{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:19:29Z","timestamp":1780582769607,"version":"3.54.1"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T00:00:00Z","timestamp":1674259200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T00:00:00Z","timestamp":1674259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100019713","name":"VA Pittsburgh Healthcare System","doi-asserted-by":"publisher","award":["CX002150"],"award-info":[{"award-number":["CX002150"]}],"id":[{"id":"10.13039\/100019713","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cardiovasc Disord"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000\u00a0mg\/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\u00a0days of study drug exposure, and 180\u00a0days 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>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.<\/jats:p>\n                <jats:p><jats:italic>Trial Registration<\/jats:italic>: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12872-023-03047-8","type":"journal-article","created":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T05:03:02Z","timestamp":1674277382000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol"],"prefix":"10.1186","volume":"23","clinical-trial-number":[{"clinical-trial-number":"nct05132439","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Katherine M.","family":"Reitz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Althouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Forman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian S.","family":"Zuckerbraun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoram","family":"Vodovotz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Zamora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Raffai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-6798","authenticated-orcid":false,"given":"Edith","family":"Tzeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,21]]},"reference":[{"key":"3047_CR1","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1161\/CIRCULATIONAHA.109.918417","volume":"122","author":"G Brevetti","year":"2010","unstructured":"Brevetti G, Giugliano G, Brevetti L, Hiatt WR. Inflammation in periapheral artery disease. Circulation. 2010;122:1862\u201375.","journal-title":"Circulation"},{"key":"3047_CR2","doi-asserted-by":"publisher","first-page":"H456","DOI":"10.1152\/ajpheart.00235.2020","volume":"319","author":"SY Park","year":"2020","unstructured":"Park SY, Pekas EJ, Headid RJ, Son WM, Wooden TK, Song J, et al. Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease. Am J Physiol Hear Circ Physiol. 2020;319:H456\u201367.","journal-title":"Am J Physiol Hear Circ Physiol"},{"key":"3047_CR3","doi-asserted-by":"publisher","first-page":"2188","DOI":"10.1001\/jama.2021.2126","volume":"325","author":"TS Polonsky","year":"2021","unstructured":"Polonsky TS, McDermott MM. Lower extremity peripheral artery disease without chronic limb-threatening ischemia: a review. JAMA J Am Med Assoc. 2021;325:2188\u201398.","journal-title":"JAMA J Am Med Assoc"},{"key":"3047_CR4","first-page":"1989","volume":"38","author":"JA Mayfield","year":"2001","unstructured":"Mayfield JA, Caps MT, Reiber GE, Maynard C, Czerniecki JM, Sangeorzan BJ. Trends in peripheral vascular procedures in the Veterans Health Administration. J Rehabil Res Dev. 2001;38:1989\u201398.","journal-title":"J Rehabil Res Dev"},{"key":"3047_CR5","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/s11606-009-1160-0","volume":"25","author":"DW Brown","year":"2010","unstructured":"Brown DW. Smoking prevalence among US veterans. J Gen Intern Med. 2010;25:147\u20139.","journal-title":"J Gen Intern Med"},{"key":"3047_CR6","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.jvs.2017.11.083","volume":"68","author":"J Willey","year":"2018","unstructured":"Willey J, Mentias A, Vaughan-Sarrazin M, McCoy K, Rosenthal G, Girotra S. Epidemiology of lower extremity peripheral artery disease in veterans. J Vasc Surg. 2018;68:527-535.e5. https:\/\/doi.org\/10.1016\/j.jvs.2017.11.083.","journal-title":"J