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Diabetes Watch

Emerging Insights On The Role Of Endovascular Revascularization In Wound Healing And Amputation Prevention

Lower extremity peripheral artery disease (PAD) has varied manifestations and is categorized according to the Rutherford classification.1,2,3 Claudication progresses from mild to severe in Rutherford categories one through three (RC1–3). Critical limb ischemia (CLI) is described as ischemic rest pain (Rutherford category 4 or RC4), minor tissue loss (Rutherford category 5 or RC5) and major tissue loss extending cephalad to the transmetatarsal level (Rutherford category 6 or RC6).3 An estimated 150,000 amputations due to CLI occur annually in the United States.4,5 Additionally, primary amputation continues to be the first-line therapy for CLI at some institutions with an average amputation rate greater than 20 percent.6,7,8

Lower extremity PAD and CLI are highly prevalent in older patients with diabetes mellitus and/or chronic kidney disease, and are associated with high risks of amputation and mortality.7,9 Diabetes-related amputations accounted for 75 percent of all non-traumatic lower extremity amputations in 2015.10 The progression of diabetes to end-stage renal failure is associated with the progression of multiple other complications of diabetes, including neuropathy and PAD.11 The pathogenesis of lower extremity amputation in diabetes is multifactorial. Several reviews have recently described the epidemiology and pathology of PAD and CLI, but there is a paucity of data on optimal revascularization strategies, especially for CLI.12,13

Unfortunately, there is scarce data on atherectomy-guided therapy in patients with diabetes and CLI. The DEFINITIVE LE study reported a comparison of clinical outcomes of diabetic and non-diabetic patients following directional atherectomy in a claudicant cohort.14 The results showed that although patients with diabetes had significantly more baseline comorbidities, 12-month primary patency (77.0 percent) was no different in comparison to nondiabetics (77.9 percent) across all anatomic territories treated. Clinically-driven target lesion revascularization was no different between patients with diabetes (83.8 percent) and non-diabetics (87.5 percent) overall or by lesion locations. Secondary clinical outcomes (Rutherford category, ankle-brachial index (ABI) and walking impairment) improved at 12 months for patients with diabetes and non-diabetics.

Understanding The Advances In Endovascular Revascularization

Over the past two decades, the use of endovascular revascularization has supplanted surgical bypass as the primary mode of revascularization in the United States.15,16 The rates of endovascular revascularization have risen dramatically and most procedures are now performed by vascular surgeons and cardiologists. Additionally, the majority of these procedures are being performed in outpatient hospital settings or office-based laboratories, leading to significant cost savings. Yet multiple studies have reported that patients who undergo major lower extremity amputation do not undergo endovascular revascularization and as many as 30 percent do not have any vascular evaluation whatsoever.17

In addition to the rise of endovascular procedures, there have been significant innovative and technologic advances for patients with severe PAD and threatened limbs. Prior endovascular techniques were confined mainly to conventional balloon angioplasty (inflating a balloon within the diseased artery) but conventional angioplasty has limited long-term patency, especially in patients with calcifed arteries and/or diffuse occlusions of the tibial and pedal arteries.

Newer techniques permit the application of anti-proliferative medications on balloons (paclitaxel-coated balloons) and stents (paclitaxel-eluting stents). Vascular surgeons may also utilize ablative therapies (excimer laser, orbital/rotational/directional atherectomy) to improve luminal gain, and the use of alternative vascular access (specifically pedal artery access) has led to a significantly higher acute procedural success and longer durability of clinical improvement. Despite these improvements, not all endovascular operators have adopted these devices and techniques, and significant variation is present. This can be related to geography (where the procedure occurs), the physician who performs the procedure and the patient.

With the maturation and rise of endovascular procedures, there has been a concomitant decline in major lower extremity ampuations, but the problem remains substantial and affects hundreds of thousands of Americans each year. When evaluating the existing evidence for patients with PAD who underwent major lower extremity amputation in the United States, the impetus to improve perfusion and minimize tissue loss is strong.18  This importance is highlighted by the subsequent morbidity following amputation (higher rates of myocardial infarction, stroke, subsequent amputation), higher overall costs and elevated risks of mortality. In one study of Medicare patients who had a major lower extremity amputation, the one-year risk of all-cause death was 48.3 percent and the three-year risk of all-cause death was 70.9 percent.19

