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  • Review Article
  • Published:

Interventions for lower extremity peripheral artery disease

Abstract

Peripheral artery disease (PAD) of the lower extremities is a common manifestation of atherosclerosis that is increasing in global prevalence and in the associated public health costs. Ageing of the general population, combined with the pandemics of diabetes mellitus, metabolic syndrome, and tobacco use, is a major underlying factor. A broad range of care providers are involved in the management of patients with PAD, and all health-care professionals require familiarity with the risk factors, diagnosis, and treatment options for this common disease. Although medical therapies are the cornerstone of secondary prevention in atherosclerotic disease, they have limited direct limb-related benefits in advanced PAD. Despite a major evolution in technologies for limb revascularization, the increasing array of treatment options has not been accompanied by adequate evidence of their comparative effectiveness, which is needed to guide treatment decisions. This Review provides a framework for examining the current status of interventions for PAD, including an overview of disease staging, treatment goals, and the key factors associated with outcomes in defined subgroups. The status of evolving approaches to PAD, such as cell-based and gene-based therapies, and persistent unmet therapeutic needs in this field are also discussed.

Key points

  • Lower extremity peripheral artery disease (PAD) is associated with considerable morbidity, diminished quality of life, and mortality; reducing the risk of cardiovascular events is the primary goal of medical treatment.

  • Intermittent claudication is the most common symptom of PAD; treatment aims to improve ambulatory function through smoking cessation, medical therapy, exercise, and (selective) revascularization.

  • Chronic limb-threatening ischaemia is associated with increased amputation risk and mortality; treatment is based on effective revascularization, which aims to relieve pain, heal wounds, and preserve limb function.

  • Advances in endovascular technologies and open surgical approaches have created a growing range of revascularization options for PAD, although their outcomes are highly dependent on the anatomical pattern of disease.

  • Active areas of investigation in PAD include cell-based and gene-based therapies, tissue-engineered vascular conduits, and drug-eluting, biomimetic, and bioresorbable scaffolds.

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Fig. 1: Hybrid approaches for simultaneous, multilevel revascularization of advanced PAD.
Fig. 2: Aortoiliac intervention for PAD.
Fig. 3: Femoropopliteal intervention for PAD.
Fig. 4: Bypass grafting to infrainguinal targets in PAD.
Fig. 5: Infrapopliteal intervention for PAD.
Fig. 6: Potential future therapeutic options for PAD.

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References

  1. Fowkes, F. G. et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 382, 1329–1340 (2013).

    Article  PubMed  Google Scholar 

  2. Fowkes, F. G. et al. Peripheral artery disease: epidemiology and global perspectives. Nat. Rev. Cardiol. 14, 156–170 (2017).

    Article  PubMed  Google Scholar 

  3. Allison, M. A. et al. Ethnic-specific prevalence of peripheral arterial disease in the United States. Am. J. Prev. Med. 32, 328–333 (2007).

    Article  PubMed  Google Scholar 

  4. Bonaca, M. P. & Creager, M. A. Pharmacological treatment and current management of peripheral artery disease. Circ. Res. 116, 1579–1598 (2015).

    Article  PubMed  CAS  Google Scholar 

  5. Olin, J. W., White, C. J., Armstrong, E. J., Kadian-Dodov, D. & Hiatt, W. R. Peripheral artery disease: evolving role of exercise, medical therapy, and endovascular options. J. Am. Coll. Cardiol. 67, 1338–1357 (2016).

    Article  PubMed  Google Scholar 

  6. Hess, C. N. et al. A structured review of antithrombotic therapy in peripheral artery disease with a focus on revascularization: a TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) initiative. Circulation 135, 2534–2555 (2017).

    Article  PubMed  CAS  Google Scholar 

  7. Norgren, L. et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). Eur. J. Vasc. Endovasc. Surg. 33 (Suppl. 1), S1–S75 (2007).

    Article  PubMed  Google Scholar 

  8. Singer, A. & Rob, C. The fate of the claudicator. Br. Med. J. 2, 633–636 (1960).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Leng, G. C. et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int. J. Epidemiol. 25, 1172–1181 (1996).

    Article  PubMed  CAS  Google Scholar 

  10. 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. 51, 395–403 (2016).

    Article  PubMed  CAS  Google Scholar 

  11. Mills, J. L. et al. The Society for Vascular Surgery lower extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot infection (WIfI). J. Vasc. Surg. 59, 220–234 e1-2 (2014).

    Article  PubMed  Google Scholar 

  12. Mills, J. L. Sr. The application of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification to stratify amputation risk. J. Vasc. Surg. 65, 591–593 (2017).

    Article  PubMed  Google Scholar 

  13. Patel, R. S. Team approach to critical limb ischemia care and research. Tech. Vasc. Interv. Radiol. 19, 101–103 (2016).

    Article  PubMed  Google Scholar 

  14. Dormandy, J. A. Management of peripheral arterial disease (PAD). TASC working group. TransAtlantic Inter-Society Consensus (TASC). J. Vasc. Surg. 31, S1–S296 (2000).

    Article  PubMed  CAS  Google Scholar 

  15. Hirsch, A. T. et al. ACC/AHA Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Associations for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease) — summary of recommendations. J. Vasc. Interv. Radiol. 17, 1383–1397 (2006).

    Article  PubMed  Google Scholar 

  16. Diehm, N. et al. Chapter III: Management of cardiovascular risk factors and medical therapy. Eur. J. Vasc. Endovasc. Surg. 42 (Suppl. 2), S33–S42 (2011).

