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January 18, 2021
Accepted
February 17, 2021
Published
February 28, 2023
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Abstract
Chronic limb ischemia (CLI) is a type of peripheral arterial disease (PAD) that is still underdiagnosed and undertreated despite the increasing incidence, thus becoming a global health burden. The prevalence of PAD is quite high, approximately around 200 million globally in the adult population and increased drastically in older age population. It might be difficult to diagnose at an early stage because around 20-50% patients may be asymptomatic. More than 70% of primary physicians also did not notice that the diagnosis was already established during screening of the PAD patients. All these problems could increase the incidence of PAD in the following year. The untreated conditions will develop into a more severe form of PAD known as chronic limb-threatening ischemia (or critical limb ischemia), and patients are at a higher risk of having limb loss, and also increased morbidity and mortality. The primary physicians in the primary health facilities hold an important role in the early diagnosis and management of patients with CLI symptoms or with risk factors of CLI. Due to the limitation of diagnostic testing modality at primary health facilities, the physician can assess the ankle-brachial index (ABI) to determine the presence of CLI. Management of the disease is different for every patient and is customized based on the other comorbidities. Risk factors should be controlled in order to achieve a better outcome. A good management strategy will improve the condition. This review aims to describe how to give an early diagnosis and management for CLI patients in primary health care.
Keywords
ankle brachial index
chronic limb ischemia
exercise program
pharmalogical therapy
risk factor
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This work is licensed under a Creative Commons Attribution 4.0 International License.
How to Cite
Purwowiyoto, S. L., & Halomoan, R. (2023). Chronic Limb Ischemia: Awareness and Treatment in Primary Care. Sanus Medical Journal, 5(1), 18–23. https://doi.org/10.22236/sanus.v5i1.6347
References
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1. Fowkes FG, Rudan D, Rudan I, 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. 2013;382(9901):1329-40. doi: 10.1016/S0140-6736(13)61249-0.
2. Olinic DM, Spinu M, Olinic M, et al. Epidemiology of peripheral artery disease in Europe: VAS Educational Paper. Int Angiol. 2018;37(4):327-334. doi: 10.23736/S0392-9590.18.03996-2.
3. Hirsch AT, Allison MA, Gomes AS, et al. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation. 2012;125(11):1449-72. doi: 10.1161/CIR.0b013e31824c39ba.
4. Tummala S, Scherbel D. Clinical assessment of peripheral arterial disease in the office: what do the guidelines say?. Semin Intervent Radiol. 2018;35(5):365-377. doi: 10.1055/s-0038-1676453
5. Cimminiello C, Kownator S, Wautrecht JC, et al. The PANDORA study: peripheral arterial disease in patients with non-high cardiovascular risk. Intern Emerg Med. 2011;6(6):509-19. doi: 10.1007/s11739-011-0511-0.
6. Street TK. What the primary care provider needs to know for limb salvage. Methodist Debakey Cardiovasc J. 2012;8(4):57-59. doi:10.14797/mdcj-8-4-57
7. Simon F, Oberhuber A, Floros N, Düppers P, Schelzig H, Duran M. Pathophysiology of chronic limb ischemia. Gefasschirurgie. 2018;23(Suppl 1):13-18. doi: 10.1007/s00772-018-0380-1
8. Kinlay S. Management of Critical Limb Ischemia. Circ Cardiovasc Interv. 2016;9(2):e001946. DOI: 10.1161/CIRCINTERVENTIONS.115.001946
9. Thukkani AK, Kinlay S. Endovascular intervention for peripheral artery disease. Circ Res. 2015;116(9):1599-613. doi: 10.1161/CIRCRESAHA.116.303503.
10. Davies MG. Criticial limb ischemia: epidemiology. Methodist Debakey Cardiovasc J. 2012;8(4):10-14. doi: 10.14797/mdcj-8-4-10
11. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the american college of cardiology/american heart association task force on clinical practice guidelines. Circulation. 2017;135(12):e726-e779. doi:10.1161/CIR.0000000000000471
12. Aboyans V, Ricco JB, Bartelink ME, et al. Editor's Choice - 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the european society for vascular surgery (esvs). Eur J Vasc Endovasc Surg. 2018;55(3):305-368. doi: 10.1016/j.ejvs.2017.07.018.
