PAD-related amputation is rarely caused by one factor alone: this evidence map shows how diabetes, tissue loss, kidney disease, delayed vascular assessment, undertreatment, and social inequality converge to decide who loses a limb. The full review highlights which therapies, warning signs, and limb-preservation pathways may reduce major amputation risk before the window for salvage is lost.
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Abstract: To synthesize current evidence regarding the predictors, pharmacological influences, clinical outcomes, and systemic disparities associated with lower extremity amputation in patients with peripheral artery disease (PAD). The review utilises 908 original studies with 17638901 total participants (topic deduplicated ΣN). Across the mapped evidence, PAD emerged as the dominant driver of major lower extremity amputation, with the diabetes–PAD combination associated with up to 51.8-fold higher amputation odds compared with diabetes alone and hazard ratios reaching 35.34 for first major amputation in diabetic foot ulcer cohorts. Recurrent signals supported a protective role for high-intensity statin therapy, proprotein convertase subtilisin/kexin type 9 inhibition, and low-dose rivaroxaban combined with aspirin after revascularization, whereas glucagon-like peptide-1 receptor agonists indicated benefit and sodium-glucose cotransporter-2 inhibitors showed heterogeneous directionality. The synthesis also highlighted persistent structural drivers of limb loss, including racial, Indigenous, and socioeconomic disparities, with 18 to 30% of patients reaching major amputation without prior vascular assessment and more than 70% lacking limb-sparing care in some cohorts. Practically, this evidence map supports earlier vascular triage, multidisciplinary limb-preservation pathways, and intensification of guideline-directed medical therapy in patients with chronic limb-threatening ischemia, tissue loss, or prior minor amputation, who represent a particularly high-risk phenotype. The mapped literature remains heterogeneous in study design, population, and follow-up, limiting the strength of any single directional signal. Future research should prioritize prospective head-to-head pharmacological comparisons across glucose-lowering classes in established PAD, validation of multi-marker and machine-learning risk models for major adverse limb events, and interventional studies targeting socioeconomic, insurance, and geographic determinants of inequitable amputation risk.
Final search date and database lock: 2026-05-01 21:41:47 CEST
Plan: Pro (expanded craft tokens; source: PubMed)
Source: PubMed
Total Abstracts/Papers: 1793
Downloaded Abstracts/Papers: 1793
Included original and non-original Abstracts/Papers (all): 1035
Included original Abstracts/Papers (Vote counting by direction of effect): 908
Reference Index (links used in paper): 183
Total participants (topic deduplicated ΣN): 17638901
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Reference Index (183)
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[127] Analysis of clinical characteristics in patients with diabetic foot ulcers undergoing amputation and establishment of a nomogram prediction model. — https://doi.org/10.1038/s41598-024-78215-7
[129] Opportunities for diabetes and peripheral artery disease-related lower limb amputation prevention in an Appalachian state: A longitudinal analysis. — https://doi.org/10.1016/j.pmedr.2021.101505
[130] Performance of prognostic markers in the prediction of wound healing or amputation among patients with foot ulcers in diabetes: a systematic review. — https://doi.org/10.1002/dmrr.2704
[132] Racial and/or ethnic and rural disparities in health care utilization before major lower extremity amputation in patients with peripheral artery disease. — https://doi.org/10.1016/j.jvs.2025.10.067
[134] The Impact of Chronic Kidney Disease on Amputation and Death Rates in Patients with Peripheral Artery Disease in the United States. — https://doi.org/10.1016/j.jvir.2025.03.013
[138] PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial. — https://doi.org/10.1093/bjs/znad437
[146] Systematic Review, Meta-analysis, and Time to Event Analysis of Contemporary Mortality after Major Lower Limb Amputation for Peripheral Arterial Disease or Diabetes Mellitus. — https://doi.org/10.1016/j.ejvs.2025.11.057