    Article  PubMed  Google Scholar 

  17. Committee, T. S. et al. An update on methods for revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: a supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II). J. Endovasc. Ther. 22, 663–677 (2015).

    Article  Google Scholar 

  18. Conte, M. S. & Pomposelli, F. B. Society for Vascular Surgery Practice guidelines for atherosclerotic occlusive disease of the lower extremities management of asymptomatic disease and claudication. Introduction. J. Vasc. Surg. 61 (Suppl. 3), 1S (2015).

    Article  PubMed  Google Scholar 

  19. Aboyans, V. et al. 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Endorsed by: the European Stroke Organization (ESO) The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur. Heart J. 39, 763–816 (2017).

    Article  Google Scholar 

  20. Gerhard-Herman, M. D. et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 69, 1465–1508 (2017).

    Article  PubMed  Google Scholar 

  21. Teraa, M., Conte, M. S., Moll, F. L. & Verhaar, M. C. Critical limb ischemia: current trends and future directions. J. Am. Heart Assoc. 5, e002938 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Achterberg, S. et al. Differential propensity for major hemorrhagic events in patients with different types of arterial disease. J. Thromb. Haemost. 9, 1724–1729 (2011).

    Article  PubMed  CAS  Google Scholar 

  23. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324, 71–86 (2002).

    Article  Google Scholar 

  24. Antithrombotic Trialists’ (ATT) Collaboration. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860 (2009).

    Article  CAS  Google Scholar 

  25. Berger, J. S., Krantz, M. J., Kittelson, J. M. & Hiatt, W. R. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 301, 1909–1919 (2009).

    Article  PubMed  CAS  Google Scholar 

  26. Fowkes, F. G. et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 303, 841–848 (2010).

    Article  PubMed  CAS  Google Scholar 

  27. Robertson, L., Ghouri, M. A. & Kovacs, F. Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment. Cochrane Database Syst. Rev. 8, CD002071 (2012).

    Google Scholar 

  28. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348, 1329–1339 (1996).

    Article  Google Scholar 

  29. Katsanos, K. et al. Comparative efficacy and safety of different antiplatelet agents for prevention of major cardiovascular events and leg amputations in patients with peripheral arterial disease: a systematic review and network meta-analysis. PLoS ONE 10, e0135692 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Hiatt, W. R. et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N. Engl. J. Med. 376, 32–40 (2017).

    Article  PubMed  CAS  Google Scholar 

  31. Jones, W. S. et al. Ticagrelor compared with clopidogrel in patients with prior lower extremity revascularization for peripheral artery disease. Circulation 135, 241–250 (2017).

    Article  PubMed  CAS  Google Scholar 

  32. Wiviott, S. D. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357, 2001–2015 (2007).

    Article  PubMed  CAS  Google Scholar 

  33. Wallentin, L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 361, 1045–1057 (2009).

    Article  PubMed  CAS  Google Scholar 

  34. Cacoub, P. P. et al. Patients with peripheral arterial disease in the CHARISMA trial. Eur. Heart. J. 30, 192–201 (2009).

    Article  PubMed  CAS  Google Scholar 

  35. Tepe, G. et al. Management of peripheral arterial interventions with mono or dual antiplatelet therapy—the MIRROR study: a randomised and double-blinded clinical trial. Eur. Radiol. 22, 1998–2006 (2012).

    Article  PubMed  Google Scholar 

  36. Belch, J. J. et al. Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial. J. Vasc. Surg. 52, 825–833.e2 (2010).

    Article  PubMed  Google Scholar 

  37. Burdess, A. et al. Randomized controlled trial of dual antiplatelet therapy in patients undergoing surgery for critical limb ischemia. Ann. Surg. 252, 37–42 (2010).

    Article  PubMed  Google Scholar 

  38. Peeters Weem, S. M., van Haelst, S. T., den Ruijter, H. M., Moll, F. L. & de Borst, G. J. Lack of evidence for dual antiplatelet therapy after endovascular arterial procedures: a meta-analysis. Eur. J. Vasc. Endovasc. Surg. 52, 253–262 (2016).

    Article  PubMed  CAS  Google Scholar 

  39. Armstrong, E. J. et al. Association of dual-antiplatelet therapy with reduced major adverse cardiovascular events in patients with symptomatic peripheral arterial disease. J. Vasc. Surg. 62, 157–165.e1 (2015).

    Article  PubMed  Google Scholar 

  40. Warfarin Antiplatelet Vascular Evaluation Trial Invesigators. et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N. Engl. J. Med. 357, 217–227 (2007).

    Article  Google Scholar 

  41. Anand, S. S. et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 391, 219–229 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. US National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02660866 (2018).

  43. US National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02548650 (2017).

  44. Izadpanah, R. et al. The impact of statins on biological characteristics of stem cells provides a novel explanation for their pleiotropic beneficial and adverse clinical effects. Am. J. Physiol. Cell Physiol. 309, C522–C531 (2015).

    Article  PubMed  CAS  Google Scholar 

  45. Aronow, W. S., Nayak, D., Woodworth, S. & Ahn, C. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment. Am. J. Cardiol. 92, 711–712 (2003).

    Article  PubMed  CAS  Google Scholar 

  46. Mondillo, S. et al. Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am. J. Med. 114, 359–364 (2003).

    Article  PubMed  CAS  Google Scholar 

  47. Abbruzzese, T. A. et al. Statin therapy is associated with improved patency of autogenous infrainguinal bypass grafts. J. Vasc. Surg. 39, 1178–1185 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Iida, O. et al. Angiographic restenosis and its clinical impact after infrapopliteal angioplasty. Eur. J. Vasc. Endovasc Surg. 44, 425–431 (2012).