Vasc Surg"},{"key":"3047_CR7","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.ejvs.2015.10.022","volume":"51","author":"B Sigvant","year":"2016","unstructured":"Sigvant B, Lundin F, Wahlberg E. The risk of disease progression in peripheral arterial disease is higher than expected: a meta-analysis of mortality and disease progression in peripheral arterial disease. Eur J Vasc Endovasc Surg. 2016;51:395\u2013403. https:\/\/doi.org\/10.1016\/j.ejvs.2015.10.022.","journal-title":"Eur J Vasc Endovasc Surg"},{"key":"3047_CR8","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1001\/jama.292.4.453","volume":"292","author":"M McDermott","year":"2004","unstructured":"McDermott M, Liu K, Greenland P, Guralnik J, Criqui M, Chan C, et al. Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. J Am Med Assoc. 2004;292:453\u201361. https:\/\/doi.org\/10.1001\/jama.292.4.453.","journal-title":"J Am Med Assoc"},{"key":"3047_CR9","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1016\/j.jacc.2008.09.063","volume":"53","author":"MM McDermott","year":"2009","unstructured":"McDermott MM, Guralnik JM, Tian L, Liu K, Ferrucci L, Liao Y, et al. Associations of borderline and low normal ankle-brachial index values with functional decline at 5-year follow-up. The WALCS (Walking and Leg Circulation Study). J Am Coll Cardiol. 2009;53:1056\u201362.","journal-title":"J Am Coll Cardiol"},{"key":"3047_CR10","doi-asserted-by":"publisher","first-page":"873","DOI":"10.7326\/0003-4819-136-12-200206180-00008","volume":"136","author":"MMG McDermott","year":"2002","unstructured":"McDermott MMG, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, et al. The ankle brachial index is associated with leg function and physical activity: the walking and leg circulation study. Ann Intern Med. 2002;136:873\u201383.","journal-title":"Ann Intern Med"},{"key":"3047_CR11","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1161\/CIR.0000000000000470","volume":"2017","author":"C Barrett","year":"2016","unstructured":"Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Gerry Fowkes FR, et al. AHA\/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary. Circulation. 2016;2017:135. https:\/\/doi.org\/10.1161\/CIR.0000000000000470.","journal-title":"Circulation"},{"key":"3047_CR12","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003748.pub4","author":"R Bedenis","year":"2014","unstructured":"Bedenis R, Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G. Cilostazol for intermittent claudication. Cochrane Database Syst Rev. 2014. https:\/\/doi.org\/10.1002\/14651858.CD003748.pub4.","journal-title":"Cochrane Database Syst Rev"},{"key":"3047_CR13","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1161\/CIRCULATIONAHA.113.007003","volume":"130","author":"WR Hiatt","year":"2014","unstructured":"Hiatt WR, Rogers RK, Brass EP. The treadmill is a better functional test than the 6-minute walk test in therapeutic trials of patients with peripheral artery disease. Circulation. 2014;130:69\u201378.","journal-title":"Circulation"},{"key":"3047_CR14","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.009380","author":"MM McDermott","year":"2019","unstructured":"McDermott MM, Kibbe MR, Guralnik JM, Ferrucci L, Criqui MH, Domanchuk K, et al. Durability of benefits from supervised treadmill exercise in people with peripheral artery disease. J Am Heart Assoc. 2019. https:\/\/doi.org\/10.1161\/JAHA.118.009380.","journal-title":"J Am Heart Assoc"},{"key":"3047_CR15","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/j.jacc.2014.12.043","volume":"65","author":"TP Murphy","year":"2015","unstructured":"Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, et al. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study. J Am Coll Cardiol. 