13. Nehler MR, Duval S, Diao L, et al. Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population. J Vasc Surg. 2014;60(3):686-95.e2. doi: 10.1016/j.jvs.2014.03.290.
14. Joosten MM, Pai JK, Bertoia ML, et al. Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. JAMA. 2012;308(16):1660-7. doi: 10.1001/jama.2012.13415.
15. Lee YH, Shin MH, Kweon SS, et al. Cumulative smoking exposure, duration of smoking cessation, and peripheral arterial disease in middle-aged and older Korean men. BMC Public Health. 2011;11:94. doi:10.1186/1471-2458-11-94
16. Lu L, Mackay DF, Pell JP. Association between level of exposure to secondhand smoke and peripheral arterial disease: cross-sectional study of 5,686 never smokers. Atherosclerosis. 2013;229(2):273-6. doi: 10.1016/j.atherosclerosis.2013.05.015.
17. Lu L, Mackay DF, Pell JP. Secondhand smoke exposure and intermittent claudication: a scotland-wide study of 4231 non-smokers. Heart. 2013;99(18):1342-5. doi: 10.1136/heartjnl-2013-304226.
18. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res. 2015;116(9):1509-26. doi: 10.1161/CIRCRESAHA.116.303849.
19. Uccioli L, Gandini R, Giurato L, et al. Long-term outcomes of diabetic patients with critical limb ischemia followed in a tertiary referral diabetic foot clinic. Diabetes Care. 2010;33(5):977-82. doi: 10.2337/dc09-0831.
20. Itoga NK, Tawfik DS, Lee CK, Maruyama S, Leeper NJ, Chang TI. Association of blood pressure measurements with peripheral artery disease events. Circulation. 2018;138(17):1805-1814. doi:10.1161/CIRCULATIONAHA.118.033348
21. Emdin CA, Anderson SG, Callender T, et al. Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults. BMJ. 2015;351:h4865. doi: 10.1136/bmj.h4865.
22. Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet. 2014;383(9932):1899-911. doi: 10.1016/S0140-6736(14)60685-1.
23. Aday AW, Everett BM. Dyslipidemia profiles in patients with peripheral artery disease. Curr Cardiol Rep. 2019;21(6):42. doi:10.1007/s11886-019-1129-5
24. Walker CM, Bunch FT, Cavros NG, Dippel EJ. Multidisciplinary approach to the diagnosis and management of patients with peripheral arterial disease. Clin Interv Aging. 2015;10:1147-1153. doi: 10.2147/CIA.S79355
25. Armstrong DW, Tobin C, Matangi MF. The accuracy of the physical examination for the detection of lower extremity peripheral arterial disease. Can J Cardiol. 2010;26(10):e346-50. doi: 10.1016/s0828-282x(10)70467-0.
26. Olin JW, Sealove BA. Peripheral artery disease: current insight into the disease and its diagnosis and management. Mayo Clin Proc. 2010;85(7):678-692. doi: 10.4065/mcp.2010.0133
27. Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL. Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta-analysis. Lancet. 2012;379(9819):905-914. doi: 10.1016/S0140-6736(11)61710-8.
28. Aboyans V, Criqui MH, Abraham P, et al. Measurement and interpretation of the ankle-brachial index: a scientific statement from the american heart association. Circulation. 2012;126(24):2890-909. doi: 10.1161/CIR.0b013e318276fbcb.
29. Arain FA, Ye Z, Bailey KR, et al. Survival in patients with poorly compressible leg arteries. J Am Coll Cardiol. 2012;59(4):400-407. doi:10.1016/j.jacc.2011.09.055
30. Shu J, Santulli G. Update on peripheral artery disease: epidemiology and evidence-based facts. Atherosclerosis. 2018;275:379-381. doi: 10.1016/j.atherosclerosis.2018.05.033
31. Aronow WS. Peripheral arterial disease of the lower extremities. Arch Med Sci. 2012;8(2):375-388. doi: 10.5114/aoms.2012.28568
32. Criqui MH, McClelland RL, McDermott MM, et al. The ankle-brachial index and incident cardiovascular events in the mesa (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2010;56(18):1506-12. doi: 10.1016/j.jacc.2010.04.060
33. Uccioli L, Meloni M, Izzo V, Giurato L, Merolla S, Gandini R. Critical limb ischemia: current challenges and future prospects. Vasc Health Risk Manag. 2018;14:63-74. doi: 10.2147/VHRM.S125065
34. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA. 2010;303(9):841-8. doi: 10.1001/jama.2010.221.