    Article  PubMed  CAS  Google Scholar 

  49. Siracuse, J. J. et al. Results for primary bypass versus primary angioplasty/stent for intermittent claudication due to superficial femoral artery occlusive disease. J. Vasc. Surg. 55, 1001–1007 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Aiello, F. A. et al. Statin therapy is associated with superior clinical outcomes after endovascular treatment of critical limb ischemia. J. Vasc. Surg. 55, 371–379 (2012).

    Article  PubMed  Google Scholar 

  51. Ridker, P. M. et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N. Engl. J. Med. 376, 1527–1539 (2017).

    Article  PubMed  CAS  Google Scholar 

  52. Koren, M. J. et al. Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA Cardiol. 2, 598–607 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Bonaca, M. P. et al. 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). Circulation 137, 338–350 (2018).

    Article  PubMed  CAS  Google Scholar 

  54. Lane, D. A. & Lip, G. Y. Treatment of hypertension in peripheral arterial disease. Cochrane Database Syst. Rev. 12, CD003075 (2013).

    Google Scholar 

  55. Heart Outcomes Prevention Evaluation Study Investigators. et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N. Engl. J. Med. 342, 145–153 (2000).

    Article  Google Scholar 

  56. Armstrong, E. J., Chen, D. C., Singh, G. D., Amsterdam, E. A. & Laird, J. R. Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use is associated with reduced major adverse cardiovascular events among patients with critical limb ischemia. Vasc. Med. 20, 237–244 (2015).

    Article  PubMed  CAS  Google Scholar 

  57. Robless, P., Mikhailidis, D. P. & Stansby, G. P. Cilostazol for peripheral arterial disease. Cochrane Database Syst. Rev. 1, CD003748 (2008).

    Google Scholar 

  58. Pande, R. L., Hiatt, W. R., Zhang, P., Hittel, N. & Creager, M. A. A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication. Vasc. Med. 15, 181–188 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Zen, K. et al. Drug-eluting stenting for femoropopliteal lesions, followed by cilostazol treatment, reduces stent restenosis in patients with symptomatic peripheral artery disease. J. Vasc. Surg. 65, 720–725 (2017).

    Article  PubMed  Google Scholar 

  60. Warner, C. J. et al. Cilostazol is associated with improved outcomes after peripheral endovascular interventions. J. Vasc. Surg. 59, 1607–1614 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Meng, Y. et al. Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease. Angiology 65, 190–197 (2014).

    Article  PubMed  Google Scholar 

  62. Stevens, J. W. et al. Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication. Br. J. Surg. 99, 1630–1638 (2012).

    Article  PubMed  CAS  Google Scholar 

  63. Robertson, L. & Andras, A. Prostanoids for intermittent claudication. Cochrane Database Syst. Rev. 4, CD000986 (2013).

    Google Scholar 

  64. Ruffolo, A. J., Romano, M. & Ciapponi, A. Prostanoids for critical limb ischaemia. Cochrane Database Syst. Rev. 1, CD006544 (2010).

    Google Scholar 

  65. Vitale, V., Monami, M. & Mannucci, E. Prostanoids in patients with peripheral arterial disease: a meta-analysis of placebo-controlled randomized clinical trials. J. Diabetes Compl. 30, 161–166 (2016).

    Article  Google Scholar 

  66. Lawall, H. et al. Efficacy and safety of alprostadil in patients with peripheral arterial occlusive disease Fontaine stage IV: results of a placebo controlled randomised multicentre trial (ESPECIAL). Eur. J. Vasc. Endovasc. Surg. 53, 559–566 (2017).

    Article  PubMed  CAS  Google Scholar 

  67. Hiatt, W. R., Wolfel, E. E., Meier, R. H. & Regensteiner, J. G. Superiority of treadmill walking exercise versus strength training for patients with peripheral arterial disease. Implications for the mechanism of the training response. Circulation 90, 1866–1874 (1994).

    PubMed  CAS  Google Scholar 

  68. Chang, P. et al. Effect of physical activity assessment on prognostication for peripheral artery disease and mortality. Mayo Clin. Proc. 90, 339–345 (2015).

    Article  PubMed  Google Scholar 

  69. Sakamoto, S. et al. Patients with peripheral artery disease who complete 12-week supervised exercise training program show reduced cardiovascular mortality and morbidity. Circ. J. 73, 167–173 (2009).

    Article  PubMed  Google Scholar 

  70. Mays, R. J., Rogers, R. K., Hiatt, W. R. & Regensteiner, J. G. Community walking programs for treatment of peripheral artery disease. J. Vasc. Surg. 58, 1678–1687 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Gardner, A. W., Parker, D. E., Montgomery, P. S. & Blevins, S. M. Step-monitored home exercise improves ambulation, vascular function, and inflammation in symptomatic patients with peripheral artery disease: a randomized controlled trial. J. Am. Heart Assoc. 3, e001107 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Murphy, T. P. et al. Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery diseaseclinical perspective. Circulation 125, 130–139 (2012).

    Article  PubMed  Google Scholar 

  73. Murphy, T. P. et al. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study. J. Am. Coll. Cardiol. 65, 999–1009 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Fakhry, F. et al. Endovascular revascularization and supervised exercise for peripheral artery disease and intermittent claudication: a randomized clinical trial. JAMA 314, 1936–1944 (2015).

