edifoligide and Ischemia

Vein bypass surgery is an effective therapy for atherosclerotic occlusive disease in the coronary and peripheral circulations; however, long-term results are limited by progressive attrition of graft patency. Failure of vein bypass grafts in patients with critical limb ischemia results in morbidity, limb loss, and additional resource use. Although technical factors are known to be critical to the success of surgical revascularization, patient-specific risk factors are not well defined. In particular, the relationship of race/ethnicity and gender to the outcomes of peripheral bypass surgery has been controversial.. We analyzed the Project of Ex Vivo Vein Graft Engineering via Transfection III (PREVENT III) randomized trial database, which included 1404 lower extremity vein graft operations performed exclusively for critical limb ischemia at 83 North American centers. Trial design included intensive ultrasound surveillance of the bypass graft and clinical follow-up to 1 year. Multivariable modeling (Cox proportional hazards and propensity score) was used to examine the relationships of demographic variables to clinical end points, including perioperative (30-day) events and 1-year outcomes (vein graft patency, limb salvage, and patient survival). Final propensity score models adjusted for 16 covariates (including type of institution, technical factors, selected comorbidities, and adjunctive medications) to examine the associations between race, gender, and outcomes. Among the 249 black patients enrolled in PREVENT III, 118 were women and 131 were men. Black men were at increased risk for early graft failure (hazard ratio [HR], 2.832 for 30-day failure; 95% confidence interval [CI], 1.393 to 5.759; P=0.0004), even when the analysis was restricted to exclude high-risk venous conduits. Black patients experienced reduced secondary patency (HR, 1.49; 95% CI, 1.08 to 2.06; P=0.016) and limb salvage (HR, 2.02; 95% CI, 1.27 to 3.20; P=0.003) at 1 year. Propensity score models demonstrate that black women were the most disadvantaged, with an increased risk for loss of graft patency (HR, 2.02 for secondary patency; 95% CI, 1.27 to 3.20; P=0.003) and major amputation (HR, 2.38; 95% CI, 1.18 to 4.83; P=0.016) at 1 year. Perioperative mortality and 1-year mortality were similar across race/gender groups.. Black race and female gender are risk factors for adverse outcomes after vein bypass surgery for limb salvage. Graft failure and limb loss are more common events in black patients, with black women being a particularly high-risk group. These data suggest the possibility of an altered biological response to vein grafting in this population; however, further studies are needed to determine the mechanisms underlying these observed disparities in outcome.

Topics: Aged; Asian People; Black People; Comorbidity; Female; Follow-Up Studies; Hispanic or Latino; Humans; Incidence; Ischemia; Limb Salvage; Male; Oligonucleotides; Peripheral Vascular Diseases; Risk Factors; Sex Distribution; Survival Analysis; Treatment Failure; Vascular Patency; Vascular Surgical Procedures; Veins; White People

Evidence suggesting a beneficial effect of cardioprotective medications in patients with lower extremity atherosclerosis derives largely from secondary prevention studies of heterogeneous populations. Patients with critical limb ischemia (CLI) have a large atherosclerotic burden with related high mortality. The effect of such therapies in this population is largely inferred and unproven.. The Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III) cohort comprised 1404 patients with CLI who underwent lower extremity bypass grafting in a multicenter, randomized prospective trial testing the efficacy of edifoligide for the prevention of graft failure. Propensity scores were used to evaluate the influence of statins, beta-blockers, and antiplatelet agents on outcomes while adjusting for demographics, comorbidities, medications, and surgical variables that may influence drug use. Primary outcomes were major adverse cardiovascular events < or =30 days, vein graft patency, and 1-year survival assessed by Kaplan-Meier method. Potential determinants of 1-year survival were modeled using a multivariate Cox regression.. In this cohort, 636 patients (45%) were taking statins, 835 (59%) were taking beta-blockers, and 1121 (80%) were taking antiplatelet drugs. Perioperative major adverse cardiovascular events (7.8%) and early mortality (2.7%) were not measurably affected by the use of any drug class. Statin use was associated with a significant survival advantage at 1 year of 86% vs 81% (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.98; P = .03) by analysis of both unweighted and propensity score-weighted data. Use of beta-blockers and antiplatelet drugs had no appreciable impact on survival. None of the drug classes were associated with graft patency measures at 1 year. Significant predictors of 1-year mortality by Cox regression modeling were statin use (HR, 0.67; 95% CI, 0.51-0.90; P = .001), age >75 (HR, 2.1; 95% CI, 1.60-2.82; P = .001), coronary artery disease (HR, 1.5; 95% CI, 1.15-2.01; P = .001), chronic kidney disease stages 4 (HR, 2.0; 95% CI, 1.17-3.55; P = .001) and 5 (HR, 3.4; 95% CI, 2.39-4.73; P < .001), and tissue loss (HR, 1.9; 95% CI, 1.23-2.80; P = .003).. Statin use is associated with improved survival in CLI patients 1 year after surgical revascularization. Further studies are indicated to determine optimal dosing in this population and to definitively address the question of relationship to graft patency. These data add to the growing literature supporting statin use in patients with advanced peripheral arterial disease.