2015;65:999\u20131009.","journal-title":"J Am Coll Cardiol"},{"key":"3047_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2021.02.045","author":"V Madabhushi","year":"2021","unstructured":"Madabhushi V, Davenport D, Jones S, Khoudoud SA, Orr N, Minion D, et al. Revascularization of intermittent claudicants leads to more chronic limb threatening ischemia and higher amputation rates. J Vasc Surg. 2021. https:\/\/doi.org\/10.1016\/j.jvs.2021.02.045.","journal-title":"J Vasc Surg"},{"key":"3047_CR17","doi-asserted-by":"crossref","unstructured":"Fakhry F, Fokkenrood HJP, Spronk S, Teijink JAW, Rouwet EV, Hunink MGM. Endovascular revascularisation versus conservative management for intermittent claudication. Cochrane Database Syst Rev. 2018;2018.","DOI":"10.1002\/14651858.CD010512.pub2"},{"key":"3047_CR18","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.jvs.2019.08.278","volume":"72","author":"SR Levin","year":"2019","unstructured":"Levin SR, Farber A, Cheng TW, Arinze N, Jones DW, Rybin D, et al. Patients undergoing interventions for claudication experience low perioperative morbidity but are at risk for worsening functional status and limb loss. J Vasc Surg. 2019;72:241\u20139.","journal-title":"J Vasc Surg"},{"key":"3047_CR19","unstructured":"American Diabetes Association. American Diabetes Association standards of medical care in diabetes. J Clin Appl Res Educ. 2018;41. www.copyright.com. Accessed 16 May 2019."},{"key":"3047_CR20","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.cell.2013.02.035","volume":"153","author":"F Cabreiro","year":"2013","unstructured":"Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochem\u00e9 HM, Noori T, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153:228\u201339. https:\/\/doi.org\/10.1016\/j.cell.2013.02.035.","journal-title":"Cell"},{"key":"3047_CR21","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1161\/CIRCRESAHA.116.308445","volume":"119","author":"A Cameron","year":"2016","unstructured":"Cameron A, Morrison V, Levin D, Mohan M, Fortheath C, Beall C, et al. Anti-inflammatory effects of metfromin irrespective of diabetes status. Circ Res. 2016;119:652\u201365.","journal-title":"Circ Res"},{"key":"3047_CR22","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1158\/1940-6207.CAPR-11-0536","volume":"5","author":"C Algire","year":"2012","unstructured":"Algire C, Moiseeva O, Desch\u00eanes-Simard X, Amrein L, Petruccelli L, Birman E, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res. 2012;5:536\u201343.","journal-title":"Cancer Prev Res"},{"key":"3047_CR23","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1016\/j.bbadis.2016.11.010","volume":"1863","author":"JS Bhatti","year":"2017","unstructured":"Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders\u2014a step towards mitochondria based therapeutic strategies. Biochim Biophys Acta Mol Basis Dis. 2017;1863:1066\u201377. https:\/\/doi.org\/10.1016\/j.bbadis.2016.11.010.","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"3047_CR24","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.arr.2017.08.003","volume":"40","author":"JM Campbell","year":"2017","unstructured":"Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev. 2017;40:31\u201344. https:\/\/doi.org\/10.1016\/j.arr.2017.08.003.","journal-title":"Ageing Res Rev"},{"key":"3047_CR25","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.2337\/diabetes.51.7.2074","volume":"51","author":"N Musi","year":"2002","unstructured":"Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51:2074\u201381.","journal-title":"Diabetes"},{"key":"3047_CR26","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/s12933-016-0408-3","volume":"15","author":"J-WW Yu","year":"2016","unstructured":"Yu J-WW, Deng Y-PP, Han X, Ren G-FF, Cai J, Jiang G-JJ. Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK\/eNOS pathway in diabetic mice. Cardiovasc Diabetol. 