35. Katsanos K, Spiliopoulos S, Saha P, 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. 2015;10(8):e0135692. doi: 10.1371/journal.pone.0135692.
36. Kumbhani DJ, Steg PG, Cannon CP, et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J. 2014;35(41):2864-72. doi: 10.1093/eurheartj/ehu080
37. Aboyans V, Ricco JB, Bartelink MEL, 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 arteriesendorsed 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. 2018;39(9):763-816. doi: 10.1093/eurheartj/ehx095.
38. Ramos R, García-Gil M, Comas-Cufí M, et al. Statins for prevention of cardiovascular events in a low-risk population with low ankle brachial index. J Am Coll Cardiol. 2016;67(6):630-640. doi: 10.1016/j.jacc.2015.11.052.
39. Giurato L, Vainieri E, Meloni M, et al. Limb salvage in patients with diabetes is not a temporary solution but a life-changing procedure. Diabetes Care. 2015;38(10):e156-7. doi: 10.2337/dc15-0989
40. Atturu G, Homer-Vanniasinkam S, Russell DA. Pharmacology in peripheral arterial disease: what the interventional radiologist needs to know. Semin Intervent Radiol. 2014;31(4):330-337. doi:10.1055/s-0034-1393969
41. Su WH, Cheng MH, Lee WL, et al. Nonsteroidal anti-inflammatory drugs for wounds: pain relief or excessive scar formation?. Mediators Inflamm. 2010;2010:413238. doi:10.1155/2010/413238
42. Anderson K, Hamm RL. Factors that impair wound healing. J Am Coll Clin Wound Spec. 2014;4(4):84-91. doi:10.1016/j.jccw.2014.03.001
43. Hennrikus D, Joseph AM, Lando HA, et al. Effectiveness of a smoking cessation program for peripheral artery disease patients: a randomized controlled trial. J Am Coll Cardiol. 2010;56(25):2105-12. doi: 10.1016/j.jacc.2010.07.031
44. Armstrong EJ, Wu J, Singh GD, et al. Smoking cessation is associated with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease. J Vasc Surg. 2014;60(6):1565-71. doi: 10.1016/j.jvs.2014.08.064.
45. Fakhry F, Rouwet EV, den Hoed PT, Hunink MG, Spronk S. Long-term clinical effectiveness of supervised exercise therapy versus endovascular revascularization for intermittent claudication from a randomized clinical trial. Br J Surg. 2013;100(9):1164-71. doi: 10.1002/bjs.9207
46. Murphy TP, Cutlip DE, Regensteiner JG, 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(10):999-1009. doi: 10.1016/j.jacc.2014.12.043
47. Abu Dabrh AM, Steffen MW, Undavalli C, et al. The natural history of untreated severe or critical limb ischemia. J Vasc Surg. 2015;62(6):1642-51.e3. doi: 10.1016/j.jvs.2015.07.065
48. Kobayashi N, Hirano K, Nakano M, et al. Prognosis of critical limb ischemia patients with tissue loss after achievement of complete wound healing by endovascular therapy. J Vasc Surg. 2015;61(4):951-9. doi: 10.1016/j.jvs.2014.11.065.
49. Chung J, Modrall JG, Ahn C, Lavery LA, Valentine RJ. Multidisciplinary care improves amputation-free survival in patients with chronic critical limb ischemia. J Vasc Surg. 2015;61(1):162-9. doi: 10.1016/j.jvs.2014.05.101
50. Sandoval DL. Critical Limb Threatening Ischemia: The Time has Come for a Multidisciplinary Approach. J Vasc Endovasc Therapy. 2019;4(1):9.