    Article  PubMed  CAS  Google Scholar 

  75. Fokkenrood, H. J. et al. Significant savings with a stepped care model for treatment of patients with intermittent claudication. Eur. J. Vasc. Endovasc. Surg. 48, 423–429 (2014).

    Article  PubMed  CAS  Google Scholar 

  76. Dormandy, J. A. & Rutherford, R. B. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J. Vasc. Surg. 31, S1–S296 (2000).

    Article  PubMed  CAS  Google Scholar 

  77. Norgren, L. et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J. Vasc. Surg. 45 (Suppl), S5–67 (2007).

    Article  PubMed  Google Scholar 

  78. Jaff, M. R. et al. An update on methods for revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: a supplement to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II): the TASC steering committee. Catheter Cardiovasc. Interv. 86, 611–625 (2015).

    Article  PubMed  Google Scholar 

  79. Adam, D. J. et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 366, 1925–1934 (2005).

    Article  PubMed  CAS  Google Scholar 

  80. Bradbury, A. W. et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: an intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy. J. Vasc. Surg. 51 (Suppl. 5), 5S–17S (2010).

    Article  PubMed  Google Scholar 

  81. Bradbury, A. W. et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: analysis of amputation free and overall survival by treatment received. J. Vasc. Surg. 51 (Suppl. 5), 18S–31S (2010).

    Article  PubMed  Google Scholar 

  82. Conte, M. S. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) and the (hoped for) dawn of evidence-based treatment for advanced limb ischemia. J. Vasc. Surg. 51 (Suppl.), 69S–75S (2010).

    Article  PubMed  Google Scholar 

  83. Menard, M. T. et al. Design and rationale of the best endovascular versus best surgical therapy for patients with critical limb ischemia (BEST-CLI)trial. J. Am. Heart Assoc. 5, e003219 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Popplewell, M. A. et al. Bypass versus angio plasty in severe ischaemia of the leg - 2 (BASIL-2) trial: study protocol for a randomised controlled trial. Trials 17, 11 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Hunt, B. D. et al. Balloon versus stenting in severe ischaemia of the leg-3 (BASIL-3): study protocol for a randomised controlled trial. Trials 18, 224 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Deloose, K. et al. Primary stenting is nowadays the gold standard treatment for TASC II A and B iliac lesions: the definitive MISAGO 1-year results. J. Cardiovasc. Surg. 58, 416–421 (2017).

    Google Scholar 

  87. Jongkind, V., Akkersdijk, G. J., Yeung, K. K. & Wisselink, W. A systematic review of endovascular treatment of extensive aortoiliac occlusive disease. J. Vasc. Surg. 52, 1376–1383 (2010).

    Article  PubMed  Google Scholar 

  88. Ye, W. et al. Early and late outcomes of percutaneous treatment of TransAtlantic Inter-Society Consensus class C and D aorto-iliac lesions. J. Vasc. Surg. 53, 1728–1737 (2011).

    Article  PubMed  Google Scholar 

  89. Sabri, S. S. et al. Outcomes of covered kissing stent placement compared with bare metal stent placement in the treatment of atherosclerotic occlusive disease at the aortic bifurcation. J. Vasc. Interv. Radiol. 21, 995–1003 (2010).

    Article  PubMed  Google Scholar 

  90. Piazza, M. et al. Outcomes of polytetrafluoroethylene-covered stent versus bare-metal stent in the primary treatment of severe iliac artery obstructive lesions. J. Vasc. Surg. 62, 1210–1218.e1 (2015).

    Article  PubMed  Google Scholar 

  91. Grimme, F. A., Goverde, P. C., Verbruggen, P. J., Zeebregts, C. J. & Reijnen, M. M. Editor’schoice — first results of the covered endovascular reconstruction of the aortic bifurcation (CERAB) technique for aortoiliac occlusive disease. Eur. J. Vasc. Endovasc. Surg. 50, (638–647 (2015).

    Google Scholar 

  92. Mwipatayi, B. P. et al. A comparison of covered versus bare expandable stents for the treatment of aortoiliac occlusive disease. J. Vasc. Surg. 54, 1561–1570 (2011).

    Article  PubMed  Google Scholar 

  93. Bekken, J. A., Vos, J. A., Aarts, R. A., de Vries, J. P. & Fioole, B. DISCOVER: Dutch Iliac Stent trial: Covered balloon-expandable versus uncovered balloon-expandable stents in the common iliac artery: study protocol for a randomized controlled trial. Trials 13, 215 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Indes, J. E. et al. Clinical outcomes of 5,358 patients undergoing direct open bypass or endovascular treatment for aortoiliac occlusive disease: a systematic review and meta-analysis. J. Endovasc. Ther. 20, 443–455 (2013).

    Article  PubMed  Google Scholar 

  95. Chiu, K. W., Davies, R. S., Nightingale, P. G., Bradbury, A. W. & Adam, D. J. Review of direct anatomical open surgical management of atherosclerotic aorto-iliac occlusive disease. Eur. J. Vasc. Endovasc. Surg. 39, 460–471 (2010).

    Article  PubMed  CAS  Google Scholar 

  96. Ricco, J. B. & Probst, H. & French University Surgeons, A. Long-term results of a multicenter randomized study on direct versus crossover bypass for unilateral iliac artery occlusive disease. J. Vasc. Surg. 47, 45–53 (2008).

    Article  PubMed  Google Scholar 

  97. Schneider, J. R. & Golan, J. F. The role of extraanatomic bypass in the management of bilateral aortoiliac occlusive disease. Semin. Vasc. Surg. 7, 35–44 (1994).

