edifoligide and Hyperplasia

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

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

Coronary artery bypass graft (CABG) surgery with autologous vein graft (VG) conduit is one of the most frequently performed operations in the United States. Unfortunately, many VGs become occluded during long-term follow-up largely because of neointimal hyperplasia. A novel approach to preventing neointimal hyperplasia is with the double-stranded oligonucleotide edifoligide (Corgentech Inc, South San Francisco, Calif). Edifoligide inhibits E2F, a transcription factor that activates cell-cycle genes responsible for neointimal hyperplasia.. PREVENT IV is a phase-III, multicenter, randomized double-blind placebo-controlled trial of ex vivo treatment of autologous VGs with edifoligide in patients undergoing initial CABG surgery. The primary end point is VG failure, defined as death or > or =75% stenosis in a treated VG at 12- to 18-month angiographic follow-up. Secondary end points include major adverse cardiac events through at least 5 years and adverse events through 30 days.. Enrollment of 3014 patients from 107 sites was completed on October 22, 2003. The baseline and procedural characteristics of the PREVENT IV population are generally well matched to a contemporary population of patients undergoing initial CABG from the Society of Thoracic Surgeons National Database. Angiographic follow-up is ongoing and scheduled to be completed in March 2005.. The PREVENT IV data will establish whether VG pretreatment with an E2F transcription factor decoy, edifoligide, can improve graft patency and reduce the long-term morbidity and mortality of patients undergoing CABG surgery.

Topics: Aged; Coronary Artery Bypass; DNA; Equipment Design; Female; Follow-Up Studies; Humans; Hyperplasia; Injections, Intravenous; Male; Middle Aged; Multicenter Studies as Topic; Oligonucleotides; Postoperative Complications; Randomized Controlled Trials as Topic; Research Design; Tunica Intima