edifoligide and Graft-Occlusion--Vascular

Surgical bypass of arterial occlusions using autogenous vein provides an effective treatment for many patients with advanced coronary or peripheral atherosclerosis. However, the long-term benefit of bypass surgery is limited by the development of de novo occlusive lesions within the vein graft, which occurs in a significant percentage of patients over time. The pathophysiology of vein graft failure involves a complex interplay between an acute vascular injury response and the hemodynamic adaptation of the vein to arterial forces. Cell proliferation, inflammation, and matrix metabolism are critical components of postimplantation remodeling. Conventional pharmacotherapy has had limited impact on graft failure. Vein grafts present a unique and attractive opportunity for molecular engineering, which is defined for purposes of this review as the local application of genomic (eg, gene transfer or gene inhibition) or proteomic interventions designed to alter the healing response. The critical enabling technologies for these strategies are described, with a perspective on preclinical and clinical development for this indication. The recently completed clinical trials of edifoligide (E2F decoy oligodeoxynucleotide) provide important lessons for future studies. A better understanding of the remodeling response of vein grafts in humans is required to design effective molecular therapies and to define the appropriate target populations and surrogate markers for future clinical trials.

Topics: Animals; Arterial Occlusive Diseases; Drug Carriers; Gene Transfer Techniques; Genetic Engineering; Genetic Therapy; Genomics; Graft Occlusion, Vascular; Graft Survival; Humans; Oligonucleotides; Proteomics; Tissue Engineering; Transplantation, Autologous; Treatment Outcome; Vascular Patency; Vascular Surgical Procedures; Veins

The era of genomics and recombinant DNA technology has ushered in an entirely new class of therapeutic agents designed to influence disease progression at a genetic level. The scope and utility of this technology is not fully realized. However, multiple trials of therapeutic agents have been completed and many more are ongoing. Here we report on edifoligide, a double-stranded oligodeoxynucleotide (ODN) that competitively inhibits the transcription factor E2F, a critical regulator of the cell cycle. Edifoligide has undergone extensive clinical testing for the treatment of intimal hyperplasia following vascular bypass procedures. In this review we address the rationale for targeting E2F in vascular disease, the pharmacology of edifoligide, and the results of preclinical and clinical studies using this novel compound.

Topics: Animals; Cell Proliferation; Coronary Artery Bypass; E2F Transcription Factors; Graft Occlusion, Vascular; Humans; Models, Biological; Muscle, Smooth, Vascular; Oligonucleotides

In vitro and animal model data suggest that intraoperative preservation solutions may influence endothelial function and vein graft failure (VGF) after coronary artery bypass graft (CABG) surgery. Clinical studies to validate these findings are lacking.. To evaluate the effect of vein graft preservation solutions on VGF and clinical outcomes in patients undergoing CABG surgery.. Data from the Project of Ex-Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) study, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 3014 patients at 107 US sites from August 1, 2002, through October 22, 2003, were used. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 planned vein grafts.. Preservation of vein grafts in saline, blood, or buffered saline solutions.. One-year angiographic VGF and 5-year rates of death, myocardial infarction, and subsequent revascularization.. Most patients had grafts preserved in saline (1339 [44.4%]), followed by blood (971 [32.2%]) and buffered saline (507 [16.8%]). Baseline characteristics were similar among groups. One-year VGF rates were much lower in the buffered saline group than in the saline group (patient-level odds ratio [OR], 0.59 [95% CI, 0.45-0.78; P < .001]; graft-level OR, 0.63 [95% CI, 0.49-0.79; P < .001]) or the blood group (patient-level OR, 0.62 [95% CI, 0.46-0.83; P = .001]; graft-level OR, 0.63 [95% CI, 0.48-0.81; P < .001]). Use of buffered saline solution also tended to be associated with a lower 5-year risk for death, myocardial infarction, or subsequent revascularization compared with saline (hazard ratio, 0.81 [95% CI, 0.64-1.02; P = .08]) and blood (0.81 [0.63-1.03; P = .09]) solutions.. Patients undergoing CABG whose vein grafts were preserved in a buffered saline solution had lower VGF rates and trends toward better long-term clinical outcomes compared with patients whose grafts were preserved in saline- or blood-based solutions.. clinicaltrials.gov Identifier: NCT00042081.