2016;15:88. https:\/\/doi.org\/10.1186\/s12933-016-0408-3.","journal-title":"Cardiovasc Diabetol"},{"key":"3047_CR27","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.cmet.2020.04.015","volume":"32","author":"LP Bharath","year":"2020","unstructured":"Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, Liu J, et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab. 2020;32:44-55.e6. https:\/\/doi.org\/10.1016\/j.cmet.2020.04.015.","journal-title":"Cell Metab"},{"key":"3047_CR28","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cmet.2016.05.011","volume":"23","author":"N Barzilai","year":"2016","unstructured":"Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23:1060\u20135.","journal-title":"Cell Metab"},{"key":"3047_CR29","first-page":"1","volume":"15213","author":"KM Reitz","year":"2020","unstructured":"Reitz KM, Marroquin OC, Zenati MS, Kennedy J, Korytkowski M, Tzeng E, et al. Association between metformin exposure and postoperative outcomes in diabetic adults. JAMA Surg. 2020;15213:1\u201310.","journal-title":"JAMA Surg"},{"key":"3047_CR30","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.jvs.2013.09.061","volume":"61","author":"N Takahashi","year":"2015","unstructured":"Takahashi N, Shibata R, Ouchi N, Sugimoto M, Murohara T, Komori K. Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model. J Vasc Surg. 2015;61:489\u201396.","journal-title":"J Vasc Surg"},{"key":"3047_CR31","doi-asserted-by":"crossref","unstructured":"Forouzandeh F, Salazar G, Patrushev N, Xiong S, Hilenski L, Fei B, et al. Metformin beyond diabetes: pleiotropic benefits of metformin in attenuation of atherosclerosis. J Am Heart Assoc. 2014;3.","DOI":"10.1161\/JAHA.114.001202"},{"key":"3047_CR32","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1097\/00005344-198409000-00027","volume":"6","author":"CR Sirtori","year":"1984","unstructured":"Sirtori CR, Franceschini G, Gianfranceschi G, Sirtori M, Montanari G, Bosisio E, et al. Metformin improves peripheral vascular flow in nonhyperlipidemic patients with arterial disease. J Cardiovasc Pharmacol. 1984;6:914\u201323.","journal-title":"J Cardiovasc Pharmacol"},{"key":"3047_CR33","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S1043-6618(05)80065-9","volume":"25","author":"G Montanari","year":"1992","unstructured":"Montanari G, Bondioli A, Rizzato G, Puttini M, Tremoli E, Mussoni L, et al. Treatment with low dose metformin in patients with peripheral vascular disease. Pharmacol Res. 1992;25:63\u201373.","journal-title":"Pharmacol Res"},{"key":"3047_CR34","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1161\/CIRCULATIONAHA.114.007002","volume":"130","author":"M McDermott","year":"2014","unstructured":"McDermott M, Guralnik J, Criqui M, Liu K, Kibbe M, Ferrucci L. The six-minute walk is a better outcome measure than treadmill walking tests in therapeutic trials of patients with peripheral artery disease. Circulation. 2014;130:61\u20138.","journal-title":"Circulation"},{"key":"3047_CR35","first-page":"220","volume":"46","author":"M McDermott","year":"2010","unstructured":"McDermott M, Ades P, Dyer A, Ferrucci L, Guralnick J, Pearce W, et al. Corridor-based functional performance measures correlate better with physical activity during daily life than treadmill measures in persons with peripheral arterial disease. J Vasc Surg. 2010;46:220\u201331.","journal-title":"J Vasc Surg"},{"key":"3047_CR36","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1111\/j.1532-5415.1998.tb03804.x","volume":"46","author":"PS Montgomery","year":"2015","unstructured":"Montgomery PS, Gardner AW. The clinical utility of a six-minute walk test in peripheral arterial occlusive disease patients. J Am Geriatr Soc. 2015;46:706\u201311. https:\/\/doi.org\/10.1111\/j.1532-5415.1998.tb03804.x.","journal-title":"J Am Geriatr Soc"},{"key":"3047_CR37","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1016\/j.jacc.2013.01.060","volume":"61","author":"A Jain","year":"2013","unstructured":"Jain A, Liu K, Ferrucci L, Criqui MH, Tian L, Guralnik JM, et al. Declining walking impairment questionnaire scores are associated with subsequent increased mortality in peripheral artery disease. J Am Coll Cardiol. 