William A. Marston

Revision of the venous clinical severity score: Venous outcomes consensus statement: Special communication of the American Venous Forum Ad Hoc Outcomes Working Group

In response to the need for a disease severity measurement, the American Venous Forum committee on outcomes assessment developed the Venous Severity Scoring system in 2000. There are three components of this scoring system, the Venous Disability Score, the Venous Segmental Disease Score, and the Venous Clinical Severity Score (VCSS). The VCSS was developed from elements of the CEAP classification (clinical grade, etiology, anatomy, pathophysiology), which is the worldwide standard for describing the clinical features of chronic venous disease. However, as a descriptive instrument, the CEAP classification responds poorly to change. The VCSS was subsequently developed as an evaluative instrument that would be responsive to changes in disease severity over time and in response to treatment. Based on initial experiences with the VCSS, an international ad hoc working group of the American Venous Forum was charged with updating the instrument. This revision of the VCSS is focused on clarifying ambiguities, updating terminology, and simplifying application. The specific language of proven quality-of-life instruments was used to better address the issues of patients at the lower end of the venous disease spectrum. Periodic review and revision are necessary for generating more universal applicability and for comparing treatment outcomes in a meaningful way.

Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery ® and the American Venous Forum.

Thomas F. O’Donnell Jr, MD, Marc A. Passman, MD, William A. Marston, MD, William J. Ennis, DO, Michael Dalsing, MD, Robert L. Kistner, MD, Fedor Lurie, MD, PhD, Peter K. Henke, MD, Monika L. Gloviczki, MD, PhD, Bo G. Eklof, MD, PhD, Julianne Stoughton, MD, Sesadri Raju, MD, Cynthia K. Shortell, MD, Joseph D. Raffetto, MD, Hugo Partsch, MD, Lori C. Pounds, MD, Mary E. Cummings, MD, David L. Gillespie, MD, Robert B. McLafferty, MD, Mohammad Hassan Murad, MD, Thomas W. Wakefield, MD, and Peter Gloviczki, MD

Healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency

OBJECTIVE Although newer techniques to promote the healing of leg ulcers associated with chronic venous insufficiency are promising, improved healing rates and cost effectiveness are unproven. We prospectively followed a series of patients who underwent treatment with outpatient compression for venous stasis ulcers without adjuvant techniques to determine healing rates and costs of treatment. METHODS Two hundred fifty-two patients with clinical or duplex scan evidence of chronic venous insufficiency and active leg ulcers underwent treatment with ambulatory compression techniques. The patients were prospectively followed with wound measurements at 1-week to 2-week intervals, and the factors that were associated with delayed healing were determined. RESULTS Of all the ulcers, 57% were healed at 10 weeks of treatment and 75% were healed at 16 weeks. Ultimately, 96% of the ulcers healed, and only 1 major amputation was necessitated (0.4%). Initial ulcer size and moderate arterial insufficiency (ankle brachial index, 0.5 to 0.8; n = 34) were factors that were independently associated with delayed healing (P <.01). Patient age, ulcer duration before treatment, and morbid obesity did not significantly affect healing times. The cost of 10 weeks of outpatient treatment with compression techniques ranged from

Prospective randomized comparison of surgical versus endovascular management of thrombosed dialysis access grafts

1444 to

Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial.

2711. CONCLUSION The treatment of venous stasis ulcers with compression techniques results in reliable, cost-effective healing in most patients. Current adjuvant techniques may prove to be useful but are likely to be cost effective only in a minority of cases, particularly in patients with large initial ulcer size or arterial insufficiency.

