PREVENT-4: Transcription-factor inhibitor fails to prolong SVG coronary-bypass patency

November 13, 2005

Dallas, TX - Pretreatment of saphenous vein grafts (SVGs) with a transcription-factor inhibitor intended to suppress neointimal hyperplasia was unsuccessful at protecting the grafts over the following year in a randomized study of coronary-bypass patients reported here today at the American Heart Association (AHA) 2005 Scientific Sessions.

Dr John H Alexander

Edifoligide (Corgentech, South San Francisco, CA), an oligonucleotide that had shown some capacity for vein-graft protection in earlier animal and clinical studies, turned out to be "no more effective than placebo in preventing vein-graft failure," Dr John H Alexander (Duke University, Durham, NC), principal investigator of the phase 3 fourth Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT-4) trial, told reporters at the meeting. The same pretreatment strategy was also unsuccessful among patients receiving peripheral-artery bypass in the PREVENT-3 trial presented last year and reported then by heart wire .

The PREVENT-4 trial was released online by the Journal of the American Medical Association today to coincide with the AHA presentation and is scheduled for the journal's November 16, 2005 issue[1].

The trial randomized 3014 patients undergoing isolated CABG surgery with at least two vein grafts to receive SVGs that had been pretreated with placebo or edifoligide, a competitive inhibitor of E2F, a transcription factor that helps promote smooth-muscle-cell (SMC) proliferation. The patients' harvested veins were incubated in a proprietary pressure chamber containing a solution of either edifoligide or placebo. The procedure forces the agent into the nuclei of cells lining the SVG wall, up to 90% of them according to previous research, Alexander told heart wire .

The primary end point of SVG failure, defined as death or stenosis >75% in at least one SVG, was tracked in the first 2400 randomized patients, who were followed with angiography; both they and the remaining 614 patients were followed clinically.

Rate of death or stenosis >75% (SVG failure) in at least one vein graft among 1920 evaluable patients over 18 months

End point Edifoligide Placebo OR (95% CI), p
Per patient n=965 n=955  
Vein-graft failure (>75% stenosis) (%) 45.2 46.3 0.96 (0.80-1.14), 0.66
Per vein graft 2303 grafts 2254 grafts  
Vein-graft failure (>75% stenosis) (%) 28.5 29.7 0.94 (0.80-1.10), 0.44

The rate of major adverse cardiac events (death, nonfatal MI, or revascularization with vein-graft failure) at one year was 6.7% in the edifoligide group and 8.1% among controls (p=0.16). Given the lack of difference in the primary end point, according to Alexander, any suggestion of a clinical trend in favor of edifoligide was likely "due to the play of chance."

Vein-graft failure in the trial was significantly related to a number of operative and patient factors. These included endoscopic saphenous-vein harvesting, which was performed in about 58% of cases and increased the graft-failure risk by 35%.

Significant correlates of SVG failure in PREVENT 4

Predictor Odds ratio p
Target artery quality   <0.001
Good vs poor 0.42  
Fair vs poor 0.56  
Surgery duration (per hour) 1.22 <0.001
Endoscopic SVG harvesting 1.35 <0.001
Multitarget grafting 1.25 0.020
Patient weight (per 10 kg increase) 0.95 0.026

The PREVENT trials were a learning experience, observes an editorial by Drs Vincent R Conti and Glenn C Hunter (University of Texas Medical Branch, Galveston) accompanying the JAMA report. More is now known, for example, about the cell-signaling mechanisms behind SMC proliferation. "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," they write.

Among the insights learned is that E2F actually represents a family of transcription factors, some of which activate SMCs and others that do the opposite, according to the PREVENT-4 investigators. So now it's "not surprising," they write, that the nonspecific E2F inhibitor edifoligide had little effect on neointimal hyperplasia. Alexander told heart wire that research into the development of agents with specificity for the SMC-suppressing E2F subfractions or that target other mechanisms associated with neointimal hyperplasia is in its very early stages.

The PREVENT IV Trial was funded by Corgentech and Bristol-Myers Squibb. Alexander and other members of the trial's steering committee—Drs Robert A Harrington, Eric D Peterson, Robert M Califf (all of Duke University), and C Michael Gibson (PERFUSE foundation, Boston, MA)—have received research funding from Corgentech Inc. Califf was on Corgentech's clinical advisory board; he is a contributing editor for theheart.org and owns stock options in the parent company, Conceptis Technologies. Dr Daniel J Gennevois is vice president of medical affairs for Corgentech. Dr Tod J Lorenz was formerly Corgentech's chief medical officer and retains significant equity ownership in the company. 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.

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