2013;61:1820\u20139. https:\/\/doi.org\/10.1016\/j.jacc.2013.01.060.","journal-title":"J Am Coll Cardiol"},{"key":"3047_CR38","doi-asserted-by":"publisher","first-page":"e894","DOI":"10.1161\/CIR.0000000000000483","volume":"135","author":"DE Forman","year":"2017","unstructured":"Forman DE, Arena R, Boxer R, Dolansky MA, Eng JJ, Fleg JL, et al. Prioritizing functional capacity as a principal end point for therapies oriented to older adults with cardiovascular disease: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2017;135:e894-918.","journal-title":"Circulation"},{"key":"3047_CR39","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1097\/HCR.0000000000000173","volume":"36","author":"MDR Chehuen","year":"2016","unstructured":"Chehuen MDR, Cucato GG, Saes GF, Costa LAR, Leicht AS, Ritti-Dias RM, et al. Reproducibility of anaerobic and pain thresholds in male patients with intermittent claudication. J Cardiopulm Rehabil Prev. 2016;36:358\u201367.","journal-title":"J Cardiopulm Rehabil Prev"},{"key":"3047_CR40","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1177\/1358863X12436708","volume":"17","author":"S Onkelinx","year":"2012","unstructured":"Onkelinx S, Cornelissen V, Goetschalckx K, Thomaes T, Verhamme P, Vanhees L. Reproducibility of different methods to measure the endothelial function. Vasc Med (United Kingdom). 2012;17:79\u201384.","journal-title":"Vasc Med (United Kingdom)"},{"key":"3047_CR41","doi-asserted-by":"crossref","unstructured":"Moerland M, Kales AJ, Schrier L, Van Dongen MGJ, Bradnock D, Burggraaf J. Evaluation of the endoPAT as a tool to assess endothelial function. Int J Vasc Med. 2012;2012.","DOI":"10.1155\/2012\/904141"},{"key":"3047_CR42","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1161\/CIRCRESAHA.116.309692","volume":"120","author":"Y D\u00f6ring","year":"2017","unstructured":"D\u00f6ring Y, Soehnlein O, Weber C. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ Res. 2017;120:736\u201343.","journal-title":"Circ Res"},{"key":"3047_CR43","doi-asserted-by":"publisher","first-page":"3 7","DOI":"10.1042\/CS20140101","volume":"127","author":"BK Chacko","year":"2014","unstructured":"Chacko BK, Kramer PA, Ravi S, Benavides GA, Mitchell T, Dranka BP, et al. The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clin Sci. 2014;127:3 7-373.","journal-title":"Clin Sci"},{"key":"3047_CR44","doi-asserted-by":"publisher","first-page":"629239","DOI":"10.3389\/fendo.2021.629239","volume":"12","author":"MM Altintas","year":"2021","unstructured":"Altintas MM, DiBartolo S, Tadros L, Samelko B, Wasse H. Metabolic changes in peripheral blood mononuclear cells isolated from patients with end stage renal disease. Front Endocrinol (Lausanne). 2021;12:629239.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"3047_CR45","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1055\/s-0034-1393976","volume":"31","author":"RL Hardman","year":"2014","unstructured":"Hardman RL, Jazaeri O, Yi J, Smith M, Gupta R. Overview of classification systems in peripheral artery disease. Semin Intervent Radiol. 2014;31:378\u201388. https:\/\/doi.org\/10.1055\/s-0034-1393976.","journal-title":"Semin Intervent Radiol"},{"key":"3047_CR46","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/S0895-4356(98)00138-3","volume":"52","author":"W Kernan","year":"1999","unstructured":"Kernan W, Viscoli C, Makuch R, Brass L, Horwitz R. Stratified randomization for clinical trials. J Clin Epidemiol. 1999;52:19\u201326. https:\/\/doi.org\/10.1016\/S0895-4356(98)00138-3.","journal-title":"J Clin Epidemiol"},{"key":"3047_CR47","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1111\/dom.12854","volume":"19","author":"F Bonnet","year":"2017","unstructured":"Bonnet F, Scheen A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes Metab. 2017;19:473\u201381.","journal-title":"Diabetes Obes Metab"},{"key":"3047_CR48","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-2356","author":"C Sardu","year":"2019","unstructured":"Sardu C, Paolisso P, Sacra C, Mauro C, Minicucci F, Portoghese M, et al. Effects of metformin therapy on coronary endothelial dysfunction in prediabetic patients with stable angina and non obstructive coronary artery stenosis: the CODYCE multicenter prospective study. Diabetes Care. 2019. https:\/\/doi.org\/10.2337\/dc18-2356.","journal-title":"Diabetes