The role of air plethysmography in the diagnosis of chronic venous insufficiency

PURPOSE Salvage of thrombosed prosthetic dialysis shunts can be performed using surgical or endovascular techniques. A prospective randomized trial was designed to compare the efficacy of these two methods in restoring dialysis access function. METHODS One hundred fifteen patients with thrombosed dialysis shunts were randomized prospectively to surgical (n = 56) or endovascular (n = 59) therapy. In the surgical group, salvage was attempted with thrombectomy alone in 22% and with thrombectomy plus graft revision in 78%. In the endovascular group, graft function was restored with mechanical (82%) or thrombolytic (18%) graft thrombectomy followed by percutaneous angioplasty. RESULTS Stenosis limited to the venous anastomotic area was the cause of shunt thrombosis in 55% of patients, and long-segment venous outflow stenosis or occlusion was the cause in 30%. In 83% of the surgical group and in 72% of the endovascular group, graft function was immediately restored (p = NS). The postoperative graft function rate was significantly better in the surgical group (p < 0.05). Thirty-six percent of grafts managed surgically remained functional at 6 months and 25% at 12 months. In the endovascular group, 11% were functional at 6 months and 9% by 12 months. Patients with long-segment venous outflow stenosis or occlusion had a significantly worse patency rate than those with venous anastomotic stenosis (p < 0.05). CONCLUSIONS Neither surgical nor endovascular management resulted in long-term function for the majority of shunts after thrombosis. However, surgical management resulted in significantly longer primary patency in this patient population, supporting its use as the primary method of management in most patients in whom shunt thrombosis develops.

Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy

BACKGROUND Many patients with venous leg ulcers do not heal with standard care. HP802-247 is a novel spray-applied cell therapy containing growth-arrested allogeneic neonatal keratinocytes and fibroblasts. We compared different cell concentrations and dosing frequencies of HP802-247 for benefit and harm when applied to chronic venous leg ulcers. METHODS We enrolled adult outpatients from 28 centres in the USA and Canada with up to three ulcers, venous reflux confirmed by doppler ultrasonography, and adequate arterial flow in this phase 2, double-blind, randomised, placebo-controlled trial if at least one ulcer measured 2-12 cm(2) in area and had persisted for 6-104 weeks. Patients were randomly assigned by computer-generated block randomisation in a 1:1:1:1:1 ratio to 5·0×10(6) cells per mL every 7 days or every 14 days, or 0·5×10(6) cells per mL every 7 days or every 14 days, or to vehicle alone every 7 days. All five groups received four-layer compression bandages. The trial sponsor, trial monitors, statisticians, investigators, centre personnel, and patients were masked to treatment allocation. The primary endpoint was mean percentage change in wound area at the end of 12 weeks. Analyses were by intention to treat, excluding one patient who died of unrelated causes before first treatment. This trial is registered with ClinicalTrials.gov NCT00852995. FINDINGS 45 patients were assigned to 5·0×10(6) cells per mL every 7 days, 44 to 5·0×10(6) cells per mL every 14 days, 43 to 0·5 ×10(6) cells per mL every 7 days, 46 to 0·5 ×10(6) cells per mL every 14 days, and 50 to vehicle alone. All required visits were completed by 205 patients. The primary outcome analysis showed significantly greater mean reduction in wound area associated with active treatment compared with vehicle (p=0·0446), with the dose of 0·5 ×10(6) cells/mL every 14 days showing the largest improvement compared with vehicle (15·98%, 95% CI 5·56-26·41, p=0·0028). Adverse events were much the same across all groups, with only new skin ulcers and cellulitis occurring in more than 5% of patients. INTERPRETATION Venous leg ulcers can be healed with a spray formulation of allogeneic neonatal keratinocytes and fibroblasts without the need for tissue engineering, at an optimum dose of 0·5×10(6) cells per mL every 14 days. FUNDING Healthpoint Biotherapeutics.

A Randomized, Controlled Pilot Study of Autologous CD34+ Cell Therapy for Critical Limb Ischemia