Topics: Adrenergic beta-Antagonists; Aged; Arteriosclerosis; Cardiotonic Agents; Cardiovascular Diseases; Female; Graft Survival; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemia; Leg; Male; Oligonucleotides; Platelet Aggregation Inhibitors; Prospective Studies; Transplantation, Autologous; Vascular Patency; Veins

Data supporting the utility of percutaneous treatment to maintain vein graft patency have been limited to a collection of single-institution, retrospective analyses. Using the prospective, multi-institutional PREVENT III database, we sought to define the outcomes for endovascular vs surgical vein bypass graft revision and to define predictors for the success or failure of these interventions.. A nested cohort study of 1404 patients in the PREVENT III trial who underwent infrainguinal vein bypass grafting for critical limb ischemia was performed to identify those patients who underwent either open surgical or endovascular graft revision. All patients in PREVENT III were followed up for 1 year from the initial bypass operation. The following were modeled as end points from the time of the initial open surgical or endovascular revision: freedom from graft reintervention, occlusion, amputation, and death.. A total of 156 open surgical and 134 endovascular reinterventions were performed, with a mean follow-up after revision of 193 and 151 days, respectively. Although the demographics for each group were similar, the choice of repair was influenced by the interval between the index graft placement and the initial revision, with a high percentage of the early graft revisions treated with an open surgical procedure (0-1 months: 84% open surgical vs 16% endovascular; P < .001). The primary end point (ie, failure resulting in repeat graft revision, graft occlusion, or major amputation) was reached in 30.2% of the endovascular and 26.2% of the open surgical individuals, with significant improvements in the durability of graft revisions noted in the open surgical group (12-month amputation-/revision-free survival of 75% for the open surgical and 56% for the endovascular group; hazard ratio, 2.2; 95% confidence interval, 0.92-5.26; P = .043). Furthermore, subgroup analysis revealed this benefit to be most profound within the subset of thrombosed grafts undergoing salvage (P = .006). For revisions performed to treat graft stenosis, early outcomes were similar, with a trend favoring the open surgical group developing beyond 6 months. Although 80% of open surgical and 64% of endovascular-revised grafts required no further intervention, endovascular revisions necessitated significantly more reinterventions to maintain patency. The mean hospital lengths of stay (open surgical, 2.1 days; endovascular, 1.7 days) and quality of life at completion of the study (VascuQoL: open surgical, 4.72; endovascular, 4.76) were similar between the groups.. Open surgical revision of infrainguinal vein grafts provides an increased freedom from further reinterventions or major amputation, but early success rates for endovascular procedures were similar, particularly for nonoccluded grafts. With time, endovascular revisions necessitate an increasing number of reinterventions and manifest higher rates of failure.

