Treatment of Critical Limb Ischemia: A shifting paradigm

Abstract

Critical limb ischemia (CLI), the most advanced stage of peripheral artery disease (PAD), is characterized by severely impaired perfusion of the lower limbs, which results in rest pain and/or tissue loss. It is associated with high risk for major amputation and cardiovascular events resulting in 6-month mortality rates up to 20%. These figures exceed numbers for every other form of occlusive cardiovascular disease and reflect the high systemic atherosclerotic burden. With an estimated annual incidence of 500-1,000 new cases per million individuals, CLI poses a substantial burden on patients, health care providers and resources. Over the past decades novel revascularizing strategies have been introduced and prognosis of CLI has gradually improved. However, current guidelines for the treatment of CLI are generally based on expert opinion and extrapolation of results from studies in milder PAD populations. Joining forces in transatlantic or continental initiatives may be necessary to be able to complete large randomized controlled trials (RCTs) in this specific population, ultimately leading to improved evidence-based treatment in CLI. Despite improvements in treatment of CLI, prognosis with respect to life and limb are still poor. CLI patients experience substantial functional impairment and pain, which leads to poor quality of life. This, together with the large number of CLI patients that is not eligible for conventional revascularization (25-40%) urges the need for novel therapeutic options aimed at improved limb perfusion. The discovery of a putative bone marrow (BM)-derived endothelial progenitor cell, resulted in a concept that BM-derived cells contribute to postnatal neovascularization. This led to the notion that BM cells might be used as a therapeutic agent in ischemic disease, such as CLI. Our recently performed meta-analysis on twelve RCTs that studied BM-derived cell therapy in CLI underlines the promising potential of this therapy, but also shows divergent results between placebo-controlled and non-placebo-controlled RCTs, stressing the need for a large, well-designed, placebo-controlled RCT with clinically relevant endpoints. Our randomized, double-blinded, placebo-controlled Juventas-trial, was designed to investigate whether repetitive intra-arterial infusion of BM-derived mononuclear cells (BM-MNC) reduces amputation rates in a large cohort of no-option CLI patients. With inclusion of 160 patients the Juventas-trial is currently the largest RCT in the field. The trial results show no benefit of BM-MNC compared to placebo infusion on all outcomes, e.g. amputation rates, ankle-brachial index, and quality of life. Moreover, the study shows general improvement in both the BM-MNC as well as the placebo group for objective and subjective outcomes. Our results contradict the reports of mainly small, non-placebo-controlled and non-randomized studies but seem in line with the results of our meta-analysis. The lack of effect of BM-MNC in the Juventas-trial could be related to our observations of reduced progenitor cell number and function in atherosclerotic CLI and related cardiovascular risk factors, which may hamper effect of autologous cell therapy in these patients. Future studies are warranted to investigate whether modified cell-based approaches, such as administration of specific cell subpobulations or interventions to restore progenitor cell function via pre-treatment strategies are effective in CLI.