    PubMed  CAS  Google Scholar 

  98. Goueffic, Y. et al. Stenting or surgery for de novo common femoral artery stenosis. JACC Cardiovasc. Interv. 10, 1344–1354 (2017).

    Article  PubMed  Google Scholar 

  99. Siracuse, J. J. et al. Endovascular treatment of the common femoral artery in the Vascular Quality Initiative. J. Vasc. Surg. 65, 1039–1046 (2017).

    Article  PubMed  Google Scholar 

  100. Yiu, W. K. & Conte, M. S. Primary stenting in femoropopliteal occlusive disease — what is the appropriate role? Circ. J. 79, 704–711 (2015).

    Article  PubMed  Google Scholar 

  101. Krankenberg, H. et al. Nitinol stent implantation versus percutaneous transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: the femoral artery stenting trial (FAST). Circulation 116, 285–292 (2007).

    Article  PubMed  CAS  Google Scholar 

  102. Chalmers, N. et al. Randomized trial of the SMART stent versus balloon angioplasty in long superficial femoral artery lesions: the SUPER study. Cardiovasc. Intervent. Radiol. 36, 353–361 (2013).

    Article  PubMed  Google Scholar 

  103. Dick, P. et al. Balloon angioplasty versus stenting with nitinol stents in intermediate length superficial femoral artery lesions. Catheter Cardiovasc. Interv. 74, 1090–1095 (2009).

    Article  PubMed  Google Scholar 

  104. Laird, J. R. et al. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial. Circ. Cardiovasc. Interv. 3, 267–276 (2010).

    Article  PubMed  Google Scholar 

  105. Schillinger, M. et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N. Engl. J. Med. 354, 1879–1888 (2006).

    Article  PubMed  CAS  Google Scholar 

  106. Rastan, A. et al. Stent placement versus balloon angioplasty for popliteal artery treatment: two-year results of a prospective, multicenter, randomized trial. J. Endovasc. Ther. 22, 22–27 (2015).

    Article  PubMed  Google Scholar 

  107. Garcia, L. et al. Wire-interwoven nitinol stent outcome in the superficial femoral and proximal popliteal arteries: twelve-month results of the SUPERB trial. Circ. Cardiovasc. Interv. 8, e000937 (2015).

    Article  PubMed  Google Scholar 

  108. Geraghty, P. J., Mewissen, M. W., Jaff, M. R. & Ansel, G. M., VIBRANT Investigators. Three-year results of the VIBRANT trial of VIABAHN endoprosthesis versus bare nitinol stent implantation for complex superficial femoral artery occlusive disease. J. Vasc. Surg. 58, 386–395.e4 (2013).

    Article  PubMed  Google Scholar 

  109. Lammer, J. et al. Heparin-bonded covered stents versus bare-metal stents for complex femoropopliteal artery lesions: the randomized VIASTAR trial (Viabahn endoprosthesis with PROPATEN bioactive surface [VIA] versus bare nitinol stent in the treatment of long lesions in superficial femoral artery occlusive disease). J. Am. Coll. Cardiol. 62, 1320–1327 (2013).

    Article  PubMed  CAS  Google Scholar 

  110. Dake, M. D. et al. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ. Cardiovasc. Interv. 4, 495–504 (2011).

    Article  PubMed  CAS  Google Scholar 

  111. Dake, M. D. et al. Durable clinical effectiveness with paclitaxel-eluting stents in the femoropopliteal artery: 5-year results of the Zilver PTX randomized trial. Circulation 133, 1472–1483 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Scheinert, D. et al. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc. Interv 7, 10–19 (2014).

    Article  PubMed  Google Scholar 

  113. Rosenfield, K. et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N. Engl. J. Med. 373, 145–153 (2015).

    Article  PubMed  CAS  Google Scholar 

  114. Laird, J. R. et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN. PACT SFA. J. Am. Coll. Cardiol. 66, 2329–2338 (2015).

    Article  PubMed  Google Scholar 

  115. McKinsey, J. F. et al. Lower extremity revascularization using directional atherectomy: 12-month prospective results of the DEFINITIVE LE study. JACC Cardiovasc. Interv. 7, 923–933 (2014).

    Article  PubMed  Google Scholar 

  116. Diamantopoulos, A. & Katsanos, K. Atherectomy of the femoropopliteal artery: a systematic review and meta-analysis of randomized controlled trials. J. Cardiovasc. Surg. 55, 655–665 (2014).

    CAS  Google Scholar 

  117. Klinkert, P., Schepers, A., Burger, D. H., van Bockel, J. H. & Breslau, P. J. Vein versus polytetrafluoroethylene in above-knee femoropopliteal bypass grafting: five-year results of a randomized controlled trial. J. Vasc. Surg. 37, 149–155 (2003).

    Article  PubMed  Google Scholar 

  118. AbuRahma, A. F., Robinson, P. A. & Holt, S. M. Prospective controlled study of polytetrafluoroethylene versus saphenous vein in claudicant patients with bilateral above knee femoropopliteal bypasses. Surgery 126, 594–601 (1999).

    Article  PubMed  CAS  Google Scholar 

  119. Johnson, W. C. & Lee, K. K. A comparative evaluation of polytetrafluoroethylene, umbilical vein, and saphenous vein bypass grafts for femoral-popliteal above-knee revascularization: a prospective randomized Department of Veterans Affairs cooperative study. J. Vasc. Surg. 32, 268–277 (2000).