[156] Statin Therapy Reduces Future Risk of Lower-Limb Amputation in Patients With Diabetes and Peripheral Artery Disease. — https://doi.org/10.1210/jc.2016-3717
[159] Diabetes Mellitus and Its Impact on Patient-Profile and In-Hospital Outcomes in Peripheral Artery Disease. — https://doi.org/10.3390/jcm10215033
[160] Functional and transcriptomic analysis of extracellular vesicles identifies calprotectin as a new prognostic marker in peripheral arterial disease (PAD). — https://doi.org/10.1080/20013078.2020.1729646
[163] The Role of Early Revascularization and Biomarkers in the Management of Diabetic Foot Ulcers: A Single Center Experience. — https://doi.org/10.3390/diagnostics12020538
[164] Vascular Diagnostic and Surgical Treatments Before Lower Limb Amputations in Patients with Arterial Vascular Diseases: A Population Based Study from 2013 to 2015 in Germany. — https://doi.org/10.1016/j.ejvs.2021.05.016
[172] Patients undergoing major amputation for peripheral arterial disease are at high risk for developing major depressive disorder and requiring long-term antidepressants. — https://doi.org/10.1016/j.jvs.2025.03.185
[177] Amputation-free survival in patients with diabetic foot ulcer and peripheral arterial disease: Endovascular versus open surgery in a propensity score adjusted analysis. — https://doi.org/10.1016/j.jdiacomp.2020.107551
[185] The long-term mobility and mortality of patients with peripheral arterial disease following bilateral amputation. — https://doi.org/10.1053/ejvs.2002.1868
[186] Quantification of the Survival Disadvantage Associated with Major Amputation in Patients with Peripheral Arterial Disease. — https://doi.org/10.3390/jcm14010104
[192] Autologous bone-marrow mononuclear cell implantation reduces long-term major amputation risk in patients with critical limb ischemia: a comparison of atherosclerotic peripheral arterial disease and Buerger disease. — https://doi.org/10.1161/circinterventions.110.955724
[194] Interpretable Machine Learning for the Prediction of Amputation Risk Following Lower Extremity Infrainguinal Endovascular Interventions for Peripheral Arterial Disease. — https://doi.org/10.1007/s00270-022-03111-4
[205] Low rate of revascularization procedures and poor prognosis particularly in male patients with peripheral artery disease - A propensity score matched analysis. — https://doi.org/10.1016/j.ijcard.2017.12.054
[210] Cost analysis of limb salvage: comparing limb revascularisation and amputation in patients with Chronic Limb-Threatening Ischaemia (CLTI) at University Hospital Limerick. — https://doi.org/10.1007/s11845-025-03885-9
[218] Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD. — https://doi.org/10.1161/circulationaha.121.055146
[225] Predictors of lower extremity amputation in patients with diabetic foot ulcer: findings from MEDFUN, a multi-center observational study. — https://doi.org/10.1186/s13047-019-0345-y
[228] Cost Analysis of Initial Treatment With Endovascular Revascularization, Open Surgery, or Primary Major Amputation in Patients With Peripheral Artery Disease. — https://doi.org/10.1177/1526602818774786
[242] The Role of Muscle Density in Predicting the Amputation Risk in Peripheral Arterial Disease: A Tissue Composition Study Using Lower Extremity CT Angiography. — https://doi.org/10.3390/diagnostics15111439
[245] Outcomes of Revascularization for Peripheral Artery Disease in Aboriginal and Torres Strait Islander Peoples and Non-Indigenous Australians. — https://doi.org/10.1016/j.avsg.2025.03.004
[249] Temporal and Geographic Trends in the Treatment of Peripheral Arterial Disease Stratified by Race Among Medicare Beneficiaries. — https://doi.org/10.1001/jamacardio.2025.1714
[260] The role of prognostic nutritional index in predicting amputation in patients with lower extremity peripheral artery disease. — https://doi.org/10.34172/jcvtr.2021.02
[261] Development of Predictive Nomograms for Clinical Use to Quantify the Risk of Amputation in Patients with Diabetic Foot Ulcer. — https://doi.org/10.1155/2021/6621035
[276] Peripheral Artery Disease Negatively Impacts Gait Function in Patients with Below-Knee Amputation with Targeted Muscle Reinnervation. — https://doi.org/10.1016/j.avsg.2025.11.126
[280] Do Women Have Worse Amputation-Free Survival Than Men Following Endovascular Procedures for Peripheral Arterial Disease? An Evaluation of the California State-Wide Database. — https://doi.org/10.1177/1538574415608269
