Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial - PREVENT

Feb 04, 2002
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Date Published:
01/01/1998
Date Updated:
02/04/2002
Original Posted Date:
02/04/2002
References

Description:

E2F decoy oligodeoxynucleotide (ODN) to prevent neointimal hyperplasia.

Hypothesis:

Blocking the expression of 2 cell cycle regulatory genes using an E2F decoy oligodeoxynucleotide (ODN) could prevent neointimal hyperplasia, while still allowing a hypertrophic response in the medial layer.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 41
Mean Follow Up: 30 days
Female: 0

Patient Populations:

Infrainguinal bypass graft with autologous vein.

Primary Endpoints:

Primary graft failure (graft occlusion or invasive revision).

Secondary Endpoints:

Safety, feasibility, and molecular efficacy of intraoperative oligonucleotide transfection.

Drug/Procedures Used:

Infrainguinal saphenous vein grafts with E2F decoy oligonucleotide treatment, untreated grafts, or a control oligonucleotide.

Principal Findings:

Based on the small sample size, these preliminary data were not expected to show any effect on clinical outcomes. Nevertheless, there was a reduction in overall graft failures noted at 30 days in the E2F-treated group compared to the untreated controls (29% vs. 63%), which was significant among patients with high-risk grafts (14% vs. 83%, p=0.03). This suggests a possible influence of this genetic manipulation on graft patency.

Using a specially developed organ culture system and polymerase chain reaction analysis, the investigators were able to measure a significant inhibition (p<0.001) of both target genes 72 hours after E2F transfection; this effect was not seen in either control group.

As expected, ex vivo, pressure-mediated transfection of this E2F decoy ODN to the graft had no influence on postoperative blood chemistries, blood counts, or urinalysis. The 10-minute gene transfection procedure did not prolong the operations or in any other way influence the course of the surgical procedure and had no detrimental effect on postoperative complication rates.

Interpretation:

Most vein graft failures are linked to a remodeling process that adapts the initially thin-walled vein to arterial pressures. However, the neointimal hyperplasia that provides this protective wall thickening can also encroach upon the lumen of these vessels, which provides a substrate for an aggressive form of accelerated atherosclerosis. This is the first phase of human clinical testing for this gene therapy strategy. Although the biology of neointimal hyperplasia has been documented in both coronary as well as peripheral bypass grafts, investigators chose first to study infrainguinal bypass grafts because of the availability of noninvasive serial ultrasound examination.

References:

1. Circulation 1998;98(Suppl I):I-321. Prelininary results

Keywords: Postoperative Complications, Atherosclerosis, Arterial Pressure, Urinalysis, Transcription Factors, Transfection, Hyperplasia, Calcium Channel Blockers, Organ Culture Techniques, DNA-Binding Proteins, Oligodeoxyribonucleotides, Genetic Therapy, Research Personnel, Saphenous Vein, Amlodipine, Cell Cycle, Polymerase Chain Reaction


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