PURPOSE The role of air plethysmography (APG) in the diagnosis of venous disease is not well defined. We conducted this study to investigate the value of APG in the diagnosis of chronic venous insufficiency and to determine its correlation with the clinical severity of disease and the anatomic distribution of reflux. METHODS We studied 186 lower extremities with duplex scanning and venography and measured the venous volume, venous filling index (VFI), ejection fraction, and residual volume fraction with APG. Limbs were categorized according to the Society for Vascular Surgery and International Society for Cardiovascular Surgery classification of clinical severity of disease and according to the anatomic distribution of valvular incompetence. RESULTS Sixty-one limbs had no evidence of disease (class 0), 60 limbs had mild disease (classes 1, 2, and 3), and 65 limbs had severe disease (classes 4, 5, and 6). According to the results of duplex scanning and venography, there was no evidence of reflux in 56 limbs. Isolated superficial venous reflux occurred in 52 limbs, and perforator reflux, alone or in conjunction with superficial reflux, occurred in 30. Deep reflux, with or without superficial reflux, was found in 25 limbs. Deep and perforator reflux, with or without superficial reflux, was found in 19 limbs. The VFI had a sensitivity of 80% and 99% positive predictive value for any type of reflux. The VFI was significantly different between groups of limbs with different clinical severities of disease or different types of reflux. The incidence of deep or perforator reflux in limbs with a normal VFI value was 7%, and it was 82% in limbs with a VFI of more than 5. Among 86 limbs with VFI values not corrected with use of a thigh tourniquet, 28% did not have evidence of deep or perforator reflux, and among 15 limbs with VFI values corrected with the use of a tourniquet, 33% had perforator reflux, deep reflux, or both. All APG parameters had low positive predictive values for severe disease or ulceration. The ejection fraction and residual volume fraction did not influence the clinical severity of disease, did not discriminate between types of reflux, and in combination with the VFI did not improve the predictive value of APG. CONCLUSIONS The VFI measured by APG is an excellent predictor of venous reflux, provides an estimate of the clinical severity of disease, and at high levels predicts deep reflux, perforator reflux, or both. Correction of an abnormal VFI with a thigh tourniquet is an unreliable predictor of the absence of deep or perforator incompetence. The predictive value of APG for severe disease or ulceration is poor. The ejection fraction and residual volume fraction, individually or in combination with the VFI, add little to the diagnostic value of APG, and their routine performance may not be clinically justified.

Cellular Therapy With Ixmyelocel-T to Treat Critical Limb Ischemia: The Randomized, Double-blind, Placebo-controlled RESTORE-CLI Trial

OBJECTIVE Elevated inflammatory cytokine levels have been implicated in the pathogenesis of non-healing chronic venous insufficiency (CVI) ulcers. The goal of this study was to determine the protein levels of a wide range of inflammatory cytokines in untreated CVI ulcer tissue before and after 4 weeks of high-strength compression therapy. These levels were compared to cytokines present in healthy tissue. METHODS Thirty limbs with untreated CVI and leg ulceration received therapy for 4 weeks with sustained high-compression bandaging at an ambulatory wound center. Biopsies were obtained from healthy and ulcerated tissue before and after therapy. A multiplexed protein assay was used to measure multiple cytokines in a single sample. Patients were designated as rapid or delayed healers based on ulcer surface area change. RESULTS The majority of pro-inflammatory cytokine protein levels were elevated in ulcer tissue compared to healthy tissue, and compression therapy significantly reduced these cytokines. TGF-beta1 was upregulated in ulcer tissue following compression therapy. Rapid healing ulcers had significantly higher levels of IL-1alpha, IL-1beta, IFN-gamma, IL-12p40, and granulocyte macrophage colony stimulating factor (GM-CSF) before compression therapy, and IL-1 Ra after therapy. IFN-gamma levels significantly decreased following therapy in the rapidly healing patients. CONCLUSION CVI ulcer healing is associated with a pro-inflammatory environment prior to treatment that reflects metabolically active peri-wound tissue that has the potential to heal. Treatment with compression therapy results in healing that is coupled with reduced pro-inflammatory cytokine levels and higher levels of the anti-inflammatory cytokine IL-1 Ra.

Dermagraft®, a bioengineered human dermal equivalent for the treatment of chronic nonhealing diabetic foot ulcer

Background—Critical limb ischemia portends a risk of major amputation of 25% to 35% within 1 year of diagnosis. Preclinical studies provide evidence that intramuscular injection of autologous CD34+ cells improves limb perfusion and reduces amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk critical limb ischemia, who were poor or noncandidates for surgical or percutaneous revascularization (ACT34-CLI). Methods and Results—Twenty-eight critical limb ischemia subjects were randomized and treated: 7 to 1×105 (low-dose) and 9 to 1×106 (high-dose) autologous CD34+ cells/kg; and 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months postinjection, 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.137). This trend continued at 12 months, with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P=0.125; 12 months: P=0.054), with the low-dose and high-dose groups individually showing trends toward improved amputation-free survival at 6 months and 12 months. No adverse safety signal was associated with cell administration. Conclusions—This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later-phase clinical trials. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00616980