    Article  PubMed  CAS  Google Scholar 

  120. Faries, P. L. et al. A comparative study of alternative conduits for lower extremity revascularization: all-autogenous conduit versus prosthetic grafts. J. Vasc. Surg. 32, 1080–1090 (2000).

    Article  PubMed  CAS  Google Scholar 

  121. Fransson, T. & Thorne, J. In situ saphenous vein bypass grafting—still first line treatment? A prospective study comparing surgical results between diabetic and non-diabetic populations. Vasa 39, 59–65 (2010).

    Article  PubMed  CAS  Google Scholar 

  122. Lawson, J. H. et al. Bioengineered human acellular vessels for dialysis access in patients with end-stage renal disease: two phase 2 single-arm trials. Lancet 387, 2026–2034 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Armstrong, E. J. et al. Angiographic characteristics of femoropopliteal in-stent restenosis: association with long-term outcomes after endovascular intervention. Catheter Cardiovasc. Interv. 82, 1168–1174 (2013).

    Article  PubMed  Google Scholar 

  124. Jones, D. W. et al. Growing impact of restenosis on the surgical treatment of peripheral arterial disease. J. Am. Heart Assoc. 2, e000345 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Mustapha, J. A., Finton, S. M., Diaz-Sandoval, L. J., Saab, F. A. & Miller, L. E. Percutaneous transluminal angioplasty in patients with infrapopliteal arterial disease: systematic review and meta-analysis. Circ. Cardiovasc. Interv. 9, e003468 (2016).

    Article  PubMed  CAS  Google Scholar 

  126. Taylor, G. I. & Palmer, J. H. The vascular territories (angiosomes) of the body: experimental study and clinical applications. Br. J. Plast. Surg. 40, 113–141 (1987).

    Article  PubMed  CAS  Google Scholar 

  127. Attinger, C. E., Evans, K. K., Bulan, E., Blume, P. & Cooper, P. Angiosomes of the foot and ankle and clinical implications for limb salvage: reconstruction, incisions, and revascularization. Plast. Reconstr. Surg. 117 (Suppl. 7), 261S–293S (2006).

    Article  PubMed  CAS  Google Scholar 

  128. Biancari, F. & Juvonen, T. Angiosome-targeted lower limb revascularization for ischemic foot wounds: systematic review and meta-analysis. Eur. J. Vasc. Endovasc. Surg. 47, 517–522 (2014).

    Article  PubMed  CAS  Google Scholar 

  129. Sumpio, B. E. et al. Clinical implications of the angiosome model in peripheral vascular disease. J. Vasc. Surg. 58, 814–826 (2013).

    Article  PubMed  Google Scholar 

  130. Jongsma, H. et al. Angiosome-directed revascularization in patients with critical limb ischemia. J. Vasc. Surg. 65, 1208–1219.e1 (2017).

    Article  PubMed  Google Scholar 

  131. Kawarada, O. et al. Predictors of adverse clinical outcomes after successful infrapopliteal intervention. Catheter Cardiovasc. Interv. 80, 861–871 (2012).

    Article  PubMed  Google Scholar 

  132. Nakama, T. et al. Clinical outcomes of pedal artery angioplasty for patients with ischemic wounds: results from the multicenter RENDEZVOUS registry. JACC Cardiovasc. Interv. 10, 79–90 (2017).

    Article  PubMed  Google Scholar 

  133. Wu, R. et al. Percutaneous transluminal angioplasty versus primary stenting in infrapopliteal arterial disease: a meta-analysis of randomized trials. J. Vasc. Surg. 59, 1711–1720 (2014).

    Article  PubMed  Google Scholar 

  134. Zeller, T. et al. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN. PACT DEEP randomized trial. J. Am. Coll. Cardiol. 64, 1568–1576 (2014).

    Article  PubMed  Google Scholar 

  135. Wu, R. et al. Drug-eluting balloon versus standard percutaneous transluminal angioplasty in infrapopliteal arterial disease: a meta-analysis of randomized trials. Int. J. Surg. 35, 88–94 (2016).

    Article  PubMed  Google Scholar 

  136. Yiu, W. K. & Conte, M. S. The roles of drug-eluting technology and atherectomy in infrapopliteal occlusive disease. Ital. J. Vasc. Endovasc. Surg. 22, 237–248 (2015).

    Google Scholar 

  137. Rastan, A. et al. Sirolimus-eluting stents for treatment of infrapopliteal arteries reduce clinical event rate compared to bare-metal stents: long-term results from a randomized trial. J. Am. Coll. Cardiol. 60, 587–591 (2012).

    Article  PubMed  CAS  Google Scholar 

  138. Scheinert, D. et al. A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial. J. Am. Coll. Cardiol. 60, 2290–2295 (2012).

    Article  PubMed  Google Scholar 

  139. Falkowski, A., Poncyljusz, W., Wilk, G. & Szczerbo-Trojanowska, M. The evaluation of primary stenting of sirolimus-eluting versus bare-metal stents in the treatment of atherosclerotic lesions of crural arteries. Eur. Radiol. 19, 966–974 (2009).

    Article  PubMed  Google Scholar 

  140. Tepe, G. et al. Drug eluting stents versus PTA with GP IIb/IIIa blockade below the knee in patients with current ulcers—the BELOW Study. J. Cardiovasc. Surg. 51, 203–212 (2010).