51. Schiattarella GG, Perrino C, Magliulo F, et al. Physical activity in the prevention of peripheral artery disease in the elderly. Front Physiol. 2014;5:12. doi:10.3389/fphys.2014.00012
52. Aggarwal S, Loomba RS, Arora R. Preventive aspects in peripheral artery disease. Ther Adv Cardiovasc Dis. 2012;6(2):53-70. doi: 10.1177/1753944712437359.
References
1. Fowkes FG, Rudan D, Rudan I, 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. 2013;382(9901):1329-40. doi: 10.1016/S0140-6736(13)61249-0.
2. Olinic DM, Spinu M, Olinic M, et al. Epidemiology of peripheral artery disease in Europe: VAS Educational Paper. Int Angiol. 2018;37(4):327-334. doi: 10.23736/S0392-9590.18.03996-2.
3. Hirsch AT, Allison MA, Gomes AS, et al. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation. 2012;125(11):1449-72. doi: 10.1161/CIR.0b013e31824c39ba.
4. Tummala S, Scherbel D. Clinical assessment of peripheral arterial disease in the office: what do the guidelines say?. Semin Intervent Radiol. 2018;35(5):365-377. doi: 10.1055/s-0038-1676453
5. Cimminiello C, Kownator S, Wautrecht JC, et al. The PANDORA study: peripheral arterial disease in patients with non-high cardiovascular risk. Intern Emerg Med. 2011;6(6):509-19. doi: 10.1007/s11739-011-0511-0.
6. Street TK. What the primary care provider needs to know for limb salvage. Methodist Debakey Cardiovasc J. 2012;8(4):57-59. doi:10.14797/mdcj-8-4-57
7. Simon F, Oberhuber A, Floros N, Düppers P, Schelzig H, Duran M. Pathophysiology of chronic limb ischemia. Gefasschirurgie. 2018;23(Suppl 1):13-18. doi: 10.1007/s00772-018-0380-1
8. Kinlay S. Management of Critical Limb Ischemia. Circ Cardiovasc Interv. 2016;9(2):e001946. DOI: 10.1161/CIRCINTERVENTIONS.115.001946
9. Thukkani AK, Kinlay S. Endovascular intervention for peripheral artery disease. Circ Res. 2015;116(9):1599-613. doi: 10.1161/CIRCRESAHA.116.303503.
10. Davies MG. Criticial limb ischemia: epidemiology. Methodist Debakey Cardiovasc J. 2012;8(4):10-14. doi: 10.14797/mdcj-8-4-10
11. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the american college of cardiology/american heart association task force on clinical practice guidelines. Circulation. 2017;135(12):e726-e779. doi:10.1161/CIR.0000000000000471
12. Aboyans V, Ricco JB, Bartelink ME, et al. Editor's Choice - 2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the european society for vascular surgery (esvs). Eur J Vasc Endovasc Surg. 2018;55(3):305-368. doi: 10.1016/j.ejvs.2017.07.018.
13. Nehler MR, Duval S, Diao L, et al. Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population. J Vasc Surg. 2014;60(3):686-95.e2. doi: 10.1016/j.jvs.2014.03.290.
14. Joosten MM, Pai JK, Bertoia ML, et al. Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. JAMA. 2012;308(16):1660-7. doi: 10.1001/jama.2012.13415.
15. Lee YH, Shin MH, Kweon SS, et al. Cumulative smoking exposure, duration of smoking cessation, and peripheral arterial disease in middle-aged and older Korean men. BMC Public Health. 2011;11:94. doi:10.1186/1471-2458-11-94
16. Lu L, Mackay DF, Pell JP. Association between level of exposure to secondhand smoke and peripheral arterial disease: cross-sectional study of 5,686 never smokers. Atherosclerosis. 2013;229(2):273-6. doi: 10.1016/j.atherosclerosis.2013.05.015.
17. Lu L, Mackay DF, Pell JP. Secondhand smoke exposure and intermittent claudication: a scotland-wide study of 4231 non-smokers. Heart. 2013;99(18):1342-5. doi: 10.1136/heartjnl-2013-304226.
18. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res. 2015;116(9):1509-26. doi: 10.1161/CIRCRESAHA.116.303849.
19. Uccioli L, Gandini R, Giurato L, et al. Long-term outcomes of diabetic patients with critical limb ischemia followed in a tertiary referral diabetic foot clinic. Diabetes Care. 2010;33(5):977-82. doi: 10.2337/dc09-0831.