Both the Institute of Medicine and the National Institutes of Health have recognized PAD as a major health concern, and the Agency for Healthcare Research and Quality has called for more comparative effectiveness research. Very few studies have detailed longitudinal patient, procedural and clinical data in patients with PAD. However, there is now compelling data with the one-year and two-year results of the LIBERTY 360 study that were recently presented at the 2018 Amputation Prevention Symposium, the Leipzig Interventional Course 2018 and 2019, and the 2019 International Symposium on Endovascular Therapy.20 Additionally, the one-year results of this study were recently published.18

What You Should Know About The LIBERTY 360 Registry

The LIBERTY 360 registry was designed to study the use of endovascular techniques for patients with all forms of PAD and the data from LIBERTY 360 has begun to better characterize these patients and fill the knowledge gap.21

Briefly, the LIBERTY 360 registry is a prospective, observational, core laboratory–assessed, multicenter study of endovascular device intervention in 1,204 participants (with a mean age of 69.8 ± 10.7 years), including 770 men.18 The study authors stratified patients with the Rutherford category classification with 501 patients in the RC 2 and RC3 group, 603 patients having CLI with no or minimal tissue loss (RC4 and RC5), and 100 patients having CLI with significant tissue loss (RC6).

Key outcomes included wound healing and freedom from major amputation. The results indicated a high freedom from major amputation at two years in patients in the RC2-3 group (99.1 percent), those in the RC4-5 group (94.5 percent), and patients in the RC6 (79.8 percent) group despite complex demographics.18 In addition, an orbital atherectomy subanalysis revealed a numerically higher freedom from major amputation in patients with RC2-3 (100 percent), RC4-5 (95.3 percent) and RC6 (88.5 percent).18

Key Conclusions From The LIBERTY 360 Study

These results indicate that lower extremity endovascular revascularization is a viable treatment option for patients in RC 2–3, RC 4–5, and RC6 as evidenced by the high freedom from major amputation as well as the improvement in wound healing over two years (see “Assessing Improved Wound Healing After Endovascular Revascularization: Two-Year Results From The LIBERTY360 Study” above).

Furthermore, primary unplanned amputation is often not necessary in patients in RC6 as endovascular revascularization is a suitable option in this subgroup. As these results are disseminated and researchers perform more analyses from the LIBERTY 360 registry, the inclusion of all clinicians who take care of patients with vascular disease, ulcerations, and gangrene will be imperative. Successful partnerships between podiatry, vascular specialists and primary care physicians to improve awareness of this disease and the available therapeutic options (specifically endovascular revascularization and the newer techniques) should be forged within our communities. 

Dr. Mustapha is a Clinical Associate Professor Of Medicine at the Michigan State University College Of Osteopathic Medicine in East Lansing, Mich. He is in private practice at Advanced Cardiac and Vascular Centers for Amputation Prevention in Grand Rapids, Mich. Dr. Mustapha has disclosed that he is a consultant with Cardiovascular Systems, Inc.

Dr. Jones is an Associate Professor Of Medicine and Associate Professor Of Population Health Sciences at the Duke University School of Medicine in Durham, N.C. He is also a member of the Duke Clinical Research Institute.

Dr. Saab is a Clinical Associate Professor Of Medicine at the Michigan State University College Of Osteopathic Medicine in East Lansing, Mich. He is in private practice at Advanced Cardiac and Vascular Centers for Amputation Prevention in Grand Rapids, Mich. Dr. Saab has disclosed that he is a consultant with Cardiovascular Systems, Inc.

Dr. Armstrong is an Associate Professor of Medicine-Cardiology at the University of Colorado School of Medicine. He is the Director of  Interventional Cardiology and Co-Director of the Vascular Laboratory with the VA Eastern Colorado Health System in Denver. Dr. Armstrong has disclosed that he is a consultant with Cardiovascular Systems, Inc.

Dr. O’Connor is the Director of Vascular Research and an Assistant Professor of Surgery at Hackensack University Medical Center in Hackensack, N.J.

Dr. Iorio is the Assistant Dean for Continuing Medical Education and Chairman of the Department of Community Medicine at the New York College of Podiatric Medicine in New York.

Dr. Driver is the Director of Translational Medicine and Professor of Orthopedic Surgery (clinical) at the Brown University School of Medicine in Cambridge, Mass.