    CAS  Google Scholar 

  141. Bosiers, M. et al. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease. J. Vasc. Surg. 55, 390–398 (2012).

    Article  PubMed  Google Scholar 

  142. Spreen, M. I. et al. Percutaneous transluminal angioplasty and drug-eluting stents for infrapopliteal lesions in critical limb ischemia (PADI)trial. Circ. Cardiovasc. Interv. 9, e002376 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Siablis, D., Kitrou, P. M., Spiliopoulos, S., Katsanos, K. & Karnabatidis, D. Paclitaxel-coated balloon angioplasty versus drug-eluting stenting for the treatment of infrapopliteal long-segment arterial occlusive disease: the IDEAS randomized controlled trial. JACC Cardiovasc. Interv. 7, 1048–1056 (2014).

    Article  PubMed  Google Scholar 

  144. Azar, Y., DeRubertis, B., Baril, D. & Woo, K. Atherectomy-associated complications in the southern california vascular outcomes improvement collaborative. Ann. Vasc. Surg. https://doi.org/10.1016/j.avsg.2017.11.029 (2017).

    Article  PubMed  Google Scholar 

  145. Ochoa Chaar, C. I. et al. Distal embolization during lower extremity endovascular interventions. J. Vasc. Surg. 66, 143–150 (2017).

    Article  PubMed  Google Scholar 

  146. Rastan, A. et al. One-year outcomes following directional atherectomy of infrapopliteal artery lesions: subgroup results of the prospective, multicenter DEFINITIVE LE trial. J. Endovasc. Ther. 22, 839–846 (2015).

    Article  PubMed  Google Scholar 

  147. Taylor, L. M. et al. Autogenous reversed vein bypass for lower extremity ischemia in patients with absent or inadequate greater saphenous vein. Am. J. Surg. 153, 505–510 (1987).

    Article  PubMed  Google Scholar 

  148. Neville, R. F. et al. A comparison of tibial artery bypass performed with heparin-bonded expanded polytetrafluoroethylene and great saphenous vein to treat critical limb ischemia. J. Vasc. Surg. 56, 1008–1014 (2012).

    Article  PubMed  Google Scholar 

  149. Donaldson, M. C., Mannick, J. A. & Whittemore, A. D. Femoral-distal bypass with in situ greater saphenous vein. Long-term results using the Mills valvulotome. Ann. Surg. 213, 457–464 (1991).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Schanzer, A. et al. Technical factors affecting autogenous vein graft failure: observations from a large multicenter trial. J. Vasc. Surg. 46, 1180–1190 (2007).

    Article  PubMed  Google Scholar 

  151. Faries, P. L. et al. The use of arm vein in lower-extremity revascularization: results of 520 procedures performed in eight years. J. Vasc. Surg. 31, 50–59 (2000).

    Article  PubMed  CAS  Google Scholar 

  152. Brochado Neto, F. et al. Arm vein as an alternative autogenous conduit for infragenicular bypass in the treatment of critical limb ischaemia: a 15 year experience. Eur. J. Vasc. Endovasc Surg. 47, 609–614 (2014).

    Article  PubMed  CAS  Google Scholar 

  153. Ruckert, R. I., Settmacher, U., Kruger, U. & Scholz, H. Femorodistal PTFE bypass grafting for severe limb ischaemia: results of a prospective clinical study using a new distal anastomotic technique. Eur. J. Vasc. Endovasc Surg. 20, 51–56 (2000).

    Article  PubMed  CAS  Google Scholar 

  154. Veith, F. J. et al. Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J. Vasc. Surg. 3, 104–114 (1986).

    Article  PubMed  CAS  Google Scholar 

  155. Klinkert, P., Van Dijk, P. J. E. & Breslau, P. J. Polytetrafluoroethylene femorotibial bypass grafting: 5-year patency and limb salvage. Ann. Vasc. Surg. 17, 486–491 (2003).

    Article  PubMed  CAS  Google Scholar 

  156. Conte, M. S. et al. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery. J. Vasc. Surg. 43, 742–751 (2006).

    Article  PubMed  Google Scholar 

  157. Setacci, C. et al. Chapter IV: Treatment of critical limb ischaemia. Eur. J. Vasc. Endovasc. Surg. 42 (Suppl. 2), S43–S59 (2011).

    Article  PubMed  Google Scholar 

  158. Mohler, E. R. & Annex, B. H. Regenerative Medicine for Peripheral Artery Disease 1st edn (Academic, 2016).

  159. Belch, J. et al. Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia. Lancet 377, 1929–1937 (2011).

    Article  PubMed  CAS  Google Scholar 

  160. Ko, S. H. & Bandyk, D. F. Therapeutic angiogenesis for critical limb ischemia. Semin. Vasc. Surg. 27, 23–31 (2014).

    Article  PubMed  Google Scholar 

  161. Miao, Y. L. et al. Clinical effectiveness of gene therapy on critical limb ischemia: a meta-analysis of 5 randomized controlled clinical trials. Vasc. Endovasc. Surg. 48, 372–377 (2014).

    Article  Google Scholar 

  162. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02144610 (2017).

  163. Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

    Article  PubMed  CAS  Google Scholar 

  164. Asahara, T. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ. Res. 85, 221–228 (1999).

    Article  PubMed  CAS  Google Scholar 

  165. Teraa, M. et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled rejuvenating endothelial progenitor cells via transcutaneous intra-arterial supplementation (JUVENTAS) trial. Circulation 131, 851–860 (2015).

    Article  PubMed  CAS  Google Scholar 

  166. Peeters Weem, S. M., Teraa, M., de Borst, G. J., Verhaar, M. C. & Moll, F. L. Bone marrow derived cell therapy in critical limb ischemia: a meta-analysis of randomized placebo controlled trials. Eur. J. Vasc. Endovasc. Surg. 50, 775–783 (2015).

