238 A randomized, double-blind placebo-controlled study of NV1FGF gene therapy in critical limb ischemia patients (TAMARIS Study) Rationale, design and baseline patient characteristics

BackgroundPatients with critical limb ischemia (CLI) unsuitable for revascularization have a high rate of amputation and mortality (30% and 25% at 1 year respectively Local gene therapy using plasmid DNA encoding acidic fibroblast growth factor (NV1FGF, riferminogene pacaplasmid) showed promising results in a phase II trial on amputation free survival. This report provides the rationale, design and baseline characteristics of CLI patients enrolled to the pivotal phase III trial (TAMARIS). It also describes baseline characteristics by diabetes status and region of origin.Table: Comparison of 6 modes of ABI calculation to predict the 5-years mortality (abstract 237).ABI mode of calculationHigh/HighMean/HighLow/HighHigh/MeanMean/MeanLow/MeanAUC0.632*0.6200.6150.6100.6180.598Sensitivity with 0.9055.7%56.7%60.4%53.6%60.8%58.8%Specificity with 0.9065.1%62.3%60.2%63.6%58.5%58.6%Optimal cutpoint0.940.970.921.000.970.92Sensitivity for optimal cutpoint63.9%72.2%64.6%72.2%74.2%62.9%Specificity for optimal cutpoint60.3%50.6%58.7%48.3%50.3%57.5%*p<0.05 vs. High/Mean and Low/MeanMethodsAn international, double-blind, placebo-controlled, randomized study included 525 CLI patients worldwide who were unsuitable for revascularization and had non-healing skin lesions, to evaluate whether repeated intramuscular administration of NV1FGF results in reduction of major amputations or deaths at 1 year.ResultsMean age of the population was 70 ± 10 years including 70% males and 53% diabetic patients. Fifty four percent of the population had previous lower extremity revascularization and 22% had previous minor amputation of the index leg. Ninety six percent of patients had an ankle pressure < 70mmHg and/or a toe pressure < 50mmHg or a TcPO2 < 30mmHg. In 94% the index leg had distal occlusive disease affecting arteries below the knee. Statins were prescribed in 54% of patients, and antiplatelet drugs in 80%. Variation in region of origin resulted in only minor demographic imbalance. Patients with diabetes had more risk factors including history of coronary artery disease, but were similar to non-diabetic patients regarding limb haemodynamics and vascular lesions.ConclusionThe clinical and vascular anatomy presentation of patients with CLI with ischemic skin lesions who were unsuitable for revascularization was homogeneous with little imbalance according to region of origin or diabetic status. The findings from this large CLI cohort are important for the understanding of the epidemiology of the disease

The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine

BACKGROUND: Diabetes mellitus continues to grow in global prevalence and to consume an increasing amount of health care resources. One of the key areas of morbidity associated with diabetes is the diabetic foot. To improve the care of patients with diabetic foot and to provide an evidence-based multidisciplinary management approach, the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine developed this clinical practice guideline. METHODS: The committee made specific practice recommendations using the Grades of Recommendation Assessment, Development, and Evaluation system. This was based on five systematic reviews of the literature. Specific areas of focus included (1) prevention of diabetic foot ulceration, (2) off-loading, (3) diagnosis of osteomyelitis, (4) wound care, and (5) peripheral arterial disease. RESULTS: Although we identified only limited high-quality evidence for many of the critical questions, we used the best available evidence and considered the patients' values and preferences and the clinical context to develop these guidelines. We include preventive recommendations such as those for adequate glycemic control, periodic foot inspection, and patient and family education. We recommend using custom therapeutic footwear in high-risk diabetic patients, including those with significant neuropathy, foot deformities, or previous amputation. In patients with plantar diabetic foot ulcer (DFU), we recommend off-loading with a total contact cast or irremovable fixed ankle walking boot. In patients with a new DFU, we recommend probe to bone test and plain films to be followed by magnetic resonance imaging if a soft tissue abscess or osteomyelitis is suspected. We provide recommendations on comprehensive wound care and various débridement methods. For DFUs that fail to improve (>50% wound area reduction) after a minimum of 4 weeks of standard wound therapy, we recommend adjunctive wound therapy options. In patients with DFU who have peripheral arterial disease, we recommend revascularization by either surgical bypass or endovascular therapy. CONCLUSIONS: Whereas these guidelines have addressed five key areas in the care of DFUs, they do not cover all the aspects of this complex condition. Going forward as future evidence accumulates, we plan to update our recommendations accordingly

