Revascularization of intermittent claudicants leads to more chronic limb-threatening ischemia and higher amputation rates

Madabhushi, Vashisht; Davenport, Daniel L.; Jones, Stuart; Khoudoud, Sami Abul; Orr, Nathan; Minion, David J.; Endean, Eric D.; Tyagi, Suresh C.

doi:10.1016/j.jvs.2021.02.045

Cited by 26 publications

(7 citation statements)

References 26 publications

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“…However, it does not address the underlying systemic atherosclerosis or the risk of associated CVD. Lower extremity revascularization may also accelerate the progression to critical limb threatening ischemia [ 16 – 18 , 66 ]. Metformin has salient properties beyond that of glucose control with mounting evidence for its pro-mitochondrial and anti-inflammatory properties, potential to promote arteriogenesis, reduction in the incidence of diseases of aging including CVDs, and improved longevity [ 21 , 24 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Exercise and revascularization can improve symptoms [ 13 ] but the improvements are not consistently sustained, are highly dependent on patient compliance, and do not reduce associated CVD morbidity and mortality [ 14 , 15 ]. Further, vascular interventions to alleviate IC may lead to accelerated PAD progression to critical limb threatening ischemia [ 16 – 18 ].…”

Section: Introductionmentioning

confidence: 99%

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MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol

Reitz

Althouse

Forman

et al. 2023

BMC Cardiovasc Disord

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Background Peripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC. Methods 200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol. Discussion MOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC. Trial Registration: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol

Reitz

Althouse

Forman

et al. 2023

BMC Cardiovasc Disord

View full text Add to dashboard Cite

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“…Therefore, the restoration of the patency of the arterial vessels guided the therapeutic process towards an invasive treatment. However, the relatively recent awareness of a progression of PAD with a consistent risk of MALE [ 55 , 81 , [188] , [189] , [190] ] has led to the fundamental recommendation to prioritize the correction of risk factors, optimize pharmacological therapy and increase exercise tolerance through the introduction of supervised exercise programs. Revascularization at any stage of PAD is an independent risk factor of worse long-term limb salvage outcomes, therefore, the real clinical need for prompt revascularization should guide the physician to seek such treatment.…”

Section: Predictors Of Male Why So Important?mentioning

confidence: 99%

Principal predictors of major adverse limb events in diabetic peripheral artery disease: A narrative review

Biscetti

Cecchini

Rando

et al. 2021

Atherosclerosis Plus

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“…The question of whether invasive treatment for IC leads to excessive later limb-related adverse events continues to be debated. Some studies suggest worse limb outcomes after invasive treatment, 12 whereas other conflicting evidence shows equivalent results. 4,13 All of these are retrospective studies, and potential selection biases such as invasive treatment being performed for more severe symptoms cannot be excluded.…”

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confidence: 99%

Long-Term Outcomes of Exercise Therapy Versus Revascularization in Patients With Intermittent Claudication

et al. 2023

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Objective: The aim was to analyze the risk of progression to chronic limb-threatening ischemia (CLTI), amputation and subsequent interventions after revascularization versus noninvasive therapy in patients with intermittent claudication (IC). Background: Conflicting evidence exists regarding adverse limb outcomes after each treatment strategy. Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. MEDLINE, Web of Science, and Google Scholar were searched aided by a health sciences librarian through August 16, 2022. Randomized control trials (RCTs) comparing invasive (endovascular or surgical revascularization) and noninvasive treatment (exercise and/or medical treatment) were included. PROSPERO registration was completed (CRD42022352831). Results: A total of 9 RCTs comprising 1477 patients (invasive, 765 patients; noninvasive, 712 patients) were eligible. During a mean of 3.6-year follow-up, progression to CLTI after invasive [5 (2–8) per 1000 person-years] and noninvasive treatment [6 (3–10) per 1000 person-years] were not statistically different [rate ratio (RR): 0.77; 95% CI, 0.35–1.69; P=0.51, I 2=0%]. Incidence of amputation (RR: 1.69; 95% CI, 0.54–5.26; P=0.36, I 2=0%) and all-cause mortality (hazard ratio: 1.26; 95% CI, 0.91–1.74; P=0.16, I 2=0%) also did not differ between the groups. However, the invasive treatment group underwent significantly more revascularizations (RR: 4.15; 95% CI, 2.80–6.16; P<0.00001, I 2=83%). The results were not changed by fixed effect or random-effects models, nor by sensitivity analysis. Conclusions: Although there is equivalent risk of progression to CLTI, major amputation and all-cause mortality compared with noninvasive treatment, invasive treatment for patients with IC led to significantly more revascularization procedures and should be used selectively in patients with major lifestyle limitation. Guideline recommendation of noninvasive treatment for first-line IC therapy is supported.

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Revascularization of intermittent claudicants leads to more chronic limb-threatening ischemia and higher amputation rates

Cited by 26 publications

References 26 publications

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol

Principal predictors of major adverse limb events in diabetic peripheral artery disease: A narrative review

Long-Term Outcomes of Exercise Therapy Versus Revascularization in Patients With Intermittent Claudication

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