ABSTRACT
Objective
The PREVENT III study was a prospective, randomized, double-blinded, multicenter phase III trial of a novel molecular therapy (edifoligide; E2F decoy) for the prevention of vein graft failure in patients undergoing infra-inguinal revascularization for critical limb ischemia (CLI).
MethodsFrom November 2001 through October 2003, 1,404 patients with CLI were randomized to a single intra-operative ex-vivo vein graft treatment with edifoligide or placebo. After surgery, patients underwent graft surveillance by duplex ultrasonography and were followed up for index graft and limb endpoints to 1 year. A blinded Clinical Events Classification committee reviewed all index graft endpoints. The primary study endpoint was the time to nontechnical index graft re-intervention or major amputation due to index graft failure. Secondary endpoints included all-cause graft failure, clinically significant graft stenosis (>70% by angiography or severe stenosis by ultrasonography), amputation/re-intervention-free survival, and nontechnical primary graft patency. Event rates were based on Kaplan-Meier estimates. Time-to-event endpoints were compared by using the log-rank test.
ResultsDemographics, comorbidities, and procedural details reflected a population with CLI and diffuse atherosclerosis. Tissue loss was the presenting symptom in 75% of patients. High-risk conduits were used in 24% of cases, including an alternative vein in 20% (15% spliced vein and 5% non-great saphenous vein) and 6% less than 3 mm in diameter; 14% of the cases were re-operative bypass grafts. Most (65%) grafts were placed to infra-popliteal targets. Perioperative (30-day) mortality occurred in 2.7% of patients. Major morbidity included myocardial infarction in 4.7% and early graft occlusion in 5.2% of patients. Ex-vivo treatment with edifoligide was well tolerated. 126There was no significant difference between the treatment groups in the primary or secondary trial endpoints, primary graft patency, or limb salvage. A statistically significant improvement was observed in secondary graft patency (estimated Kaplan-Meier rates were 83% edifoligide and 78% placebo; P = 0.016) within 1 year. The reduction in secondary patency events was manifest within 30 days of surgery (the relative risk for a 30-day event for edifoligide was 0.45; 95% confidence interval, 0.27–0.76; P = 0.005). For the overall cohort at 1 year, the estimated Kaplan-Meier rate for survival was 84%, that for primary patency was 61%, that for primary assisted patency was 77%, that for secondary patency was 80%, and that for limb salvage was 88%.
ConclusionsIn this prospective, randomized, placebo-controlled clinical trial, ex vivo treatment of lower extremity vein grafts with edifoligide did not confer protection from re-intervention for graft failure.
