A series of animal experiments has demonstrated that intracoronary and local delivery of FGF improves myocardial perfusion and function and increases collateral flow in myocardial ischemia (91-94). Several phase 1 trials have been performed to evaluate the safety of recombinant FGF-1 and FGF-2 for therapeutic angiogenesis in patients with myocardial ischemia (95-100). Each of these small studies showed reductions in anginal status, need for anti-anginal medications, and improvements in nuclear perfusion scanning. These studies, however, were limited by the fact that these patients were all scheduled for coronary artery bypass graft surgery. Therefore, any potential applicability of these approaches would be limited to patients able to undergo thoracotomy. Intravenous and intracoronary administration of recombinant FGF-2 have also been evaluated in phase 1 studies of patients with symptomatic coronary artery disease with mixed results (100-103). Intravenous injection of recombinant FGF-2 was associated with improvements in anginal status, exercise time, and left ventricular function. However, intracoronary administration resulted in no change in exercise time or time to ischemia.
Several patients experienced persistent hypotension for up to 3 d, conduction system disturbances, thrombocytopenia, and proteinuria.
The FGF-2 Initiating Revascularization Support Trial (FIRST) was a phase 2 trial that randomized 337 patients with inoperable coronary artery disease to receive either placebo or one of three doses of intracoronary recombinant FGF-2 (104). The results of this trial did not show dramatic improvements in objective endpoints in patients receiving intracoronary FGF-2. The 90-d exercise time and stress nuclear perfusion results were not significantly different between FGF-2-treated patients and placebo-treated patients. There was a trend toward improved anginal status in patients receiving intracoronary FGF-2, particularly in older and more symptomatic patients.
Results of these phase 1 and 2 trials again point to the potential shortcomings of recombinant protein therapy for therapeutic angiogenesis. FGF gene therapy in animal models of coronary ischemia has shown promise for therapeutic angiogenesis. In a chronic coronary occlusion animal model, human FGF-5 carried by an adenovirus vector (Ad5-FGF5) administered by intracoronary infusion resulted in sustained production of growth factors at 12 wk, effective development of coronary collaterals, and relief of stress-induced ischemia (25,105).
Thus far, only one clinical trial in humans using FGF gene therapy for myocardial ischemia has been reported. Grines et al. conducted the Angiogenic Gene Therapy (AGENT) trial in which 79 patients with chronic stable angina (Canadian Cardiovascular Class II and III) were randomized to receive placebo or one of five escalating doses of Ad5-FGF4 in a double-blind fashion (106). The Ad5-FGF4 was administered by a single intracoronary injection. Overall, patients receiving Ad5-FGF4 tolerated the infusion well with few immediate adverse events. One patient developed a fever during the first day after virus transfer, and two patients had minor, self-limited elevations of liver enzymes. There were no significant differences in adverse events in patients receiving placebo and Ad5-FGF4 at a mean of 311 d of follow-up. Overall, patients receiving Ad5-FGF4 experienced a trend towards increased exercise times at 4 wk. The trial prespecified a subgroup analysis in the 50 patients with baseline exercise times of less than 10 min. There was a significant improvement in exercise time in this more symptomatic subgroup of patients in those who received Ad5-FGF5 (1.6 vs 0.6 min, p < 0.01). These data suggest that the intracoronary infusion of Ad5-FGF4 is safe and may be effective at improving hard clinical endpoints in patients with myocardial ischemia. Interestingly, in this study, patients enrolled were not "no-option" patients. The effects of intracoronary Ad5-FGF5 may be more dramatic in no-option patients. The true clinical value of this approach will be evaluated in future clinical trials designed to assess hard clinical endpoints.
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