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[302] Single Center Outcomes of Percutaneous Deep Vein Arterialization in Patients with End-Stage Peripheral Artery Disease. — https://doi.org/10.1177/15385744231226047
[312] Prognostic value of C-reactive protein to albumin ratio for long-term outcomes of patients with peripheral arterial disease underwent endovascular treatment. — https://doi.org/10.1177/17085381211025172
[322] High hemoglobin A associated with increased adverse limb events in peripheral arterial disease patients undergoing revascularization. — https://doi.org/10.1016/j.jvs.2017.06.101
[324] Impact of COVID-19 Pandemic on Clinical Care of Peripheral Arterial Disease Patients: A Single-Center Experience. — https://doi.org/10.3390/jcm12030890
[330] Reducing Nontraumatic Lower-Extremity Amputations by 20% by 2030: Time to Get to Our Feet: A Policy Statement From the American Heart Association. — https://doi.org/10.1161/cir.0000000000000967
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[342] Three-Year Outcomes From the LIBERTY 360 Study of Endovascular Interventions for Peripheral Artery Disease Stratified by Rutherford Category. — https://doi.org/10.1177/1526602820962972
[384] Risk factors for lower extremity amputation in patients with diabetic foot ulcers: a hospital-based case-control study. — https://doi.org/10.3402/dfa.v6.29629
[390] Risk of lower extremity complications with GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors in peripheral artery disease. — https://doi.org/10.1016/j.diabres.2025.112982
[400] Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: The EUCLID trial. — https://doi.org/10.1177/1358863x19864172
[427] Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). — https://doi.org/10.1161/circulationaha.117.032235
[439] Editor's Choice - Major Adverse Limb Events in Patients Undergoing Revascularisation for Lower Limb Peripheral Arterial Disease: A Nationwide Observational Study. — https://doi.org/10.1016/j.ejvs.2024.07.041
[445] Cohort Study Examining the Presentation, Distribution, and Outcomes of Peripheral Artery Disease in Aboriginal, Torres Strait Islander, and Non-Indigenous Australians. — https://doi.org/10.1016/j.ejvs.2023.05.027
[456] A Belarusian Perspective on Revascularization Outcomes in Patients with Peripheral Arterial Disease and Associated Diabetes Mellitus. — https://doi.org/10.1016/j.avsg.2025.10.024
[461] The Use of Paclitaxel-Coated Devices in the Treatment of Peripheral Arterial Disease is Not Associated With Increased Mortality or Amputations. — https://doi.org/10.1016/j.avsg.2022.04.047
[464] Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: A trial-level meta-analysis including 51 713 individuals. — https://doi.org/10.1111/dom.14159
[482] Effects of PCSK9 inhibitors on vascular function, lipid profile, and cardiovascular outcomes in patients with peripheral artery disease: A systematic review and meta-analysis. — https://doi.org/10.1016/j.ijcrp.2026.200590
[487] Reconsidering the Impact of Endovascular Repair on Short-Term and Mid-Term Outcomes in Peripheral Arterial Disease: A Retrospective Analysis. — https://doi.org/10.1016/j.avsg.2023.12.068
[496] Evaluation of Risk Factors for Limb-Specific Peripheral Vascular Events in Patients With Peripheral Artery Disease: A Post Hoc Analysis of the SEASON Prospective Observational Study. — https://doi.org/10.1177/0003319718814351
[504] The Impact of Chronic Kidney Disease on Hospitalized Patients With Peripheral Arterial Disease and Critical Limb Ischemia. — https://doi.org/10.1177/0003319716638797
[513] Editor's Choice - Effect of Physical Activity and Tobacco Use on Mortality and Morbidity in Patients with Peripheral Arterial Disease After Revascularisation: A Korean Nationwide Population Based Cohort Study. — https://doi.org/10.1016/j.ejvs.2022.05.047
[515] The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: real-world study. — https://doi.org/10.1093/eurheartj/ehaa956
[546] Descriptive Analysis of Types and Diagnoses Associated with Lower Extremity Amputation: Analysis of the US Veterans Health Administration Database 2019-2023. — https://doi.org/10.1007/s12325-024-03005-6
[554] Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Safety and Therapeutic Efficacy of Angiogenesis Induced by Intraarterial Autologous Bone Marrow-Derived Stem Cells in Patients with Severe Peripheral Arterial Disease. — https://doi.org/10.1016/j.jvir.2020.09.003
