An Update on Methods for Revascularization and Expansion of the TASC Lesion Classification to Include Below-the-Knee Arteries: A Supplement to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).

The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today.

An update on methods for revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: A supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II): The TASC steering committee.

The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today.

An Update on Methods for Revascularization and Expansion of the TASC Lesion Classification to Include Below-the-Knee Arteries: A Supplement to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).

The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today.

An Update on Methods for Revascularization and Expansion of the TASC Lesion Classification to Include Below-the-Knee Arteries: A Supplement to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II): The TASC Steering Comittee(.).

The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today.

Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity: an analysis of the PROactive study population.

CONTEXT: Although weight reduction is a recommended goal in type 2 diabetes mellitus (T2DM), weight loss is linked to impaired survival in patients with some chronic cardiovascular diseases. OBJECTIVE: To assess the association of weight and weight change with mortality and non-fatal cardiovascular outcomes (hospitalisation, myocardial infarction and stroke) in T2DM patients with cardiovascular co-morbidity and the effect of pioglitazone-induced weight change on mortality. SETTING AND PARTICIPANTS: We assessed in a post hoc analysis body weight and weight change in relation to outcome in 5202 patients from the PROactive trial population who had T2DM and evidence of pre-existing cardiovascular disease. Patients were randomized to treatment with pioglitazone or placebo in addition to their concomitant glucose-lowering and cardiovascular medication. Mean follow up was 34.5 months. MAIN OUTCOME MEASURE: The impact of body weight and body weight change on all-cause mortality, cardiovascular mortality, on non-fatal cardiovascular events and on hospitalisation. RESULTS: The lowest mortality was seen in patients with BMI 30-35 kg/m(2) at baseline. In comparison to this (reference group), patients in the placebo group with BMI <22 kg/m(2) (Hazard Ratio (95% confidence intervals) 2.96 [1.27 to 6.86]; P=0.012) and BMI 22 to 25 kg/m(2) (HR 1.88 [1.11 to 3.21]; P=0.019) had a higher all-cause mortality. Weight loss was associated with increased total mortality (HR per 1% body weight: 1.13 [1.11 to 1.16]; P<0.0001), with increased cardiovascular mortality, all-cause hospitalisation and the composite of death, myocardial infarction and stroke. Weight loss of ≥7.5% body weight (seen in 18.3% of patients) was the strongest cut-point to predict impaired survival (multivariable adjusted HR 4.42 [3.30 to 5.94]. Weight gain was not associated with increased mortality. Weight gain in patients treated with pioglitazone (mean+4.0±6.1 kg) predicted a better prognosis (HR per 1% weight gain: 0.96 [0.92 to 1.00] P=0.037) compared to patients without weight gain. CONCLUSION: Among patients with T2DM and cardiovascular co-morbidity, overweight and obese patients had a lower mortality compared to patients with normal weight. Weight loss but not weight gain was associated with increased mortality and morbidity. There may be an "obesity paradox" in patients with type 2 diabetes and cardiovascular risk. The original PROactive trial is registered as an International Standard Randomized Controlled Trial (Number ISRCTN NCT00174993).

Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive.