    Article  PubMed  CAS  Google Scholar 

  167. Heeschen, C. et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation 109, 1615–1622 (2004).

    Article  PubMed  Google Scholar 

  168. Chavakis, E., Koyanagi, M. & Dimmeler, S. Enhancing the outcome of cell therapy for cardiac repair: progress from bench to bedside and back. Circulation 121, 325–335 (2010).

    Article  PubMed  Google Scholar 

  169. Gu, W., Hong, X., Potter, C., Qu, A. & Xu, Q. Mesenchymal stem cells and vascular regeneration. Microcirculation 24, e12324 (2017).

    Article  Google Scholar 

  170. Caplan, A. I. & Correa, D. The MSC: an injury drugstore. Cell Stem Cell 9, 11–15 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Le Blanc, K., Tammik, C., Rosendahl, K., Zetterberg, E. & Ringden, O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp. Hematol. 31, 890–896 (2003).

    Article  PubMed  CAS  Google Scholar 

  172. Le Blanc, K., Tammik, L., Sundberg, B., Haynesworth, S. E. & Ringden, O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand. J. Immunol. 57, 11–20 (2003).

    Article  PubMed  Google Scholar 

  173. Gremmels, H., Fledderus, J. O., Teraa, M. & Verhaar, M. C. Mesenchymal stromal cells for the treatment of critical limb ischemia: context and perspective. Stem Cell Res. Ther. 4, 140 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Hare, J. M. et al. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM trial. J. Am. Coll. Cardiol. 69, 526–537 (2017).

    Article  PubMed  Google Scholar 

  175. Dash, N. R., Dash, S. N., Routray, P., Mohapatra, S. & Mohapatra, P. C. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuven. Res. 12, 359–366 (2009).

    Article  CAS  Google Scholar 

  176. Debin, L. et al. Autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia. J. Med. Coll. PLA 23, 106–115 (2008).

    Article  Google Scholar 

  177. Lu, D. et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res. Clin. Pract. 92, 26–36 (2011).

    Article  PubMed  Google Scholar 

  178. Gupta, P. K. et al. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J. Transl Med. 11, 143 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Gupta, P. K. et al. Administration of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells in critical limb ischemia due to Buerger’s disease: phase ii study report suggests clinical efficacy. Stem Cells Transl Med. 6, 689–699 (2017).

    Article  PubMed  Google Scholar 

  180. Abu Dabrh, A. M. et al. Nonrevascularization-based treatments in patients with severe or critical limb ischemia. J. Vasc. Surg. 62, 1330–1339.e1313 (2015).

    Article  PubMed  Google Scholar 

  181. Klomp, H. M., Steyerberg, E. W., Habbema, J. D. & van Urk, H., ESES Study Group. What is the evidence on efficacy of spinal cord stimulation in (subgroups of) patients with critical limb ischemia? Ann. Vasc. Surg. 23, 355–363 (2009).

    Article  PubMed  CAS  Google Scholar 

  182. Pedrini, L. & Magnoni, F. Spinal cord stimulation for lower limb ischemic pain treatment. Interact. Cardiovasc. Thorac. Surg. 6, 495–500 (2007).

    Article  PubMed  Google Scholar 

  183. Alvarez, O. M., Wendelken, M. E., Markowitz, L. & Comfort, C. Effect of high-pressure, intermittent pneumatic compression for the treatment of peripheral arterial disease and critical limb ischemia in patients without a surgical option. Wounds 27, 293–301 (2015).

    PubMed  Google Scholar 

  184. Ruiz-Aragon, J. & Marquez Calderon, S. Effectiveness of lumbar sympathectomy in the treatment of occlusive peripheral vascular disease in lower limbs: systematic review [Spanish]. Med. Clin. 134, 477–482 (2010).

    Article  Google Scholar 

  185. Sanni, A., Hamid, A. & Dunning, J. Is sympathectomy of benefit in critical leg ischaemia not amenable to revascularisation? Interact. Cardiovasc. Thorac. Surg. 4, 478–483 (2005).

    Article  PubMed  Google Scholar 

  186. Karanth, V. K., Karanth, T. K. & Karanth, L. Lumbar sympathectomy techniques for critical lower limb ischaemia due to non-reconstructable peripheral arterial disease. Cochrane Database Syst. Rev. 12, CD011519 (2016).

    PubMed  Google Scholar 

  187. Patel, M. R. et al. Evaluation and treatment of patients with lower extremity peripheral artery disease: consensus definitions from Peripheral Academic Research Consortium (PARC). J. Am. Coll. Cardiol. 65, 931–941 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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J.S.H., M.T., and M.S.C. researched data for the article and contributed substantially to discussions of its content. All authors contributed to writing the article and reviewing or editing of the manuscript before submission.

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Glossary

Atherectomy

The removal of obstructive atherosclerotic disease from the arterial lumen.

Angiosome

A concept based on anatomical studies that links major terminating branches of the tibial arteries to specific regions of perfusion in the foot.

Transcutaneous oxygen

The measurement of local oxygen released from the skin through the capillaries, which reflects the metabolic state of the lower limb.

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Hiramoto, J.S., Teraa, M., de Borst, G.J. et al. Interventions for lower extremity peripheral artery disease. Nat Rev Cardiol 15, 332–350 (2018). https://doi.org/10.1038/s41569-018-0005-0

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