A pattern of underutilization of established medical therapies and lifestyle interventions was shown throughout all geographic regions studied and vascular disease subtypes.4 Chronic limb ischemia reflects the local manifestations of a lethal systemic disease — atherosclerosis. If left untreated, chronic limb ischemia can result in major limb

loss. Critical limb ischemia can be separated into four distinct cohorts: asymptomatic, claudication, critical limb ischemia with rest pain, and critical limb ischemia with tissue loss. The natural history of critical limb ischemia is well documented. At 1 year, #FHPI keyword# 25% of patients will be dead, 30% will have undergone amputation, and 45% will be alive with Inhibitors,research,lifescience,medical both limbs.1 More than 60% of patients with critical limb ischemia will be dead at 5 years.6 Patients with critical limb ischemia are at an exceptionally high risk for cardiovascular events, and the majority will eventually die of a cardiac or cerebrovascular event. The more symptomatic and severe the critical limb

ischemia as objectively measured by the Inhibitors,research,lifescience,medical ankle-brachial index (ABI), the worse the overall patient prognosis (Figure 1). In the REACH registry, the relative risk of dying among patients with large-vessel critical limb ischemia versus none was 3.1 (95% CI 1.9–4.9) for deaths from all causes and 5.9 (95% CI 3.0–11.4) for Inhibitors,research,lifescience,medical all deaths from cardiovascular disease. Mortality due to cardiovascular disease was 15-fold higher among symptomatic subjects with severe large-vessel critical limb ischemia. Finally, critical limb ischemia has been classified as a coronary heart disease (CHD) risk equivalent Inhibitors,research,lifescience,medical (i.e., carrying >20% risk of a coronary event in 10 years). Figure 1 10-year survival in patients with asymptomatic and

symptomatic peripheral arterial disease. The Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001)7 classified diabetes, multiple cardiac risk factors, and critical limb ischemia, including carotid disease and abdominal aortic aneurysm, as a CHD risk equivalent. The epidemic of diabetes Casein kinase 1 and metabolic syndrome has escalated the number of lower-extremity problems presenting for treatment. It has been estimated that 50% of diabetic patients have evidence of chronic critical limb ischemia.8 Diabetics suffer from both micro- and macro-vascular disease of complex etiology, manifested often as ischemia but more frequently as motor or sensory neuropathies.9 Globally, diabetes accounts for 1 amputation every 30 seconds and 80,000 amputations annually in the United States alone. Fifty percent of these patients will have an above- or below-knee amputation, 50% will require a second amputation within 5 years, and 50% will be dead in five years.