People with type 2 diabetes mellitus have an excess risk of macrovascular disease and a poorer prognosis. PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) was a landmark study of secondary cardiovascular disease (CVD) prevention in type 2 diabetes that suggested a beneficial effect of pioglitazone therapy on macrovascular outcomes. Previous studies have already shown that pioglitazone has a good safety and tolerability profile in people with type 2 diabetes, but PROactive provided an opportunity to assess tolerability and safety associated with long-term exposure in a vulnerable subpopulation at very high cardiovascular risk. This review discusses all the key safety and tolerability characteristics associated with pioglitazone therapy in PROactive. As in previous studies, pioglitazone was associated with typical, but manageable, increases in oedema (26.4% vs 15.1% for placebo) and weight gain (mean change of +3.8 kg vs -0.6 kg for placebo). Increased hypoglycaemia with pioglitazone was consistent with improved glycaemic control. Despite more reports of serious heart failure in the pioglitazone group (5.7% vs 4.1% for placebo), there was a proportional improvement in macrovascular outcomes among patients developing heart failure, and absolute rates of macrovascular events and mortality were similar to those in the placebo group. Liver function tests confirmed the hepatic safety of pioglitazone with long-term use and revealed a tendency to improved hepatic function, which may reflect reductions in liver fat. The comparative incidence of malignancies was similar; however, more cases of bladder neoplasm (14 vs 5) and fewer cases of breast cancer (3 vs 11) were observed in the pioglitazone versus placebo arms of the study. A higher rate of bone fractures observed among pioglitazone-treated female patients (5.1% vs 2.5%) warrants further investigation. Overall, safety and tolerability was predictable, and adverse events were not treatment limiting. These results suggest that any beneficial effects of pioglitazone on macrovascular outcomes are accompanied by good long-term tolerability in this population of very high-risk patients with type 2 diabetes and established CVD.

PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the PROactive study.

Patients with type 2 diabetes face an increased risk of macrovascular disease compared to those without. Significant reductions in the risk of major cardiovascular events can be achieved with appropriate drug therapy, although patients with type 2 diabetes remain at increased risk compared with non-diabetics. The thiazolidinedione, pioglitazone, is known to offer multiple, potentially antiatherogenic, effects that may have a beneficial impact on macrovascular outcomes, including long-term improvements in insulin resistance (associated with an increased rate of atherosclerosis) and improvement in the atherogenic lipid triad (low HDL-cholesterol, raised triglycerides, and a preponderance of small, dense LDL particles) that is observed in patients with type 2 diabetes. The recent PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study showed that pioglitazone can reduce the risk of secondary macrovascular events in a high-risk patient population with type 2 diabetes and established macrovascular disease. Here, we summarize the key results from the PROactive study and place them in context with other recent outcome trials in type 2 diabetes.

Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08).

OBJECTIVE: PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. RESEARCH DESIGN AND METHODS: PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. RESULTS: More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025). CONCLUSIONS: Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.

The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study.

OBJECTIVES: This analysis from the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study assesses the effects of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes and a previous myocardial infarction (MI). BACKGROUND: People with type 2 diabetes have an increased incidence of MI compared with the general population. Those with diabetes and MI have a worse prognosis than nondiabetic patients with cardiovascular disease. METHODS: The PROactive study was a prospective, multicenter, double-blind, placebo-controlled trial of 5,238 patients with type 2 diabetes and macrovascular disease. Patients were randomized to either pioglitazone or placebo in addition to their other glucose-lowering and cardiovascular medication. Treatment of diabetes, dyslipidemia, and hypertension was encouraged according to the International Diabetes Federation guidelines. Patients were followed for a mean of 2.85 years. The primary end point was the time to first occurrence of macrovascular events or death. Of the total cohort, the subgroup of patients who had a previous MI (n = 2,445 [46.7%]; n = 1,230 in the pioglitazone group and n = 1,215 in the placebo group) was evaluated using prespecified and post-hoc analyses. RESULTS: Pioglitazone had a statistically significant beneficial effect on the prespecified end point of fatal and nonfatal MI (28% risk reduction [RR]; p = 0.045) and acute coronary syndrome (ACS) (37% RR; p = 0.035). There was a 19% RR in the cardiac composite end point of nonfatal MI (excluding silent MI), coronary revascularization, ACS, and cardiac death (p = 0.033). The difference in the primary end point defined in the main PROactive study did not reach significance in the MI population (12% RR; p = 0.135). The rates of heart failure requiring hospitalization were 7.5% (92 of 1,230) with pioglitazone and 5.2% (63 of 1,215) with placebo. Fatal heart failure rates were similar (1.4% [17 of the 92] with pioglitazone versus 0.9% [11 of the 63] with placebo). CONCLUSIONS: In high-risk patients with type 2 diabetes and previous MI, pioglitazone significantly reduced the occurrence of fatal and nonfatal MI and ACS. (PROspective pioglitAzone Clinical Trial In macroVascular Events; http://www.clinicaltrials.gov/ct/show/NCT00174993?order = 1; ISRCTN NCT00174993).

