title: Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA).
abstract: BACKGROUND
  Critical limb ischemia due to peripheral arterial occlusive disease is associated with a severely increased morbidity and mortality. There is no effective pharmacological therapy available. Injection of autologous bone marrow-derived mononuclear cells (BM-MNC) is a promising therapeutic option in patients with critical limb ischemia, but double-blind, randomized trials are lacking.
  
  
  RESULTS
  Forty patients with critical limb ischemia were included in a multicenter, phase II, double-blind, randomized-start trial to receive either intraarterial administration of BM-MNC or placebo followed by active treatment with BM-MNC (open label) after 3 months. Intraarterial administration of BM-MNC did not significantly increase ankle-brachial index and, thus, the trial missed its primary end point. However, cell therapy was associated with significantly improved ulcer healing (ulcer area, 3.2±4.7 cm(2) to 1.89±3.5 cm(2) [P=0.014] versus placebo, 2.92±3.5 cm(2) to 2.89±4.1 cm(2) [P=0.5]) and reduced rest pain (5.2±1.8 to 2.2±1.3 [P=0.009] versus placebo, 4.5±2.4 to 3.9±2.6 [P=0.3]) within 3 months. Limb salvage and amputation-free survival rates did not differ between the groups. Repeated BM-MNC administration and higher BM-MNC numbers and functionality were the only independent predictors of improved ulcer healing. Ulcer healing induced by repeated BM-MNC administration significantly correlated with limb salvage (r=0.8; P<0.001).
  
  
  CONCLUSIONS
  Intraarterial administration of BM-MNC is safe and feasible and accelerates wound healing in patients without extensive gangrene and impending amputation. These exploratory findings of this pilot trial need to be confirmed in a larger randomized trial in patients with critical limb ischemia and stable ulcers.
authors.affiliation: Division of Cardiology and Angiology, Department of Radiology, University of Frankfurt, Theodor-Stern Kai 7, Frankfurt, Germany. dirkhwalter@yahoo.com
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Walter
authors.forename: Hans
authors.initials: H
authors.lastname: Krankenberg
authors.forename: Jörn O
authors.initials: JO
authors.lastname: Balzer
authors.forename: Christoph
authors.initials: C
authors.lastname: Kalka
authors.forename: Iris
authors.initials: I
authors.lastname: Baumgartner
authors.forename: Michael
authors.initials: M
authors.lastname: Schlüter
authors.forename: Torsten
authors.initials: T
authors.lastname: Tonn
authors.forename: Florian
authors.initials: F
authors.lastname: Seeger
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Edelgard
authors.initials: E
authors.lastname: Lindhoff-Last
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
mesh_terms: D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007269:Injections, Intra-Arterial; D007511:Ischemia / Q000601:surgery*; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D058729:Peripheral Arterial Disease / Q000601:surgery*; D010865:Pilot Projects; D033581:Stem Cell Transplantation; D013234:Stem Cells; D016896:Treatment Outcome