Published Online
on August 8, 2005

A more recent version of this article appeared on August 16, 2005

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Submitted on December 19, 2004
Revised on April 10, 2005
Accepted on May 3, 2005

START Trial. A Pilot Study on STimulation of ARTeriogenesis Using Subcutaneous Application of Granulocyte-Macrophage Colony-Stimulating Factor as a New Treatment for Peripheral Vascular Disease

Niels van Royen MD, PhD^*, Stephan H. Schirmer MD, Bektas Atasever MD, Casper Y.H. Behrens MD, Dirk Ubbink MD, PhD, Eva E. Buschmann MD, Michiel Voskuil MD, PhD, Pieter Bot MD, Imo Hoefer MD, PhD, Reinier O. Schlingemann MD, PhD, Bart J. Biemond MD, PhD, J. G. Tijssen PhD, Christoph Bode MD, Wolfgang Schaper MD, PhD, Jacques Oskam MD, PhD, Dink A. Legemate MD, PhD, Jan J. Piek MD, PhD, and Ivo Buschmann MD

From the Department of Cardiology (N.v.R., B.A., C.Y.H.B., M.V., P.B., J.G.T., J.J.P.), the Department of Vascular Surgery (D.U., D.A.L.), the Department of Ophthalmology (R.O.S.), and the Department of Hematology (B.J.B.), University of Amsterdam, the Netherlands; the Department of Cardiology, University of Freiburg, Germany (S.H.S., E.E.B., I.H., C.B., I.B.); the Department of Experimental Cardiology, Max Planck Institute, Bad Nauheim, Germany (W.S.); and the Department of Vascular Surgery, Rijnland Hospital, Leiderdrop, the Netherlands (J.O.).

^* To whom correspondence should be addressed. E-mail: n.vanroyen{at}amc.uva.nl.

Background--Granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently shown to increase collateral flow index in patients with coronary artery disease. Experimental models showed beneficial effects of GM-CSF on collateral artery growth in the peripheral circulation. Thus, in the present study, we evaluated the effects of GM-CSF in patients with peripheral artery disease.

Methods and Results--A double-blinded, randomized, placebo-controlled study was performed in 40 patients with moderate or severe intermittent claudication. Patients were treated with placebo or subcutaneously applied GM-CSF (10 µg/kg) for a period of 14 days (total of 7 injections). GM-CSF treatment led to a strong increase in total white blood cell count and C-reactive protein. Monocyte fraction initially increased but thereafter decreased significantly as compared with baseline. Both the placebo group and the treatment group showed a significant increase in walking distance at day 14 (placebo: 127±67 versus 184±87 meters, P=0.03, GM-CSF: 126±66 versus 189±141 meters, P=0.04) and at day 90. Change in walking time, the primary end point of the study, was not different between groups. No change in ankle-brachial index was found on GM-CSF treatment at day 14 or at day 90. Laser Doppler flowmetry measurements showed a significant decrease in microcirculatory flow reserve in the control group (P=0.03) and no change in the GM-CSF group.

Conclusions--The present study does not support the use of GM-CSF for treatment of patients with moderate or severe intermittent claudication. Issues that need to be addressed are dosing, the selection of patients, and potential differences between GM-CSF effects in the coronary and the peripheral circulation.

Key words: angiogenesis • collateral circulation • growth substances • leukocytes • peripheral vascular disease

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