Adjunctive parenteral therapy with lipo-ecraprost, a prostaglandin E1 analog, in patients with critical limb ischemia undergoing distal revascularization does not improve 6-month outcomes.

PURPOSE: In patients with critical limb ischemia (CLI), distal revascularization remains the procedure of choice for preventing limb loss, but long-term outcomes for pain relief, wound healing, and prevention of amputation remain suboptimal. Prostaglandin drug therapy as an adjuvant to revascularization may improve these outcomes. The current trial was designed to test the hypothesis that the use of lipo-ecraprost, a lipid encapsulated prostaglandin E(1) prodrug, as an adjunctive therapy after distal revascularization would improve amputation-free survival in patients with CLI. METHODS: The study was randomized, multicenter, double blind, and placebo controlled. Patients meeting clinical and hemodynamic criteria for CLI who were undergoing either bypass or endovascular revascularization of the below knee popliteal or more distal arteries were randomized to receive placebo or a 60-microg dose of lipo-ecraprost administered intravenously starting

Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04).

BACKGROUND AND PURPOSE: Diabetes is an important risk factor for stroke. We conducted analyses in patients who had entered the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) with a history of stroke or without stroke. METHODS: The prospective, double-blind PROactive (mean duration, 34.5 months) randomized 5238 patients with type 2 diabetes and a history of macrovascular disease to pioglitazone (titrated to 45 mg) or placebo, in addition to current diabetes and cardiovascular medications. Cardiovascular end-point events were independently adjudicated. This analysis evaluated the risk of stroke and other cardiovascular outcomes in patients with (n=984) and without (n=4254) prior stroke. RESULTS: In patients with previous stroke (n=486 in the pioglitazone group and n=498 in the placebo group), there was a trend of benefit with pioglitazone for the primary end point of all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac intervention (including coronary artery bypass graft or percutaneous coronary intervention), stroke, major leg amputation, or bypass surgery or leg revascularization (hazard ratio[HR]=0.78, event rate=20.2% pioglitazone vs 25.3% placebo; 95% CI=0.60-1.02; P=0.0670) and for the main secondary end point of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.78, event rate=15.6% pioglitazone vs 19.7% placebo; 95% CI=0.58-1.06; P=0.1095). Pioglitazone reduced fatal or nonfatal stroke (HR=0.53, event rate=5.6% pioglitazone vs 10.2% placebo; 95% CI=0.34-0.85; P=0.0085) and cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.72, event rate=13.0% pioglitazone vs 17.7% placebo; 95% CI=0.52-1.00; P=0.0467). Higher event rates were observed in patients with prior stroke compared with those without prior stroke. In patients without prior stroke, no treatment effect was observed for a first stroke. CONCLUSIONS: In a subgroup analysis from PROactive, pioglitazone reduced the risk of recurrent stroke significantly in high-risk patients with type 2 diabetes.

Parenteral therapy with lipo-ecraprost, a lipid-based formulation of a PGE1 analog, does not alter six-month outcomes in patients with critical leg ischemia.

