CLINICAL STUDY: ANGIOGENESIS
Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a Phase I open-label dose escalation study
Roger J. Laham, MD*  ,
Nicholas A. Chronos, MD ,
Marilyn Pike, MD, PhD ,
Mark E. Leimbach, MD||,
James E. Udelson, MD¶,
Justin D. Pearlman, MD, PhD*,
Roderic I. Pettigrew, MD||,
M. J. Whitehouse, MD,
Carl Yoshizawa, PhD and
Michael Simons, MD*
* Angiogenesis Research Center, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Interventional Cardiology Section, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Atlanta Cardiology Group, Atlanta, Georgia, USA
Chiron Corporation, Emeryville, California, USA
|| Division of Cardiology, Emory University, Atlanta, Georgia, USA
¶ Division of Cardiology, New England Medical Center and Tufts University, Boston, Massachusetts, USA
Manuscript received April 7, 2000;
revised manuscript received June 22, 2000,
accepted August 7, 2000.
Reprint requests and correspondence: Dr. Michael Simons, MD, Angiogenesis Research Center, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215
msimons{at}caregroup.harvard.edu
OBJECTIVES
Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2).
BACKGROUND
FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia.
METHODS
Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA.
RESULTS
Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 µg/kg). Hypotension was dose-dependent and dose-limiting, with 36 µg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510 ± 24 s at baseline, 561 ± 26 s at day 29 [p = 0.023], 609 ± 26 s at day 57 (p < 0.001), and 633 ± 24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34 ± 1.7%, day 29: 38.7 ± 1.9% [p = 0.006], day 57: 41.4 ± 1.9% [p < 0.001], and day 180: 42.0 ± 2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline.
CONCLUSIONS
Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 µk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.
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Abbreviations and Acronyms
| | CAD | = coronary artery disease | | CABG | = coronary artery bypass surgery | | ETDRS | = early treatment diabetic retinopathy | | ETT | = exercise tolerance test | | FGF | = fibroblast growth factor | | IC | = intracoronary | | MRI | = magnetic resonance imaging | | MTD | = maximally tolerated dose | | PTCA | = percutaneous transluminal angioplasty | | SAQ | = Seattle Angina Questionnaire | | VEGF | = vascular endothelial growth factor |
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