20. Itoga NK, Tawfik DS, Lee CK, Maruyama S, Leeper NJ, Chang TI. Association of blood pressure measurements with peripheral artery disease events. Circulation. 2018;138(17):1805-1814. doi:10.1161/CIRCULATIONAHA.118.033348
21. Emdin CA, Anderson SG, Callender T, et al. Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults. BMJ. 2015;351:h4865. doi: 10.1136/bmj.h4865.
22. Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet. 2014;383(9932):1899-911. doi: 10.1016/S0140-6736(14)60685-1.
23. Aday AW, Everett BM. Dyslipidemia profiles in patients with peripheral artery disease. Curr Cardiol Rep. 2019;21(6):42. doi:10.1007/s11886-019-1129-5
24. Walker CM, Bunch FT, Cavros NG, Dippel EJ. Multidisciplinary approach to the diagnosis and management of patients with peripheral arterial disease. Clin Interv Aging. 2015;10:1147-1153. doi: 10.2147/CIA.S79355
25. Armstrong DW, Tobin C, Matangi MF. The accuracy of the physical examination for the detection of lower extremity peripheral arterial disease. Can J Cardiol. 2010;26(10):e346-50. doi: 10.1016/s0828-282x(10)70467-0.
26. Olin JW, Sealove BA. Peripheral artery disease: current insight into the disease and its diagnosis and management. Mayo Clin Proc. 2010;85(7):678-692. doi: 10.4065/mcp.2010.0133
27. Clark CE, Taylor RS, Shore AC, Ukoumunne OC, Campbell JL. Association of a difference in systolic blood pressure between arms with vascular disease and mortality: a systematic review and meta-analysis. Lancet. 2012;379(9819):905-914. doi: 10.1016/S0140-6736(11)61710-8.
28. Aboyans V, Criqui MH, Abraham P, et al. Measurement and interpretation of the ankle-brachial index: a scientific statement from the american heart association. Circulation. 2012;126(24):2890-909. doi: 10.1161/CIR.0b013e318276fbcb.
29. Arain FA, Ye Z, Bailey KR, et al. Survival in patients with poorly compressible leg arteries. J Am Coll Cardiol. 2012;59(4):400-407. doi:10.1016/j.jacc.2011.09.055
30. Shu J, Santulli G. Update on peripheral artery disease: epidemiology and evidence-based facts. Atherosclerosis. 2018;275:379-381. doi: 10.1016/j.atherosclerosis.2018.05.033
31. Aronow WS. Peripheral arterial disease of the lower extremities. Arch Med Sci. 2012;8(2):375-388. doi: 10.5114/aoms.2012.28568
32. Criqui MH, McClelland RL, McDermott MM, et al. The ankle-brachial index and incident cardiovascular events in the mesa (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2010;56(18):1506-12. doi: 10.1016/j.jacc.2010.04.060
33. Uccioli L, Meloni M, Izzo V, Giurato L, Merolla S, Gandini R. Critical limb ischemia: current challenges and future prospects. Vasc Health Risk Manag. 2018;14:63-74. doi: 10.2147/VHRM.S125065
34. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA. 2010;303(9):841-8. doi: 10.1001/jama.2010.221.
35. Katsanos K, Spiliopoulos S, Saha P, 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. 2015;10(8):e0135692. doi: 10.1371/journal.pone.0135692.
36. Kumbhani DJ, Steg PG, Cannon CP, et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J. 2014;35(41):2864-72. doi: 10.1093/eurheartj/ehu080
37. Aboyans V, Ricco JB, Bartelink MEL, 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 arteriesendorsed 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. 2018;39(9):763-816. doi: 10.1093/eurheartj/ehx095.
38. Ramos R, García-Gil M, Comas-Cufí M, et al. Statins for prevention of cardiovascular events in a low-risk population with low ankle brachial index. J Am Coll Cardiol. 2016;67(6):630-640. doi: 10.1016/j.jacc.2015.11.052.