[559] Effectiveness of revascularization of the ulcerated foot in patients with diabetes and peripheral artery disease: a systematic review. — https://doi.org/10.1002/dmrr.2705
[560] Racial and Ethnic Disparities in the Diagnosis and Care of Peripheral Artery Disease in the United States: A Systematic Review. — https://doi.org/10.7759/cureus.104538
[602] Development and evaluation of a prediction model for peripheral artery disease-related major adverse limb events using novel biomarker data. — https://doi.org/10.1016/j.jvs.2024.03.450
[608] Vascular surgery trends in Australia: 2001-2015: less open surgery, less limb loss and more endovascular intervention. — https://doi.org/10.1111/ans.14878
[613] Editor's Choice - Comparison of Outcomes After Open Surgical and Endovascular Lower Extremity Revascularisation Among End Stage Renal Disease Patients on Dialysis. — https://doi.org/10.1016/j.ejvs.2018.09.008
[620] Efficacy of a Guideline-Recommended Risk-Reduction Program to Improve Cardiovascular and Limb Outcomes in Patients With Peripheral Arterial Disease. — https://doi.org/10.1001/jamasurg.2016.0415
[648] Multidisciplinary approach achieves limb salvage without revascularization in patients with mild to moderate ischemia and tissue loss. — https://doi.org/10.1016/j.jvs.2019.07.103
[658] Adverse cardiovascular, limb, and renal outcomes in patients with diabetes after peripheral artery disease revascularization treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors. — https://doi.org/10.1186/s13098-023-00982-6
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[704] Reducing major lower extremity amputations after the introduction of a multidisciplinary team in patient with diabetes foot ulcer. — https://doi.org/10.1186/s12902-016-0111-0
[716] Higher long-term cardiovascular morbidity after open surgery for intermittent claudication caused by infrainguinal atherosclerotic disease in patients with diabetes - a nationwide observational cohort study. — https://doi.org/10.1024/0301-1526/a000929
[726] No Clinical Benefit of Intramuscular Delivery of Bone Marrow-derived Mononuclear Cells in Nonreconstructable Peripheral Arterial Disease: Results of a Phase-III Randomized-controlled Trial. — https://doi.org/10.1097/sla.0000000000002896
[727] Nationwide Trends in Hospital Outcomes and Utilization After Lower Limb Revascularization in Patients on Hemodialysis. — https://doi.org/10.1016/j.jcin.2017.05.050
[731] Association of Health Care Utilization and Access to Care With Vascular Assessment Before Major Lower Extremity Amputation Among US Veterans. — https://doi.org/10.1001/jamasurg.2023.0479
[738] Validation of the global limb anatomical staging system in Vietnamese patients treated for chronic limb-threatening ischemia. — https://doi.org/10.1186/s42155-024-00433-x
[770] The Identification and Evaluation of Interleukin-7 as a Myokine Biomarker for Peripheral Artery Disease Prognosis. — https://doi.org/10.3390/jcm13123583
[772] Glucagon-like peptide-1 receptor agonists are associated with fewer major adverse cardiovascular and limb events in patients with moderate peripheral arterial disease. — https://doi.org/10.1016/j.jvs.2025.05.037
[783] Malnutrition is Associated with Increased Morbidity and Death in Dialysis Patients Undergoing Endovascular Therapy for Peripheral Artery Disease. — https://doi.org/10.1016/j.ejvs.2022.03.045
[792] Effectiveness and safety of rivaroxaban following peripheral arterial endovascular revascularization in real-world practice. — https://doi.org/10.1016/j.jvs.2026.02.032
[819] Understanding the Prevalence of Medial Arterial Calcification Among Complex Reconstructive Patients: Insights from a Decade of Experience at a Tertiary Limb Salvage Center. — https://doi.org/10.3390/jcm14020596
[942] Major adverse cardiovascular and limb events in patients with diabetes and concomitant peripheral artery disease treated with sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase-4 inhibitor. — https://doi.org/10.1186/s12933-020-01118-0
[988] Paclitaxel-Coated Balloons for Femoropopliteal Artery Disease Treatment in French Patients: A Longitudinal Observational Study. — https://doi.org/10.1002/ccd.31581
[1017] Thirty-day outcomes from the Disrupt PAD BTK II study of the Shockwave Intravascular Lithotripsy System for treatment of calcified below-the-knee peripheral arterial disease. — https://doi.org/10.1016/j.jvs.2024.11.003
