Contralateral Major Amputation Following Diabetes- and Peripheral Artery Disease-Related Limb Loss: A Systematic Review and Pooled Meta-Analysis

Major amputation remains a devastating and understudied outcome in patients with peripheral artery disease (PAD), chronic limb-threatening ischemia (CLTI), and diabetes mellitus (DM)-related limb disease. Although modern vascular care emphasizes index and symptomatic limb surveillance, the population-level risk of non-index limb (NIL) major amputation remains incompletely defined. We performed a systematic review and meta-analysis to quantify NIL major amputation incidence and evaluate factors associated with contralateral limb loss.

A systematic search of PubMed (MEDLINE), Embase, and Scopus through January 2026 was conducted in accordance with PRISMA guidelines. Studies reporting contralateral above- or below-knee amputation in adults with PAD, CLTI, DM-related limb disease, or prior ipsilateral major amputation were included. Single-arm random-effects meta-analysis using the restricted maximum likelihood (REML) estimator was performed with log-transformed effect sizes. Subgroup analyses were conducted by clinical phenotype, geographic location, study era, and DM prevalence. Secondary outcomes included overall mortality, bilateral major amputation, NIL minor amputation, NIL revascularization, and development of NIL CLTI.

Seventeen cohorts encompassing 30,359 patients were included. The pooled incidence of NIL major amputation was 6 per 100 person-years (95% CI, 3-9), with substantial heterogeneity (I2=98.93%). Meta-regression showed no significant differences by clinical phenotype (P=.622), geographic region (P=.662), study era (P=.893), or DM prevalence (P=.127). Clinical phenotypes included CLTI versus non-CLTI PAD or DM versus post-ipsilateral major amputation. Geographic region was divided into United States and international studies. Study era was divided into modern (2010-2025) and legacy (pre-2010) studies. Longer follow-up duration was inversely associated with reported incidence (P<.001). Pooled mortality rate was 38% (95% CI, 30-47%), and the pooled rate of bilateral major amputation was 12% (95% CI, 8-18%). Other secondary outcomes included a pooled NIL minor amputation rate of 11% (95% CI, 3-37%), NIL revascularization rate of 19% (95% CI, 6-47%), and NIL CLTI development rate of 32% (95% CI, 11-64%).

NIL major amputation remains a persistent risk in PAD and DM-related limb disease. These findings support the need for structured bilateral limb surveillance and early NIL risk stratification to inform comprehensive limb preservation care.