Evolving Paradigms in Chronic Limb-threatening Ischemia: A Systematic Review of Current and Emerging Diagnostic and Therapeutic Approaches

Abstract Chronic limb-threatening ischemia (CLTI) is the most advanced and serious stage of peripheral artery disease and associated with severe ischemic pain, non-healing wounds, high rates of amputation, and significant mortality. Although it affects fewer patients than other forms of peripheral artery disease, CLTI creates a larger burden on healthcare. The global prevalence of CLTI is increasing due to aging populations with risk factors like diabetes. Despite significant progress in revascularization, achieving durable limb salvage is challenging. This is due to complex multilevel arterial disease, severe calcification, microvascular dysfunction, infection, neuropathy, and poor wound healing. These challenges highlight the need for a current review of both existing and new treatment strategies. This review looks at the changing understanding of CLTI pathophysiology, diagnostic methods, and risk assessment tools. Better anatomical and clinical staging systems, like GLASS and WIfI, allow for more accurate risk assessment treatment plans tailored to them. The review discusses current medical, endovascular, surgical, and hybrid revascularization methods in light of current evidence. Endovascular technologies like intravascular imaging, drug-eluting devices, and atherectomy can now be used for complex vascular diseases. Multidisciplinary limb preservation programs with vascular intervention, wound care, infection management, and rehabilitation have decreased rates of amputations and hospitalization. For patients with challenging anatomy, deep venous arterialization and regenerative and biologic therapies, which target microvascular problems, have shown promise. Future advancements in CLTI treatment will rely on combining technological innovation, biologically targeted therapies, and multidisciplinary care pathways to prevent amputations and enhance the quality of life for CLTI patients.