Care"},{"key":"3047_CR49","doi-asserted-by":"crossref","unstructured":"Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010.","DOI":"10.1002\/14651858.CD002967.pub4"},{"key":"3047_CR50","doi-asserted-by":"publisher","first-page":"e037690","DOI":"10.1136\/bmjopen-2020-037690","volume":"10","author":"KM Reitz","year":"2020","unstructured":"Reitz KM, Seymour CW, Vates J, Quintana M, Viele K, Detry M, et al. Strategies to Promote ResiliencY (SPRY): a randomised embedded multifactorial adaptative platform (REMAP) clinical trial protocol to study interventions to improve recovery after surgery in high-risk patients. BMJ Open. 2020;10:e037690.","journal-title":"BMJ Open"},{"key":"3047_CR51","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.jval.2014.02.012","volume":"17","author":"CD Mullins","year":"2014","unstructured":"Mullins CD, Vandigo J, Zheng Z, Wicks P. Patient-centeredness in the design of clinical trials. Value Health. 2014;17:471\u20135. https:\/\/doi.org\/10.1016\/j.jval.2014.02.012.","journal-title":"Value Health"},{"key":"3047_CR52","doi-asserted-by":"publisher","first-page":"2176","DOI":"10.1377\/hlthaff.2012.0171","volume":"31","author":"H Sox","year":"2012","unstructured":"Sox H. The patient-centered outcomes research institute should focus on high-impact problems that can be solved quickly. Health Aff. 2012;31:2176\u201382.","journal-title":"Health Aff"},{"key":"3047_CR53","doi-asserted-by":"publisher","first-page":"604","DOI":"10.3736\/jcim20100702","volume":"8","author":"KF Schulz","year":"2010","unstructured":"Schulz KF, Altman DG, Moher D, Barbour V, Berlin JA, Boutron I, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. Consort. 2010;8:604\u201312. https:\/\/doi.org\/10.3736\/jcim20100702.","journal-title":"Consort"},{"key":"3047_CR54","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1177\/1358863X18762599","volume":"23","author":"AW Gardner","year":"2018","unstructured":"Gardner AW, Montgomery PS, Wang M. Minimal clinically important differences in treadmill, 6-minute walk, and patient-based outcomes following supervised and home-based exercise in peripheral artery disease. Vasc Med (United Kingdom). 2018;23:349\u201357.","journal-title":"Vasc Med (United Kingdom)"},{"key":"3047_CR55","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.jvs.2020.03.052","volume":"73","author":"MM McDermott","year":"2021","unstructured":"McDermott MM, Tian L, Criqui MH, Ferrucci L, Conte MS, Zhao L, et al. Meaningful change in 6-minute walk in people with peripheral artery disease. J Vasc Surg. 2021;73:267-276.e1.","journal-title":"J Vasc Surg"},{"key":"3047_CR56","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1001\/jama.2017.17437","volume":"318","author":"MM McDermott","year":"2017","unstructured":"McDermott MM, Ferrucci L, Tian L, Guralnik JM, Lloyd-Jones D, Kibbe MR, et al. Effect of granulocyte-macrophage colony-stimulating factor with or without supervised exercise on walking performance in patients with peripheral artery disease: the PROPEL randomized clinical trial. JAMA. 2017;318:2089\u201398.","journal-title":"JAMA"},{"key":"3047_CR57","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1001\/jama.2013.7231","volume":"310","author":"MM McDermott","year":"2013","unstructured":"McDermott MM, Liu K, Guralnik JM, Criqui MH, Spring B, Tian L, et al. Home-based walking exercise intervention in peripheral artery disease: a randomized clinical trial. JAMA. 2013;310:57\u201365. https:\/\/doi.org\/10.1001\/jama.2013.7231.","journal-title":"JAMA"},{"key":"3047_CR58","first-page":"1391","volume":"3","author":"J Grizzle","year":"1982","unstructured":"Grizzle J. Covariate adjustment increases statistical power in randomized controlled trials. J Clin Epidemiol. 1982;3:1391.","journal-title":"J Clin Epidemiol"},{"key":"3047_CR59","first-page":"975","volume":"5","author":"S Nidich","year":"2018","unstructured":"Nidich S, Mills P, Rainforth M, Heppner P, Schneider R, Rosenthal N, et al. Non-trauma-focused mediation versus exposure therapy in veterans with post-traumatic stress disorder: a randomied controlled trial. Lancet. 