39. Giurato L, Vainieri E, Meloni M, et al. Limb salvage in patients with diabetes is not a temporary solution but a life-changing procedure. Diabetes Care. 2015;38(10):e156-7. doi: 10.2337/dc15-0989
40. Atturu G, Homer-Vanniasinkam S, Russell DA. Pharmacology in peripheral arterial disease: what the interventional radiologist needs to know. Semin Intervent Radiol. 2014;31(4):330-337. doi:10.1055/s-0034-1393969
41. Su WH, Cheng MH, Lee WL, et al. Nonsteroidal anti-inflammatory drugs for wounds: pain relief or excessive scar formation?. Mediators Inflamm. 2010;2010:413238. doi:10.1155/2010/413238
42. Anderson K, Hamm RL. Factors that impair wound healing. J Am Coll Clin Wound Spec. 2014;4(4):84-91. doi:10.1016/j.jccw.2014.03.001
43. Hennrikus D, Joseph AM, Lando HA, et al. Effectiveness of a smoking cessation program for peripheral artery disease patients: a randomized controlled trial. J Am Coll Cardiol. 2010;56(25):2105-12. doi: 10.1016/j.jacc.2010.07.031
44. Armstrong EJ, Wu J, Singh GD, et al. Smoking cessation is associated with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease. J Vasc Surg. 2014;60(6):1565-71. doi: 10.1016/j.jvs.2014.08.064.
45. Fakhry F, Rouwet EV, den Hoed PT, Hunink MG, Spronk S. Long-term clinical effectiveness of supervised exercise therapy versus endovascular revascularization for intermittent claudication from a randomized clinical trial. Br J Surg. 2013;100(9):1164-71. doi: 10.1002/bjs.9207
46. Murphy TP, Cutlip DE, Regensteiner JG, 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(10):999-1009. doi: 10.1016/j.jacc.2014.12.043
47. Abu Dabrh AM, Steffen MW, Undavalli C, et al. The natural history of untreated severe or critical limb ischemia. J Vasc Surg. 2015;62(6):1642-51.e3. doi: 10.1016/j.jvs.2015.07.065
48. Kobayashi N, Hirano K, Nakano M, et al. Prognosis of critical limb ischemia patients with tissue loss after achievement of complete wound healing by endovascular therapy. J Vasc Surg. 2015;61(4):951-9. doi: 10.1016/j.jvs.2014.11.065.
49. Chung J, Modrall JG, Ahn C, Lavery LA, Valentine RJ. Multidisciplinary care improves amputation-free survival in patients with chronic critical limb ischemia. J Vasc Surg. 2015;61(1):162-9. doi: 10.1016/j.jvs.2014.05.101
50. Sandoval DL. Critical Limb Threatening Ischemia: The Time has Come for a Multidisciplinary Approach. J Vasc Endovasc Therapy. 2019;4(1):9.
51. Schiattarella GG, Perrino C, Magliulo F, et al. Physical activity in the prevention of peripheral artery disease in the elderly. Front Physiol. 2014;5:12. doi:10.3389/fphys.2014.00012
52. Aggarwal S, Loomba RS, Arora R. Preventive aspects in peripheral artery disease. Ther Adv Cardiovasc Dis. 2012;6(2):53-70. doi: 10.1177/1753944712437359.
2. Olinic DM, Spinu M, Olinic M, et al. Epidemiology of peripheral artery disease in Europe: VAS Educational Paper. Int Angiol. 2018;37(4):327-334. doi: 10.23736/S0392-9590.18.03996-2.
3. Hirsch AT, Allison MA, Gomes AS, et al. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation. 2012;125(11):1449-72. doi: 10.1161/CIR.0b013e31824c39ba.
4. Tummala S, Scherbel D. Clinical assessment of peripheral arterial disease in the office: what do the guidelines say?. Semin Intervent Radiol. 2018;35(5):365-377. doi: 10.1055/s-0038-1676453
5. Cimminiello C, Kownator S, Wautrecht JC, et al. The PANDORA study: peripheral arterial disease in patients with non-high cardiovascular risk. Intern Emerg Med. 2011;6(6):509-19. doi: 10.1007/s11739-011-0511-0.
6. Street TK. What the primary care provider needs to know for limb salvage. Methodist Debakey Cardiovasc J. 2012;8(4):57-59. doi:10.14797/mdcj-8-4-57
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