Coronary artery bypass graft (CABG) surgery is one of the most common surgical procedures performed in the United States, according to background information in the article. In appropriately selected patients, CABG surgery results in improved survival, relief of angina, and improved quality of life. Despite frequent use of artery grafts, vein grafts remain the most frequently used conduit. The long-term patency (duration of remaining open) of vein grafts is limited and graft failure has consequences similar to those of coronary artery disease: recurrent angina, myocardial infarction (MI), additional revascularization procedures, and premature death.
Neointimal hyperplasia (abnormal increase in the cells lining the inner wall of the blood vessel) leading to accelerated atherosclerosis and thrombosis is one proposed mechanism of vein graft failure. Neointimal hyperplasia begins as an adaptive response to the increased pressure and shear forces of arterial circulation. A new approach to inhibiting neointimal hyperplasia and preventing graft failure involves using edifoligide, which was developed to work via gene therapy to inhibit cell proliferation. For this study, researchers took each patient's harvested vein (that would be used for the graft) prior to CABG and treated the vein for 10 minutes with a pressure-mediated delivery system with either edifoligide or saline placebo.
John H. Alexander, M.D., M.S., of Duke University Medical Center, Durham, N.C., and colleagues conducted the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT IV) trial to assess the efficacy of edifoligide in preventing angiographic vein graft failure. The study included 3,014 patients undergoing primary CABG surgery with at least 2 planned vein grafts. The first 2,400 patients enrolled were scheduled for 12- to 18-month follow-up angiography. The patients were enrolled in the study between August 2002 and October 2003 at 107 U.S. sites.
A total of 1,920 patients (80 percent) either died (n=91) or underwent follow-up angiography (n=1,829). The researchers found that edifoligide had no effect on the primary end point of per patient vein graft failure (436 [45.2 percent] of 965 patients in the edifoligide group vs. 442 [46.3 percent] of 955 patients in the placebo group; or on any secondary angiographic end point, or on the incidence of major adverse cardiac events at 1 year (101 [6.7 percent] of 1,508 patients in the edifoligide group vs. 121 [8.1 percent] of 1,506 patients in the placebo group.
"Despite negative results, PREVENT IV provided a number of noteworthy lessons. First, an unusual approach to drug delivery was investigated in PREVENT IV; edifoligide was administered directly to the harvested vein graft prior to implantation. This type of specific, targeted application of a therapy to a specific tissue or organ may limit systemic toxicity and be a future direction of surgical intervention. Second, PREVENT IV includes and was powered to both a surrogate end point (angiographic vein graft failure) and a long-term clinical confirmatory end point (major adverse cardiac events). For important interventions believed to have long-term effects, this approach may allow beneficial therapies to be adopted earlier based on surrogate effects yet still ensure rigorous ultimate proof of safety and efficacy. Finally, the long-term clinical follow-up in PREVENT IV is being conducted centrally, from a single center, rather than by the 107 sites that enrolled patients and conducted angiographic follow-up and should result in considerable resource saving and perhaps more complete and systematic follow-up," the authors write.
"Failure of at least one vein graft is quite common within 12 to 18 months after CABG surgery. Although safe and well tolerated, inhibition ... with edifoligide is no more effective than placebo in preventing these events. Longer-term follow-up and additional research are needed to explain the mechanism and clinical consequences of vein graft failure and to improve the durability of CABG surgery," the researchers conclude. (JAMA.2005; 294:2446-2454. Available pre-embargo to the media at www.jamamedia.org)
The PREVENT IV Trial was funded by Corgentech Inc. (South San Francisco, Calif.). Drs. Alexander, Harrington, Peterson, Gibson, and Califf have received research funding from Corgentech Inc. Dr. Gennevois is an employee of Corgentech. Dr. Lorenz is a former employee of Corgentech and retains significant equity ownership.
Editorial: Gene Therapy and Vein Graft Patency in Coronary Artery Bypass Graft Surgery
In an accompanying editorial, Vincent R. Conti, M.D., and Glenn C. Hunter, M.D., of the University of Texas Medical Branch, Galveston, comment on the findings of PREVENT IV.
"Perhaps one of the most important lessons from the PREVENT IV study was that its planning, organization, and execution resulted in a conclusive result. A promising therapeutic agent was identified and tested in the experimental laboratory and preliminary clinical studies. The structure and size of the clinical study was established in collaboration with leading academic cardiac surgeons, and participating academic and private centers were identified and contacted through the Society of Thoracic Surgeons' National Database participation list. This ensured that the study would be adequately powered and that data analysis, which was centralized, would be consistent and accurate. Although results were negative for this agent, this large, adequately powered, and well-executed clinical study established this conclusion with some finality. The study also was powered for long-term clinical events, and the results of that analysis, when available, should be of interest," they write.
"As a result of PREVENT IV, more has been learned about the signaling mechanisms involving ... hyperplasia since edifoligide was developed and tested experimentally. Further studies specifically targeting the precise mechanisms operative in vein graft failure still hold promise for improving intermediate and perhaps long-term vein graft patency." (JAMA.2005; 294:2495-2496. Available pre-embargo to the media at www.jamamedia.org)
Editor's Note: Dr. Conti owns stock in Pfizer, Genentech, Millennium Pharmaceuticals, Celegene, Gilead, Amgen, Tanox, Isis Pharmaceuticals, GlaxoSmithKline, Icós, Amylin Pharmaceuticals, Ligand Pharmaceuticals, Affymetrix, Encysive Pharmaceuticals, Avant Immunotherapeutics, Elan Pharmaceuticals, and ImClone Systems.