Abstract

BACKGROUND: Intermittent claudication (IC) is a common pathology, affecting 4.5% of the United Kingdom population, and is associated with significant health burden if disease progresses to chronic limb-threatening ischemia (CLTI). The natural history of conservatively managed IC remains poorly described, and this study aimed to examine the rate and predictors of progression from IC to CLTI. METHODS: Systematic review (PROSPERO ID: CRD42023401259) in accordance with Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines of available literature using Scopus, World of Science, Medline, Embase, and CINAHL databases. Adult patients with IC managed conservatively were included. Progression rate was defined as percentage of IC patients developing CLTI at follow-up. Predictors identified from univariate and multivariate analyses were included. A quantitative synthesis was planned if studies depicted homogeneity. RESULTS: Search terms yielded 6,404 unique reports. Nine studies (7 retrospective and 2 prospective cohorts) on a total of 4,115 patients were included in the primary synthesis. Women constituted 22.7% on average (0-30.1%) of patients included within studies. All included studies were nonrandomized cohort designs with expected limitations in terms of determining causal effect. The risk of bias was assessed as "moderate" in 5, and "serious" in 4 of the 9 included studies. 1.1-36.7% of claudicants from studies included developed CLTI by end of follow-up (mean 5.4 ± 2.72 years). A pooled progression rate of 15.26% at maximal (10 years) follow-up did not reach significance (P = 0.67) in meta-analysis and is likely unreliable, demonstrating 99% heterogeneity (P < 0.01). Predictors of progression were advanced age, diabetes, hemodialysis, smoking, serum low-density lipoprotein, HbA1c, and baseline severity of ischemia (Ankle-brachial index, Toe-brachial index and claudication distance) in univariate analysis. Diabetes, smoking and hemodialysis were predictors of progression in multivariate analysis. Only three studies investigating biomarkers of peripheral arterial disease (PAD) progression were found. CONCLUSIONS: Diabetes, renal failure, and smoking are significant predictors of PAD progression. Poor quality evidence and data heterogeneity preclude conclusive estimates of progression rates. Women are underrepresented among studies. Future structured, prospective prognostic studies addressing the progression of conservatively managed IC are needed to inform personalized management strategies.