on January 14, 2002
Circulation. 2002
Published online before print January 14, 2002, doi: 10.1161/hc0802.104407
Published online before print January 14, 2002, doi: 10.1161/hc0802.104407
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© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Pharmacological Treatment of Coronary Artery Disease With Recombinant Fibroblast Growth Factor-2
Double-Blind, Randomized, Controlled Clinical Trial
From Dartmouth-Hitchcock Medical Center, Lebanon, NH (M.S.); Duke University Medical Center, Durham, NC (B.H.A.); Beth Israel Deaconess Medical Center, Boston, Mass (R.J.L., E.V.G.); Methodist Hospital, Houston, Tex (N.K.); Hennepin County Medical Center, Minneapolis, Minn (T.H.); University of Massachusetts Memorial Health Care, Worcester, Mass (H.D.); New England Medical Center, Boston, Mass (J.E.U.); Chiron Corporation, Emeryville, Calif (M.P., M.J.W., T.M.); and Atlanta Cardiology Research Institute, Atlanta, Ga (N.A.C.).
The Appendix lists the clinical sites and investigators that participated in FIRST.Correspondence to Michael Simons, MD, Section of Cardiology, Dartmouth-Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756. E-mail Michael.Simons{at}Dartmouth.edu
Background— Single-bolus intracoronary administration of fibroblast growth factor-2 (FGF2) improved symptoms and myocardial function in a phase I, open-label trial in patients with coronary artery disease. We conducted the FGF Initiating RevaScularization Trial (FIRST) to evaluate further the efficacy and safety of recombinant FGF2 (rFGF2).
Methods and Results— FIRST is a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 µg/kg (n=337 patients). Efficacy was evaluated at 90 and 180 days by exercise tolerance test, myocardial nuclear perfusion imaging, Seattle Angina Questionnaire, and Short-Form 36 questionnaire. Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. rFGF2 reduced angina symptoms as measured by the angina frequency score of the Seattle Angina Questionnaire (overall P=0.035) and the physical component summary scale of the Short-Form 36 (pairwise P=0.033, all FGF groups versus placebo). These differences were more pronounced in highly symptomatic patients (baseline angina frequency score 
40 or Canadian Cardiovascular Society score of III or IV). None of the differences were significant at 180 days because of continued improvement in the placebo group. Adverse events were similar across all groups, except for hypotension, which occurred with higher frequency in the 30-µg/kg rFGF2 group.
Conclusions— A single intracoronary infusion of rFGF2 does not improve exercise tolerance or myocardial perfusion but does show trends toward symptomatic improvement at 90 (but not 180) days.
Key Words: coronary disease • angina • revascularization • angiogenesis • trials
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|
|
|
|
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|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
M. Simons Angiogenesis: Where Do We Stand Now? Circulation, March 29, 2005; 111(12): 1556 - 1566. [Full Text] [PDF]
|
|
|
|
 |
|
 C. J Teng, K. Lachapelle, and R. C. Chiu Reappraisal of Recent Clinical Trials of Angiogenic Therapy in Myocardial Ischemia Asian Cardiovasc Thorac Ann, March 1, 2005; 13(1): 90 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
J. Waltenberger Growth factor signal transduction defects in the cardiovascular system Cardiovasc Res, February 15, 2005; 65(3): 574 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Cao, A. Hong, H. Schulten, and M. J. Post Update on therapeutic neovascularization Cardiovasc Res, February 15, 2005; 65(3): 639 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. H. Annex and M. Simons Growth factor-induced therapeutic angiogenesis in the heart: protein therapy Cardiovasc Res, February 15, 2005; 65(3): 649 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Filion and A. S. Popel Intracoronary administration of FGF-2: a computational model of myocardial deposition and retention Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H263 - H279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
A. Kawamoto, T. Murayama, K. Kusano, M. Ii, T. Tkebuchava, S. Shintani, A. Iwakura, I. Johnson, P. von Samson, A. Hanley, et al. Synergistic Effect of Bone Marrow Mobilization and Vascular Endothelial Growth Factor-2 Gene Therapy in Myocardial Ischemia Circulation, September 14, 2004; 110(11): 1398 - 1405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.M Rubanyi The design and preclinical testing of Ad5FGF-4 to treat chronic myocardial ischaemia Eur. Heart J. Suppl., September 1, 2004; 6(suppl_E): E12 - E17. [Abstract] [Full Text]
|
|
|
|
|
|
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|
|
|
|
|
|
J. C. Wu, I. Y. Chen, Y. Wang, J. R. Tseng, A. Chhabra, M. Salek, J.-J. Min, M. C. Fishbein, R. Crystal, and S. S. Gambhir Molecular Imaging of the Kinetics of Vascular Endothelial Growth Factor Gene Expression in Ischemic Myocardium Circulation, August 10, 2004; 110(6): 685 - 691. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hattan, D. Warltier, W. Gu, C. Kolz, W. M. Chilian, and D. Weihrauch Autologous vascular smooth muscle cell-based myocardial gene therapy to induce coronary collateral growth Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H488 - H493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Williams and B. H. Annex Plasticity of Myocytes and Capillaries: A Possible Coordinating Role for VEGF Circ. Res., July 9, 2004; 95(1): 7 - 8. [Full Text] [PDF]
|
|
|
|
|
|
L. Ye, H. K Haider, S.-J. Jiang, and E. K. Sim Therapeutic Angiogenesis Using Vascular Endothelial Growth Factor Asian Cardiovasc Thorac Ann, June 1, 2004; 12(2): 173 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Losordo and S. Dimmeler Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease: Part I: Angiogenic Cytokines Circulation, June 1, 2004; 109(21): 2487 - 2491. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
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