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A Multicenter, Prospective, Randomized Trial of Intracoronary Administration of Ad5FGF-4 in Patients With No Revascularization Options - AGENT-3
Description:
Trial investigators evaluated angiogenesis-induction by fibroblast growth factor (Ad5FGF-4) as an alternative therapy for treating ischemic heart disease in patients who are suboptimal candidates for revascularization.
Hypothesis:
Angiogenesis-induction by fibroblast growth factor (Ad5FGF-4) would lead to improved exercise tolerance as well as quality of life.
Study Design
Patients Enrolled: 415
Mean Follow Up: Five years (data reported through one year)
Patient Populations:
1) Patients with CCS class II-IV angina despite optimal medical treatment who were not in need of immediate traditional revascularization strategies.
2) Patients had to be able to walk between 3 and 10 minutes with inducible ST depression of at least 1 mm and variability between successive baseline exercise tests of 20% or less.
3) At least one proximal vessel with less than 70% stenosis.
Exclusions:
Ejection fraction had to be ≥30%, MI within six months, percutaneous coronary intervention within six months, malignancy within 10 years, proliferative retinopathy, chronic heart failure (New York Heart Association class IV), severe concurrent illness (hepatic, renal, immunosuppression), thrombocytopenia, proteinuria, previous angiogenic therapy, or female of child-bearing potential
Primary Endpoints:
Change in ETT time from baseline to 12 weeks. A co-primary endpoint was the proportion of patients with 30% or greater increase in treadmill exercise duration at 12 weeks.
Secondary Endpoints:
Time to a number of patients with coronary events (nonfatal myocardial infarction [MI], unplanned hospitalization, or revascularization for myocarial ischemia) and death at 12 months; and time to ST depression, angina, and quality of life parameters
Drug/Procedures Used:
The amino acid protein Ad5FGF-4 was given in comparison doses of 1x109 virus particles (n=150) and 1x1010 virus particles (n=150) by intracoronary infusion and compared to control (n=150).
Principal Findings:
Baseline characteristics were similar across all arms. The primary endpoint of change in exercise tolerance test (ETT) duration from baseline to 4 and 12 weeks did not demonstrate any statistically significant difference. The mean change in exercise duration at 12 weeks was (71 seconds for placebo, 72 seconds for low-dose Ad5FGF-4, and 69 seconds for high-dose Ad5FGF-4). There was also no change in exercise duration at six months.
In a prespecified analysis on the effect of age and severity of angina, older patients (>55 years) with more severe angina (Canadian Cardiovascular Society [CCS] class III or IV angina) had a significantly greater increase in ETT time at 12 weeks (p=0.08 for low-dose, p=0.02 for high-dose) and six months (p=0.07 for low-dose, p=0.08 for high-dose). Similarly, older patients (>55 years) with exercise time 300 seconds or less had a significantly greater increase in ETT time at 12 weeks (p=0.06 for low-dose, p=0.03 for high-dose) and six months (p=0.03 for low-dose, p=0.017 for high-dose).
No significant differences in the combined endpoint of coronary events or death at one year in patients completing 12-month follow-up were identified (20% control, 19% low-dose Ad5FGF-4, and 17% high-dose Ad54FGF-4; p=NS).
Interpretation:
This study is the largest randomized gene therapy trial for myocardial angiogenesis. Ad5FGF-4 was not associated with increased exercise time compared to placebo. The favorable safety profile of this drug seen in this trial makes further evaluation using higher doses possible. The beneficial effect demonstrated in the prespecified subgroup analysis of higher risk patients warrants further study.
References:
Henry TD, Grines CL, Watkins MW, et al. Effects of Ad5FGF-4 in Patients With Angina: An Analysis of Pooled Data From the AGENT-3 and AGENT-4 Trials. J Am Coll Cardiolo 2007; 50; 1038-46.
Keywords: Exercise Tolerance, Myocardial Ischemia, Coronary Artery Disease, Constriction, Pathologic, Fibroblast Growth Factors, Genetic Therapy, Vascular Endothelial Growth Factor A, Quality of Life, Angiogenesis Inducing Agents, Virion, Exercise Test
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