PURPOSE: Eicosanoids with vasodilating and angiogenic properties have been postulated to be effective therapies for critical leg ischemia (CLI) secondary to atherosclerotic peripheral arterial disease. The ability to deliver active drug to the site of action at adequate doses for sufficient duration has been a major limitation in the clinical development of such therapies. Lipo-ecraprost is a lipid-encapsulated prostaglandin E1 prodrug with the potential to deliver active prostaglandin to the site of critical arterial ischemia. The current trial was designed to test the hypothesis that lipo-ecraprost would improve amputation-free survival in patients with CLI who had no revascularization options. METHODS: The study was randomized, multicenter, double blind, and placebo controlled. Patients who met clinical and hemodynamic criteria were randomized to receive placebo or lipo-ecraprost (60 microg) administered intravenously on each of 5 days per week, for a total of 8 weeks. The study's primary endpoint was the rate of a composite end point of death or amputation above the level of the ankle at 180 days (6 months). RESULTS: The study was terminated on a recommendation from the Data and Safety Monitoring Board after the completion of a protocol-specified interim analysis for futility. At the time of termination, 383 of the planned 560 patients had been randomized, of which 379 received at least one dose of study medication and thus were included in the intention-to-treat population. Twenty-three patients were lost to follow-up and were not available for 6-month assessments. At 6 months of follow-up, there were 23 amputations in the 177 patients who received placebo, and 29 amputations in the 179 patients randomized to lipo-ecraprost. At 6 months, 10 deaths had occurred in the placebo group and 18 deaths had occurred in the lipo-ecraprost arm. Changes in lower-extremity hemodynamics over the 6-month study period did not differ between the placebo and lipo-ecraprost treatment arms. CONCLUSION: Intensive treatment with lipo-ecraprost failed to modify the 6-month amputation rate in patients with CLI who were not candidates for revascularization.

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.

BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients.

OBJECTIVE: The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) assesses the effect of pioglitazone, a peroxisome proliferator-activated receptor agonist, with anti-inflammatory and vascular properties, on the secondary prevention of macrovascular events in type 2 diabetes. RESEARCH DESIGN AND METHODS: PROactive is an on-going randomized, double-blind outcome study in patients with type 2 diabetes managed with diet and/or oral blood glucose-lowering drugs (combination of oral agents with insulin is permitted) who have a history of macrovascular disease. Patients are randomized to receive pioglitazone (forced titration from 15 to 30 to 45 mg, depending on tolerability) or placebo in addition to existing therapy. The primary end point is the time from randomization to occurrence of a new macrovascular event or death. Follow-up is estimated to span 4 years. RESULTS: A total of 5238 patients have been randomized from 19 countries. At entry into the study, patients enrolled are a mean age of 61.8 years, with type 2 diabetes for a mean of 9.5 years; 60.9 and 61.5% are taking metformin or a sulfonylurea, respectively; and 33.6% are using insulin in addition to oral glucose-lowering drugs. The majority of patients are men (66.1%). Patients are required to meet one or more of entry criteria, as follows: >6 months' history of myocardial infarction (46.7%); coronary artery revascularization (30.8%), stroke (18.8%), or acute coronary syndrome for >3 months (13.7%); other evidence of coronary artery disease (48.1%); or peripheral arterial occlusive disease (19.9%). One-half (48.5%) of the patients have two or more of these risk factors. Three-quarters (75.4%) have hypertension, and 58.8% are current or previous smokers. CONCLUSIONS: The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events. The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes.

Therapeutic angiogenesis for critical limb ischemia: design of the hepatocyte growth factor therapeutic angiogenesis clinical trial.

The objective of the HGF-STAT clinical trial is to determine whether perfusion can be improved by gene transfer with a plasmid DNA containing hepatocyte growth factor (HGF) in the affected limb of patients with unreconstructable critical limb ischemia (CLI). CLI results in a high rate of limb loss and impaired quality of life. The current therapeutic strategies, including bypass surgery and percutaneous interventions, are only successful in treating a subset of patients. Therapeutic angiogenesis is an investigational method that seeks to favorably impact tissue perfusion in CLI. HGF-STAT is a double-blind, parallel-group, placebo-controlled, dose-response study in 100 patients with unreconstructable CLI. Eligible subjects will be randomized 1:1:1:1 to receive saline placebo or one of three dose/regimens of HGF plasmid DNA. The selection of outcome measures, including the primary endpoint, and changes in transcutaneous oxygen pressure (TcPO2) from baseline to 3 months will be discussed. In conclusion, this study will help to determine whether therapeutic angiogenesis with HGF is a viable option in the treatment of patients with CLI.