Topics: Aged; Buffers; Coronary Artery Bypass; Double-Blind Method; Female; Follow-Up Studies; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Oligonucleotides; Organ Preservation Solutions; Sodium Chloride; Treatment Outcome; 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

Coronary artery bypass graft (CABG) surgery with autologous vein grafting is commonly performed. Progressive neointimal hyperplasia, however, contributes to considerable vein graft failure. Edifoligide is an oligonucleotide decoy that binds to and inhibits E2F transcription factors and thus may prevent neointimal hyperplasia and vein graft failure.. To assess the efficacy and safety of pretreating vein grafts with edifoligide for patients undergoing CABG surgery.. A phase 3 randomized, double-blind, placebo-controlled trial of 3014 patients undergoing primary CABG surgery with at least 2 planned saphenous vein grafts and without concomitant valve surgery, who were enrolled between August 2002 and October 2003 at 107 US sites.. Vein grafts were treated ex vivo with either edifoligide or placebo in a pressure-mediated delivery system. The first 2400 patients enrolled were scheduled for 12- to 18-month follow-up angiography.. The primary efficacy end point was angiographic vein graft failure (> or =75% vein graft stenosis) occurring 12 to 18 months after CABG surgery. Other end points included other angiographic variables, adverse events through 30 days, and major adverse cardiac events.. A total of 1920 patients (80%) either died (n = 91) or underwent follow-up angiography (n = 1829). Edifoligide had no effect on the primary end point of per patient vein graft failure (436 [45.2%] of 965 patients in the edifoligide group vs 442 [46.3%] of 955 patients in the placebo group; odds ratio, 0.96 [95% confidence interval {CI}, 0.80-1.14]; P = .66), on any secondary angiographic end point, or on the incidence of major adverse cardiac events at 1 year (101 [6.7%] of 1508 patients in the edifoligide group vs 121 [8.1%] of 1506 patients in the placebo group; hazard ratio, 0.83 [95% CI, 0.64-1.08]; P = .16).. Failure of at least 1 vein graft is quite common within 12 to 18 months after CABG surgery. Edifoligide is no more effective than placebo in preventing these events. Longer-term follow-up and additional research are needed to determine whether edifoligide has delayed beneficial effects, to understand the mechanisms and clinical consequences of vein graft failure, and to improve the durability of CABG surgery. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00042081.

Topics: Aged; Angiography; Coronary Artery Bypass; DNA; Double-Blind Method; E2F Transcription Factors; Female; Genetic Therapy; Graft Occlusion, Vascular; Humans; Hyperplasia; Male; Middle Aged; Oligonucleotides; Saphenous Vein; Survival Analysis; Tissue and Organ Harvesting; Transfection; Transplantation, Autologous; Transplants; Vascular Patency

Topics: Coronary Artery Bypass; Female; Graft Occlusion, Vascular; Humans; Male; Oligonucleotides; Organ Preservation Solutions; Veins

Longevity of lower-extremity revascularization procedures has typically been limited because of restenosis of grafts, as well as stents and other percutaneous techniques. The ability to prevent or ameliorate neointimal hyperplasia and improve durability of lower-extremity arterial reconstruction is the focus of significant scientific and clinical research. The transcription factor decoy edifoligide was investigated as a potential inhibitor of neointimal hyperplasia, but the results of the pivotal clinical trial did not demonstrate significant improvement in graft reintervention, although secondary patency was improved. Similar to the coronary circulation, drug-eluting stents are a potential tool for prevention of restenosis after percutaneous arterial reconstruction. The SIROCCO study did not demonstrate improvement in superficial femoral artery stent patency with sirolimus-eluting stents. Studies are underway that are investigating paclitaxel-eluting stents for use in the superficial femoral artery. Other potential mediators of restenosis include absorbable drug-eluting stents and antibody-coated stents designed to promote endothelialization of the stent or graft surface. In addition, absorbable wraps eluting paclitaxel can be used at arterial and arteriovenous anastomoses to prevent restenosis. Clinical trials investigating these novel technologies are underway.

Topics: Arterial Occlusive Diseases; Blood Vessel Prosthesis Implantation; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Hyperplasia; Leg; Oligonucleotides; Paclitaxel; Radiography; Tunica Intima; Vascular Patency

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

Topics: Coronary Artery Bypass; DNA; E2F Transcription Factors; Genetic Therapy; Graft Occlusion, Vascular; Humans; Oligonucleotides; Saphenous Vein; Transplants; Vascular Patency

Topics: Coronary Artery Bypass; DNA; E2F Transcription Factors; Fibrinolytic Agents; Genetic Therapy; Graft Occlusion, Vascular; Humans; Oligonucleotides; Saphenous Vein; Transplants; Vascular Patency

Topics: Coronary Artery Bypass; DNA; E2F Transcription Factors; Genetic Therapy; Graft Occlusion, Vascular; Humans; Oligonucleotides; Saphenous Vein; Transplants; Vascular Patency

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