Topics: Aged; Amputation, Surgical; Angioplasty; Cardiovascular Agents; Critical Illness; Double-Blind Method; Extremities; Female; Graft Occlusion, Vascular; Humans; Ischemia; Length of Stay; Male; North America; Oligonucleotides; Patient Selection; Prospective Studies; Quality of Life; Reoperation; Risk Assessment; Risk Factors; Secondary Prevention; Time Factors; Treatment Failure; Ultrasonography, Doppler, Duplex; Vascular Patency; Vascular Surgical Procedures; Veins

The influence of operator-dependent variables on the outcomes of lower extremity bypass (LEB) surgery have primarily been reported in single-institution, retrospective studies. We utilized data from a prospective, multicenter trial to identify technical variables that were significantly associated with early and midterm results of autogenous LEB for limb salvage.. The PREVENT III trial database includes 1404 North American patients with critical limb ischemia (CLI) who underwent LEB using excised autogenous vein. The study protocol excluded claudicants and in situ reconstructions. Technical factors analyzed included vein diameter, conduit type, graft length, vein orientation, location of proximal and distal anastomoses, and performance of completion imaging. Univariate analysis was used to determine the effect of these factors on 30 day and 1-year outcomes. Multivariate Cox regression models evaluated the influence of these factors while adjusting for age, sex, race, tobacco, diabetes, dialysis-dependency, previous index limb bypass, and study drug (edifoligide) administration. The primary outcomes were primary patency (PP), primary assisted patency (PAP), and secondary patency (SP) assessed by Kaplan-Meier method.. Univariate analysis revealed that vein diameter <3.5 mm and composite graft type were significantly associated with early (30 day) graft failure. At 1 year, multivariate analysis revealed that patency rates were negatively associated with diameter <3.5 mm (PP, PAP, SP), non-great saphenous vein (GSV) type (PP, SP), and graft lengths >50 cm (PP only). Limb salvage and survival at 1 year were not significantly impacted by technical variables. Employing a prespecified trial definition of high-risk conduits (diameter <3mm or nonsingle segment GSV; 24% of entire cohort) revealed that use of such conduits was associated with a 2.1-fold increased risk of 30 day graft failure (P < .05), as well as reduced PP, PAP, and SP at 1 year. Use of a high-risk conduit was also associated with an increased index length of stay (mean 9.37 vs 8.71 days, P = .03) and a greater number of reinterventions (mean 0.67 vs 0.42, P < .0001) over the ensuing year.. In this large, multicenter cohort of patients undergoing LEB for CLI, vein diameter and conduit type were the dominant technical determinants of early and late graft failure. High-risk conduits and longer grafts may benefit from aggressive postoperative graft surveillance.

Topics: Aged; Aged, 80 and over; Cardiovascular Agents; Double-Blind Method; Extremities; Female; Graft Occlusion, Vascular; Humans; Ischemia; Length of Stay; Limb Salvage; Male; Middle Aged; North America; Oligonucleotides; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Transplantation, Autologous; Treatment Failure; Ultrasonography; Vascular Patency; Vascular Surgical Procedures; Veins

Infrainguinal bypass (IB) surgery is an effective means of improving arterial circulation to the lower extremity for patients with critical limb ischemia (CLI). However, wound complications (WC) of the surgical incision following IB can impart significant morbidity.. A retrospective analysis of WC from the 1404 patients enrolled in a multicenter clinical trial of vein bypass grafting for CLI was performed. Univariate and multivariable regression models were used to determine WC predictors and associated outcomes, including graft patency, limb salvage, quality of life (QoL), resource utilization (RU), and mortality.. A total of 543 (39%) patients developed a reported WC within 30 days of surgery, with infections (284, 52%) and hematoma/hemorrhage (121, 22%) being the most common type. Postoperative anticoagulation (odds ratio [OR], 1.554; 95% confidence interval [CI] 1.202 to 2.009; P = .0008) and female gender (OR, 1.376; 95% CI, 1.076 to 1.757; P = .0108) were independent factors associated with WC. Primary, primary-assisted, and secondary graft patency rates were not influenced by the presence of WC; though, patients with WC were at increased risk for limb loss (hazard ratio [HR], 1.511; 95% CI 1.096 to 2.079; P = .0116) and higher mortality (HR, 1.449; 95% CI 1.098 to 1.912; P = .0089). WC was not significantly associated with lower QoL at 3 months (4.67 vs 4.79, P = .1947) and 12 months (5.02 vs 5.13, P = .2806). However, the subset of patients with serious WC (SWC) demonstrated significantly lower QoL at 3 months compared with patients without WC, (4.43 vs 4.79, respectively, P = .0166), though this difference was not seen at 12 months (4.94 vs 5.13, P = .2411). Patients with WC had higher RU than patients who did not have WC. Mean index length of hospital stay (LOS) was 2.3 days longer, mean cumulative 1-year LOS was 8.1 days longer, and mean number of hospitalizations was 0.5 occurrences greater for patients with WC compared with patients without WC (all P < .0001).. WC is a frequent complication of IB for CLI, associated with increased risk for major amputation, mortality, and greater RU. Further detailed investigation into the link between female gender and oral anticoagulation use with WC may help identify causes of WC and perhaps prevent or lessen their occurrence.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cardiovascular Agents; Extremities; Female; Graft Occlusion, Vascular; Health Care Costs; Health Resources; Hematoma; Humans; Incidence; Ischemia; Limb Salvage; Male; Middle Aged; North America; Odds Ratio; Oligonucleotides; Postoperative Hemorrhage; Quality of Life; Retrospective Studies; Risk Assessment; Risk Factors; Sex Factors; Surgical Wound Infection; Transplantation, Autologous; Treatment Outcome; Vascular Patency; Vascular Surgical Procedures; Veins

