The Program in Ex Vivo Vein Graft Engineering Via Transfection II Study: E2F Decoy in CABG - PREVENT II

Description:

The Program in Ex Vivo Vein Graft Engineering Via Transfection II Study: E2F Decoy in CABG.

Hypothesis:

Ex vivo, intra-operative treatment of vein grafts with E2F Decoy, inhibits graft intimal disease and reduces rates of critical graft stenosis and failure.

Study Design

Study Design:

Patients Enrolled: 200
Mean Follow Up: 12 months
Female: 16

Patient Populations:

Men and women thought to require at least 2 coronary grafts during coronary artery bypass graft (CABG) surgery.

Primary Endpoints:

Safety and feasibility: toxicity and side effects; incidence of graft occlusion or critical graft stenosis; angiography and intravascular ultrasound (IVUS) at 12 months.

Drug/Procedures Used:

DNA therapy to block gene expression and redirect graft biology to reduce repeat surgeries due to graft failure.

Principal Findings:

Angiographic follow-up was completed in 123 patients (69 E2F Decoy, 54 placebo).

In the graft analysis, graft stenosis was defined as lesions that reduce vein graft lumen by more than 75%. In this group, E2F Decoy group produced significantly better results at follow-up (27.3% vs 38.7%, p=0.03) for a relative reduction of 30%.

Eliminating the patients with a flow lower than 25 ml/min, the treatment effect is more pronounced (18.3% vs 30.3%, p=0.03 with a relative reduction of 40%).

Although PREVENT II was not powered to delineate the difference in major adverse clinical events (MACE), the E2F Decoy group trended lower: composite MACE, 12% vs 16%; death, 6% vs 10%; myocardial infarction, 4% vs 6%; percutaneous coronary intervention, 0% vs 1%; repeat CABG, 0% vs 3%; and revisions, 2% vs 3%.

No toxic effect was seen as basic post-operative complications were evenly distributed and balanced between the groups.

A total of 108 cases were submitted for IVUS; 65 (35 E2F Decoy, 30 placebo) were considered suitable for 3-dimensional (3D) IVUS.

In the 3D IVUS analysis, the E2F Decoy group had significantly lower intimal volume (78.6 mm3 vs 114.8 mm3, p=0.024). When indexed for vessel volume, the E2F Decoy arm presents even better results (12.5% vs 18.4%, p=0.005).

The investigators concluded that in this first randomized, controlled trial of genetic suppression via transcription factor inhibition in CABG patients, the drug was safe and well tolerated. The application required no changes in surgical technique or procedure, yet was associated with significant decreases in vein graft stenosis, vascular wall volume and wall volume index at 1 year.

A phase III peripheral and coronary study is currently planned.

Interpretation:

Coronary bypass grafts undergo severe changes after implantation due to stress as the thin-walled veins are forced to do the work of arteries. The thin-walled veins normally respond to the increased pressure with intimal hyperplasia. Following the initial injury, smooth muscle cells (SMC) activate, migrate, proliferate and then form the intima, leading to plaque and ultimate stenosis. Consequently, patency decreases; after 10 to 15 years, the patency rate in venous bypass grafts stands at 50% to 60%.

The initial wave of SMC activation lasts about 12 days, which is the time frame in which the E2F Decoy remains in the graft tissue once transcribed.

This phase II study suggests a marked clinical efficacy of the E2F Decoy treatment throughout the entire length of the bypass graft. Additionally, the study confirmed the safety and minimal toxicity observed in the PREVENT I study. The overall results warrant additional phase III studies.

During the AHA 2001 annual meeting, discussant Dr. Elizabeth Nabel noted that, “This is an outstanding example of translational medicine, something that many of us want to see going forward in the future. (The investigators are) taking a discovery of a gene at the bench, understanding the molecular pathways, and then applying that to design a very specific treatment that then can be applied to a clinical disease. Hopefully this study will serve as a model for many bench-to-bedside studies in the future. That is, harnessing the discoveries of molecular biology in the genome into designing new important treatments for clinical cardiovascular disease.”

References:

1. Therapeutic potential. Proc Natl Acad Sci USA 1995;92:5855-9.
2. PREVENT I results. Lancet 1999; 354:1493-8.
3. Therapeutic applications. J Clin Invest 2000;106:1071-5.
4. Clinical application review. Curr Cardiol Rep 2001 3:29-36.
5. Long-term stabilization. J Thorac Cardiovasc 2001;121:714-22.
6. Gene therapy advances and perspectives. Pharmacol Ther 2001;91:105-14.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery

Keywords: Myocardial Infarction, Follow-Up Studies, Transcription Factors, Translational Medical Research, Constriction, Pathologic, Transfection, Hyperplasia, Stents, DNA-Binding Proteins, Percutaneous Coronary Intervention, Genetic Therapy, Myocytes, Smooth Muscle, Research Personnel, Coronary Artery Bypass, Suppression, Genetic


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