Angiogenic GENe Therapy Trial - AGENT-2

Description:

The goal of this trial was to evaluate whether intracoronary administration of the adenoviral gene for fibroblast growth factor (Ad5FGF-4) improves myocardial perfusion compared with placebo in patients with stable angina and reversible ischemia.

Hypothesis:

Treatment with intracoronary Ad5FGF-4 will be associated with improvements in myocardial perfusion compared with placebo in patients with stable angina and reversible ischemia.

Study Design

Study Design:

Patients Screened: 148
Patients Enrolled: 52
Mean Follow Up: 8 weeks for SPECT; 12 months for events
Mean Patient Age: mean age 58 years
Female: 11
Mean Ejection Fraction: Mean LVEF at baseline 48%

Patient Populations:

Age 30 to 75 years; symptomatic stable angina (≥4 weeks, angina class II-IV) despite using antianginal drugs; not optimal candidates for revascularization by surgical or percutaneous means; single- or multivessel coronary artery disease ≥1 proximal major vessel with <70% stenosis to allow adequate infusion of study product; and left ventricular ejection fraction (LVEF) ≥30% and adenosine-induced (ischemic) left ventricular RPDS >9% by gated SPECT

Exclusions:

Left main coronary arterial stenosis ≥70% (unless protected with a patent graft), bypass surgery within past six months, angioplasty within four months, unstable angina, patients requiring immediate revascularization, myocardial infarction <6 weeks, chronic heart failure (class IV), chronic atrial fibrillation/flutter, HIV positive, chronic immunosuppressive therapy, hepatic disease, previous administration of any gene product or growth factor protein, type 1 diabetes, severe preproliferative or proliferative retinopathy, malignant tumors within the past 10 years, thrombocytopenia, use of abciximab within 30 days, child-bearing potential, and patients in whom adenosine administration was contraindicated

Primary Endpoints:

Change from baseline to week eight in stress-related reversible perfusion defect size (RPDS)

Secondary Endpoints:

Change from baseline to week eight in total perfusion defect size

Drug/Procedures Used:

Patients with stable angina and reversible ischemia comprising >9% of the left ventricle on adenosine single-photon emission computed tomography (SPECT) imaging were randomized to gene therapy (n=35) or placebo (n=17). Follow-up SPECT was performed at eight-week follow-up. Patients were followed for 12 months for clinical events.

Principal Findings:

Mean total perfusion defect size at baseline was 32.4% of the left ventricle (20% reversible ischemia and 12.5% scar). Reversible ischemic defect size at follow-up was significantly lower than baseline in the Ad5FGF-4 arm (4.2% absolute, p<0.001), but did not differ in the placebo arm (1.6%, p=0.32).

However, the difference between the Ad5FGF-4 arm and the placebo arm, the primary endpoint, was not statistically different (4.2% vs. 1.6%, p=0.14). When a single outlier was excluded, the difference was significant (4.2% vs. 0.8%, p<0.05).

Freedom from angina was reported in 30% of the Ad5FGF-4 arm versus 13% of the placebo arm, and freedom from nitroglycerin use was 43% versus 17%, respectively. Ad5FGF-4 was well tolerated, with no increase in serious adverse events.

Interpretation:

Among patients with stable angina and reversible ischemia, intracoronary treatment with the adenoviral gene for fibroblast growth factor Ad5FGF-4 was associated with a nonsignificant improvement in the primary endpoint of myocardial perfusion compared with placebo. While prior nonrandomized or nonblinded studies of gene therapy have used SPECT myocardial perfusion, the present trial is the first randomized placebo-controlled trial to test the effect of gene therapy for angiogenesis on myocardial perfusion in humans using SPECT.

The AGENT-1 trial showed that intracoronary administration of FGF-4 delivered using an adenoviral vector was associated with an increase in treadmill exercise time by 1.5 minute versus 0.9 minute in placebo-treated patients. Exercise time is a surrogate, not a direct measure of myocardial perfusion. Although the improvement in the primary endpoint of perfusion defect size in the gene therapy arm versus placebo arm did not reach statistical significance, the trend toward improvement over placebo and the improvement from baseline may warrant further trials of Ad5FGF-4 on clinical outcomes.

References:

Grines CL, Watkins MW, Mahmarian JJ, et al., for the Angiogene GENe Therapy (AGENT-2) Study Group. A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. J Am Coll Cardiol 2003;42:1339-47.

Clinical Topics: Noninvasive Imaging, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Computed Tomography, Nuclear Imaging, Chronic Angina

Keywords: Coronary Artery Disease, Angina, Stable, Tomography, Emission-Computed, Single-Photon, Constriction, Pathologic, Genetic Therapy, Cicatrix, Vascular Endothelial Growth Factor A, Stroke Volume, Heart Ventricles, Exercise Test, Nitroglycerin


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