Patients who require infrainguinal revascularization for critical limb ischemia (CLI) are at elevated risk for cardiovascular events. The PREVENT III study was a prospective, randomized, multicenter, phase 3 trial of edifoligide for the prevention of vein graft failure in patients with CLI. We examined the baseline characteristics, perioperative medical therapies, and 30-day incidence of major cardiovascular events in the PREVENT III cohort.. Demographics, medical and surgical history, mode of presentation for the index limb, procedural details, and concomitant medications were reviewed for all patients enrolled in PREVENT III (N = 1,404). Major adverse cardiovascular events, including death, myocardial infarction, or cerebrovascular event (stroke or transient ischemic attack) were tabulated. Univariate and multivariate analyses were performed to discern factors that were associated with the utilization of medical therapies and with perioperative events.. Demographics and comorbidities reflected a population with diffuse, advanced atherosclerosis. Perioperative mortality was 2.7%, and major morbidity included myocardial infarction in 4.7% and stroke/transient ischemic attack in 1.4%. Among this population of CLI patients, 33% were not on antiplatelet therapy at study entry, and 24% were not receiving antithrombotics of any type. In addition, 54% of patients were not receiving lipid-lowering therapy, and 52% were not prescribed beta-blocker medications at study entry. On multivariate analysis, race was a significant determinant of antithrombotic utilization, with African-American patients less frequently treated both at baseline and discharge (adjusted odd ratios, 0.5 and 0.6, P < .0001). Antithrombotic and beta-blocker drug usage increased in the overall cohort from baseline (76% and 48%) to discharge (88% and 60%; P < .0001). Patients treated in a university hospital setting were more likely to be prescribed antiplatelet, lipid-lowering, and beta-blocker medications. Advanced age (>75 years), coronary artery disease (prior myocardial infarction or revascularization), and dialysis-dependent renal failure were associated with an increased 30-day risk of death, myocardial infarction, or stroke. Protective effects of beta-blocker and lipid-lowering medications were noted in these defined subgroups.. A significant percentage of the population that undergoes surgical revascularization for CLI is not prescribed therapies of proven benefit in reducing cardiovascular events. Utilization of antithrombotics and beta-blockers increases during hospitalization for limb salvage surgery but that of lipid-lowering therapy does not. African-American patients appear to be at greater risk for undertreatment with antithrombotics, and the data suggest that patients undergoing leg bypass surgery in a university hospital setting receive more comprehensive medical treatment of atherosclerosis. Treatment guidelines for medical therapy are needed to standardize care and improve outcomes for patients with CLI.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Vessel Prosthesis; Cardiotonic Agents; Chi-Square Distribution; Clinical Trials, Phase III as Topic; DNA; Double-Blind Method; Female; Graft Occlusion, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inguinal Canal; Ischemia; Leg; Limb Salvage; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Oligonucleotides; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors