …… of left lower extremity

                               I87.013 …… of bilateral lower extremity

                               I87.019 …… of unspecified lower extremity

                           I87.03 Postthrombotic syndrome with ulcer and inflammation

                               I87.031 …… of right lower extremity

                               I87.032 …… of left lower extremity

                               I87.033 …… of bilateral lower extremity

                               I87.039 …… of unspecified lower extremity

                    Coding – varicose ulcer (Back to text)

                    I83 Varicose veins of lower extremities

                       I83.0 Varicose veins of lower extremities with ulcer

                           I83.00 Varicose veins of unspecified lower extremity with ulcer

                               I83.001 …… of thigh

                               I83.002 …… of calf

                               I83.003 …… of ankle

                               I83.004 …… of heel and midfoot

                               I83.005 …… other part of foot

                               I83.008 …… other part of lower leg

                               I83.009 …… of unspecified site

                           I83.01 Varicose veins of right lower extremity with ulcer

                               I83.011 …… of thigh

                               I83.012 …… of calf

                               I83.013 …… of ankle

                               I83.014 …… of heel and midfoot

                               I83.015 …… other part of foot

                               I83.018 …… other part of lower leg

                               I83.019 …… of unspecified site

                       I83.02 Varicose veins of left lower extremity with ulcer

                               I83.021 …… of thigh

                               I83.022 …… of calf

                               I83.023 …… of ankle

                               I83.024 …… of heel and midfoot

                               I83.025 …… other part of foot

                               I83.028 …… other part of lower leg

                               I83.029 …… of unspecified site

                       I83.2 Varicose veins of lower extremities with both ulcer and inflammation

                           I83.20 Varicose veins of unspecified lower extremity with both ulcer and inflammation

                               I83.201 Varicose veins of unspecified lower extremity with both ulcer of thigh and inflammation

                               I83.202 Varicose veins of unspecified lower extremity with both ulcer of calf and inflammation

                               I83.203 Varicose veins of unspecified lower extremity with both ulcer of ankle and inflammation

                               I83.204 Varicose veins of unspecified lower extremity with both ulcer of heel and midfoot and inflammation

                               I83.205 Varicose veins of unspecified lower extremity with both ulcer other part of foot and inflammation

                               I83.208 Varicose veins of unspecified lower extremity with both ulcer of other part of lower extremity and inflammation

                               I83.209 Varicose veins of unspecified lower extremity with both ulcer of unspecified site and inflammation

                           I83.21 Varicose veins of right lower extremity with both ulcer and inflammation

                               I83.211 Varicose veins of right lower extremity with both ulcer of thigh and inflammation

                               I83.212 Varicose veins of right lower extremity with both ulcer of calf and inflammation

                               I83.213 Varicose veins of right lower extremity with both ulcer of ankle and inflammation

                               I83.214 Varicose veins of right lower extremity with both ulcer of heel and midfoot and inflammation

                               I83.215 Varicose veins of right lower extremity with both ulcer other part of foot and inflammation

                               I83.218 Varicose veins of right lower extremity with both ulcer of other part of lower extremity and inflammation

                               I83.219 Varicose veins of right lower extremity with both ulcer of unspecified site and inflammation

                           I83.22 Varicose veins of left lower extremity with both ulcer and inflammation

                               I83.221 Varicose veins of left lower extremity with both ulcer of thigh and inflammation

                               I83.222 Varicose veins of left lower extremity with both ulcer of calf and inflammation

                               I83.223 Varicose veins of left lower extremity with both ulcer of ankle and inflammation

                               I83.224 Varicose veins of left lower extremity with both ulcer of heel and midfoot and inflammation

                               I83.225 Varicose veins of left lower extremity with both ulcer other part of foot and inflammation

                               I83.228 Varicose veins of left lower extremity with both ulcer of other part of lower extremity and inflammation

                               I83.229 Varicose veins of left lower extremity with both ulcer of unspecified site and inflammation

                    Coding – nonpressure ulcer (Back to text)

                       L97.2 Non-pressure chronic ulcer of calf

                            L97.20 Non-pressure chronic ulcer of unspecified calf

                               L97.201 …… limited to breakdown of skin

                               L97.202 …… with fat layer exposed

                               L97.203 …… with necrosis of muscle

                               L97.204 …… with necrosis of bone

                               L97.209 …… with unspecified severity

                           L97.21 Non-pressure chronic ulcer of right calf

                               L97.211 …… limited to breakdown of skin

                               L97.212 …… with fat layer exposed

                               L97.213 …… with necrosis of muscle

                               L97.214 …… with necrosis of bone

                               L97.219 …… with unspecified severity

                           L97.22 Non-pressure chronic ulcer of left calf

                               L97.221 …… limited to breakdown of skin

                               L97.222 …… with fat layer exposed

                               L97.223 …… with necrosis of muscle

                               L97.224 …… with necrosis of bone

                               L97.229 …… with unspecified severity

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