2018;5:975\u201386.","journal-title":"Lancet"},{"key":"3047_CR60","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1161\/STROKEAHA.108.532051","volume":"40","author":"DM Kent","year":"2009","unstructured":"Kent DM, Trikalinos TA, Hill MD. Are unadjusted analyses of clinical trials inappropriately biased toward the null? Stroke. 2009;40:672\u20133.","journal-title":"Stroke"},{"key":"3047_CR61","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1136\/bmj.323.7321.1123","volume":"323","author":"AJ Vickers","year":"2001","unstructured":"Vickers AJ, Altman DG. Statistics notes: analysing controlled trials with baseline and follow up measurements. BMJ. 2001;323:1123\u20134. https:\/\/doi.org\/10.1136\/bmj.323.7321.1123.","journal-title":"BMJ"},{"key":"3047_CR62","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","volume":"42","author":"PA Harris","year":"2009","unstructured":"Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)\u2014a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377\u201381. https:\/\/doi.org\/10.1016\/j.jbi.2008.08.010.","journal-title":"J Biomed Inform"},{"key":"3047_CR63","doi-asserted-by":"publisher","first-page":"103208","DOI":"10.1016\/j.jbi.2019.103208","volume":"95","author":"PA Harris","year":"2019","unstructured":"Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O\u2019Neal L, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. https:\/\/doi.org\/10.1016\/j.jbi.2019.103208.","journal-title":"J Biomed Inform"},{"key":"3047_CR64","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j5748","volume":"360","author":"E Colantuoni","year":"2018","unstructured":"Colantuoni E, Scharfstein DO, Wang C, Hashem MD, Leroux A, Needham DM, et al. Statistical methods to compare functional outcomes in randomized controlled trials with high mortality. BMJ. 2018;360: j5748.","journal-title":"BMJ"},{"key":"3047_CR65","unstructured":"Food and Drug Administration. Center for Drug Evaluation and Research\u2014Pletal. 1999."},{"key":"3047_CR66","first-page":"1","volume":"15213","author":"KM Reitz","year":"2021","unstructured":"Reitz KM, Althouse AD, Meyer J, Arya S, Goodney PP, Shireman PK, et al. Association of smoking with postprocedural complications following open and endovascular interventions for intermittent claudication. JAMA Cardiol. 2021;15213:1\u201310.","journal-title":"JAMA Cardiol"}],"container-title":["BMC Cardiovascular Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12872-023-03047-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12872-023-03047-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12872-023-03047-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T05:03:51Z","timestamp":1674277431000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccardiovascdisord.biomedcentral.com\/articles\/10.1186\/s12872-023-03047-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,21]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["3047"],"URL":"https:\/\/doi.org\/10.1186\/s12872-023-03047-8","relation":{},"ISSN":["1471-2261"],"issn-type":[{"value":"1471-2261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,21]]},"assertion":[{"value":"23 September 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The MOBILE IC Trial was reviewed by the FDA and was identified as exempt from Investigational New Drug review (IND145416). The VAPHS Investigational Review Board approved the procedures specified by the MOBILE IC study protocol which includes written informed consent for each participant completed by the investigators in combination with study personnel (1622906; Supplement). Any future protocol modifications will be reviewed by the institutional review board, discussed with the DMC, and any other relevant parties prior to implementation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"No author reports any disclosures, conflict of interest or relevant financial interests related to the content of the manuscript. The opinions expressed here are those of the authors and do not necessarily reflect the position of the Department of Veterans Affairs or the US government.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"38"}}