PRoject of Ex-Vivo vein graft ENgineering via Transfection - PREVENT IV

Description:

The goal of the trial was to evaluate treatment of vein grafts with edifoligide, an oligonucleotide decoy that binds to and inhibits E2F transcription factors and prevents neointimal hyperplasia, compared with placebo among patients undergoing coronary artery bypass graft (CABG) surgery.

Hypothesis:

Treatment of vein grafts with edifoligide will be associated with lower rates of vein graft failure compared with placebo at 12 to 18 months among patients undergoing CABG surgery.

Study Design

Patients Enrolled: 3014
Mean Follow Up: up to 5 years (reported through 1 year to date)
Mean Patient Age: Median age 64 years
Female: 21
Mean Ejection Fraction: Median 50% at baseline

Patient Populations:

Age 18 to 80 years; undergoing a first, isolated CABG surgery for atherosclerotic coronary artery disease with at least 2 planned vein grafts

Exclusions:

Prior cardiac surgery or planned concomitant valve surgery, vasculitis or another nonatherosclerotic cause of coronary artery disease, hypercoagulable state, involvement in another investigational drug or device study within 30 days, or a comorbid illness that would make 5-year survival unlikely.

Primary Endpoints:

Angiographic vein graft failure (≥75% vein graft stenosis) occurring 12 to 18 months after surgery

Secondary Endpoints:

Major adverse coronary events (MACE), defined as the composite of death, MI, or repeat revascularization with vein graft failure; per-patient incidence of vein graft occlusion; per-graft incidence of vein graft failure (≥75% stenosis) and vein graft occlusion; and mean vein graft lumen diameter

Drug/Procedures Used:

Patients were randomized to treatment of vein grafts ex vivo with either edifoligide (n=1508) or placebo (n=1506) in a pressure-mediated delivery system. The first 2400 patients enrolled were assigned to an angiography cohort and scheduled to return for angiography 12 to 18 months after surgery. All patients were to be followed for clinical outcomes for 5 years.

Concomitant Medications:

At 30 days, aspirin 91%, beta-blocker 79%, HMG-CoA reductase inhibitor 73%, ACE inhibitor 36%.

Principal Findings:

Baseline clinical and procedural characteristics were similar between groups, with 38% diabetics, a median ejection fraction of 50%, and 26% with New York Heart Association class III or IV heart failure. The surgery was urgent in 49% of cases, and was performed off-pump in 21% of cases. The saphenous vein graft was harvested endoscopically in 58% of patients and a median of 2 vein grafts were used per patient. Internal thoracic artery graft was placed in slightly more patients in the placebo group (94% vs 91%, p

Among the 2,400 patients in the angiographic cohort, 1,920 patients (80%) either died prior to the follow-up (4.7%) or had angiography performed. There was no difference between groups in the primary endpoint of vein graft failure (stenosis ≥75%) (45.2% for edifoligide vs 46.3% for placebo, p=0.66), the majority of which were vein graft occlusion (41.8% vs 41.7%, p=0.97). Results were similar in a per graft analysis as well (failure 28.5% vs 29.7%, p=0.44). Mean vein graft diameter in non-occluded grafts did not differ by treatment group (2.92 mm for edifoligide vs 2.97 mm for placebo, p=0.17).

At one year clinical follow-up, the composite of death, MI or revascularization with vein graft failure occurred in 6.7% of the edifoligide group and 8.1% of the placebo group (p=0.16). There was no difference in mortality (3.5% vs 2.9%). Safety events did not differ between groups, with atrial fibrillation in 26% of patients, perioperative MI in 9.8%, and bleeding requiring reoperation in 2.5% of patients.

Interpretation:

Among patients undergoing coronary artery bypass graft surgery, treatment of vein grafts with edifoligide, an oligonucleotide decoy that binds to and inhibits E2F transcription factors and prevents neointimal hyperplasia, was not associated with a difference in vein graft failure at 12 to 18 months post-surgery compared with placebo.

Although there was no benefit on angiographic parameters, clinical events at one year trended lower in the edifoligide group. Longer clinical follow-up is planned. Edifoligide acts as a decoy for the entire E2F transcription factor family. However, eight E2F transcription factors have been identified, some of which promote and some of which inhibit neointimal hyperplasia. A therapy that acts on one rather than all of the E2F transcription factors may prove more promising.

Vein graft failure in the present trial was somewhat higher than previous studies. The authors suggest that this may reflect the higher risk population that now undergoes CABG surgery, which generally has more extensive and severe disease.

References:

PREVENT IV Investigators. Efficacy and Safety of Edifoligide, an E2F Transcription Factor Decoy, for Prevention of Vein Graft Failure Following Coronary Artery Bypass Graft Surgery. JAMA. 2005;294:2446-2454.

Presented by Dr. John H. Alexander at the American Heart Association Scientific Session, Dallas, Texas, November 2005.

Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Heart Failure, Novel Agents, Acute Heart Failure, Interventions and Coronary Artery Disease

Keywords: Oligonucleotides, Coronary Artery Disease, Follow-Up Studies, Constriction, Pathologic, Hyperplasia, Reoperation, Vascular Patency, Saphenous Vein, Mammary Arteries, Heart Failure, Coronary Artery Bypass, Diabetes Mellitus


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