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

Critical limb ischemia (CLI) portends a risk of major amputation of 25-35% within 1 year of diagnosis. Pre-clinical studies provide evidence that intramuscular injection of autologous CD34+ cells improve limb perfusion and reduce 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 CLI who were poor or non-candidates for surgical or percutaneous revascularization (ACT34-CLI)

Foot ulcers in the diabetic patient, prevention and treatment

Stephanie C Wu1, Vickie R Driver1, James S Wrobel2, David G Armstrong21Center for Lower Extremity Ambulatory Research,William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine and Science, and National Center of Limb Salvage, Advocate Lutheran General Hospital, Chicago, IL, USA; 2Center for Lower Extremity Ambulatory Research, Dr. William M. Scholl College of Podiatric Medicine at Rosalind Franklin University of Medicine, Chicago, IL, USAAbstract: Lower extremity complications in persons with diabetes have become an increasingly significant public health concern in both the developed and developing world. These complications, beginning with neuropathy and subsequent diabetic foot wounds frequently lead to infection and lower extremity amputation even in the absence of critical limb ischemia. In order to diminish the detrimental consequences associated with diabetic foot ulcers, a common-sense-based treatment approach must be implemented. Many of the etiological factors contributing to the formation of diabetic foot ulceration may be identified using simple, inexpensive equipment in a clinical setting. Prevention of diabetic foot ulcers can be accomplished in a primary care setting with a brief history and screening for loss of protective sensation via the Semmes-Weinstein monofilament. Specialist clinics may quantify neuropathy, plantar foot pressure, and assess vascular status with Doppler ultrasound and ankle-brachial blood pressure indices. These measurements, in conjunction with other findings from the history and physical examination, may enable clinicians to stratify patients based on risk and help determine the type of intervention. Other effective clinical interventions may include patient education, optimizing glycemic control, smoking cessation, and diligent foot care. Recent technological advanced combined with better understanding of the wound healing process have resulted in a myriad of advanced wound healing modalities in the treatment of diabetic foot ulcers. However, it is imperative to remember the fundamental basics in the healing of diabetic foot ulcers: adequate perfusion, debridement, infection control, and pressure mitigation. Early recognition of the etiological factors along with prompt management of diabetic foot ulcers is essential for successful outcome.Keywords: diabetes, ulcer, prevention, infection, amputatio

Podiatrist care and outcomes for patients with diabetes and foot ulcer

We examined whether outcomes of care (amputation and hospitalisation) among patients with diabetes and foot ulcer differ between those who received pre‐ulcer care from podiatrists and those who did not. Adult patients with diabetes and a diagnosis of a diabetic foot ulcer were found in the MarketScan Databases, 2005–2008. Multivariate Cox proportional hazard models estimated the hazard of amputation and hospitalisation. Logistic regression estimated the likelihood of these events. Propensity score weighting and regression adjustment were used to adjust for potentially different characteristics of patients who did and did not receive podiatric care. The sample included 27 545 patients aged greater than 65+ years (Medicare‐eligible patients with employer‐sponsored supplemental insurance) and 20 208 patients aged lesser than 65 years (non Medicare‐eligible commercially insured patients). Care by podiatrists in the year prior to a diabetic foot ulcer was associated with a lower hazard of lower extremity amputation, major amputation and hospitalisations in both non Medicare‐eligible commercially insured and Medicare‐eligible patient populations. Systematic differences between patients with diabetes and foot ulcer, receiving and not receiving care from podiatrists were also observed; specifically, patients with diabetes receiving care from podiatrists tend to be older and sicker.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109633/1/iwj12021.pd

Case studies evaluating transdermal continuous oxygen for the treatment of chronic sickle cell ulcers

Objective: Refractory leg ulcerations are common in homozygous sickle cell anemia. In this case series, patients were treated with transdermal continuous oxygen therapy (TCOT), based on the hypothesis that oxygen deprivation caused by arteriovenous shunting may be remedied by providing oxygen directly to the wound bed. The authors believe this is the first attempt to treat sickle cell ulcers with TCOT. Case Presentation: Five patients with long histories of recurring sickle cell disease ulcers that would not heal with various conventional and/or other adjunctive wound healing modalities were treated with TCOT. The patients had recurring nonhealing wounds for 30, 21, 20, 20, and 15 years, respectively. All 5 patients healed or showed substantial improvement in the treatment periods of 3 to 36 weeks. Conclusion: The authors conclude that TCOT may be a novel, effective, and inexpensive modality in treating patients with sickle cell disease ulcers. Improvement was typically noticeable within 2 weeks. Further clinical trials may be considered to evaluate the efficacy of TCOT in sickle cell ulcers