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J Am Coll Cardiol, 2000; 36:2132-2139
© 2000 by the American College of Cardiology Foundation
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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* {dagger}, Nicholas A. Chronos, MD{ddagger}, 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
{dagger} Interventional Cardiology Section, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
{ddagger} 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.

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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