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One to 2% of individuals with peripheral arterial disease experience its most severe stage, critical limb ischemia (CLI). Within 1 year after an episode of CLI, 25% will undergo a major amputation.1 Ischemic ulcers associated with CLI are more likely to heal if distal bypass surgery increases skin perfusion pressure to at least 35 mmHg.2 If bypass surgery is ineffective3 or no longer suitable, there are limited options for achieving ischemic ulcer healing, improving walking time and distance, limiting CLI-related pain, or delaying amputation or death. Research exploring autologous mononuclear bone marrow stem cells (ABMC),1 stents,4 intermittent pneumatic compression,5 gene therapy,6,7 or other options for improving CLI healing, pain, amputation, or mortality outcomes, have met with varying success.
Though a Cochrane review of studies published through November 2010 found insufficient evidence supporting efficacy of ABMC therapy in CLI patients without other options, 2 recent double-blind, randomized controlled trials (RCTs)8,9 reviewed in this month’s Evidence Corner, bring ABMC therapy effects into clearer focus.
Laura Bolton, PhD, FAPWCA
Adjunct Associate Professor
Department of Surgery, UMDNJ
WOUNDS Editorial Advisory Board Member and Department Editor
Tissue Loss Affects Amputations for CLI Patients
Reference: Benoit E, O’Donnell TF Jr, Iafrati MD, et al. The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design. J Transl Med. 2011;9:165.
Rationale: Subjects with no established options for treating CLI (No-Option CLI) face amputation and related death. Only a double-blind RCT can eliminate patient and physician bias in reporting time and reason for major amputation.
Objective: Evaluate clinical efficacy of ABMC in preventing major amputations in a prospective double-blind RCT and conduct a meta-analysis of the related literature on No-Option CLI subjects receiving intramuscular ABMC.
Methods: ABMC or autologous peripheral blood were injected intramuscularly into 48 randomly assigned (2:1 therapy to control) No-Option CLI patients. Patients and the treating and evaluating teams were blinded to assignment. The primary outcome measure was percent of major amputations experienced by each group within 6 months after treatment. A systematic review of 9 RCTs on No-Option CLI subjects with tissue loss placed these results into perspective.
Results: Of 15 amputations observed, most occurred in the first 4 months. One amputation (5.6%) occurred in a patient with a Rutherford score of 4 (rest pain with no tissue damage) compared to 46.7% of subjects with a Rutherford score of 5 (tissues loss) experiencing amputations (P = 0.003). Among subjects with tissue loss, 39% of ABMC subjects, or 71% of placebo subjects, experienced an amputation during the first 6 months after treatment. Neither this difference, nor a similar trend toward longer amputation-free survival time, was statistically significant, due to the small sample size. A meta-analysis of studies including CLI patients with tissue loss or with only rest pain confirmed the higher incidence of major amputations in subjects with tissue loss, as compared to those with only rest pain.
Authors’ Conclusions: While the ABMC compared to placebo effect on amputation rate is clinically meaningful, a larger double-blind RCT is required to support ABMC clinical efficacy.