Intraarterial Administration of Bone Marrow Mononuclear Cells in Patients With Critical Limb Ischemia A Randomized-Start, Placebo-Controlled Pilot Trial (PROVASA)

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. Methods and 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.