Dr. Adams is the Director of Cardiovascular and Peripheral Vascular Research at Rex Hospital in Raleigh, NC. He is in private practice at North Carolina Heart and Vascular in Raleigh, N.C. Dr. Adams has disclosed that he is a consultant with Bard Peripheral Vascular, Terumo Interventional Systems, Medtronic, Boston Scientific, Spectranetics and Cardiovascular Systems, Inc.

Diabetes Watch
By Jihad A. Mustapha, MD, W. Schuyler Jones, MD, Fadi A. Saab, MD, Ehrin J. Armstrong, MD, David O’Connor, MD, Anthony R. Iorio, DPM, MPH, Vickie Driver, DPM, FACFAS, and George L. Adams, MD, MHS, MBA

1. 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.

2. 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 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. 2018;39(9):763-816.

3. Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg. 1997;26(3):517-538.

4. Li Y, Burrows NR, Gregg EW, Albright A, Geiss LS. Declining rates of hospitalization for nontraumatic lower-extremity amputation in the diabetic population aged 40 years or older: U.S., 1988-2008. Diabetes Care. 2012;35(2):273-277.

5. Hirsch AT, Duval S. The global pandemic of peripheral artery disease. Lancet. 2013;382(9901):1312-1314.

6. Mustapha J, Martinsen BJ, Igyarto Z. LIBERTY 360° study presentation at AMP 2016 reveals hope for Rutherford-6 CLI patients. Cath Lab Dig. 2016;24(10). Available at: Published October 7, 2016. Accessed July 3, 2019.

7. 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):1642-1651.

8. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45 Suppl S:S5-67.

9. Eggers PW, Gohdes D, Pugh J. Nontraumatic lower extremity amputations in the Medicare end-stage renal disease population. Kidney Int. 1999;56:1524-1533.

10. Geiss LS, Li Y, Hora I, Albright A, Rolka D, Gregg EW. Resurgence of diabetes-related nontraumatic lower-extremity amputation in the young and middle-aged adult U.S. population. Diabetes Care. 2019;42:50-54.

11. Fernando DJS, Hutchison A, Veves A, Gokal R, Boulton AJM. Risk factors for non-ischemic foot ulceration in diabetic nephropathy. Diabet Med. 1991; 8(3):223-225.

12. Conte SM, Vale PR. Peripheral arterial disease. Heart Lung Circ. 2018;27(4):427-432.

13. Swaminathan A, Vemulapalli S, Patel MR, Jones WS. Lower extremity amputation in peripheral artery disease: improving patient outcomes. Vasc Health Risk Manag. 2014;10:417-424.

14. Garcia LA, Jaff MR, Rocha-Singh KJ, et al. A comparison of clinical outcomes for diabetic and nondiabetic patients following directional atherectomy in the DEFINITIVE LE claudicant cohort. J Endovasc Ther. 2015;22(5):701-711.

15. Goodney PP, Beck AW, Nagle J, Welch HG, Zwolak RM. National trends in lower extremity bypass surgery, endovascular interventions, and major amputations. J Vasc Surg. 2009;50(1):54-60.

16. Jones WS, Patel MR, Dai D, et al. Temporal trends and geographic variation of lower extremity amputation in patients with peripheral artery disease: Results from U.S. Medicare 2000-2008. J Am Coll Cardiol. 2012;60(21):2230-2236.

17. Vemulapalli S, Greiner MA, Jones WS, Patel MR, Hernandez AH, Curtis LH. Arterial testing prior to lower extremity amputation among Medicare beneficiaries, 2002-2010. Circ Cardiovasc Qual Outcomes. 2014;7(1):142-150.

18. Mustapha J, Gray W, Martinsen BJ, et al. One-year results of the LIBERTY 360 study: evaluation of acute and midterm clinical outcomes of peripheral endovascular device interventions. J Endovasc Ther. 2019;26(2):143-154.

19. Jones WS, Patel MR, Dai D, et al. Acute and long-term outcomes following major amputation of the lower extremity in Medicare patients with peripheral artery disease. Am Heart J. 2013;165(5):809-815.

20. LIBERTY 360 two-year data show high freedom from major amputation in PAD
patients. Vascular News. Available at: August 15, 2018. Accessed July 16, 2019.

21.Adams GL, Mustapha J, Gray W, et al. The LIBERTY study: Design of a prospective, observational, multicenter trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease. Am Heart J. 2016;174:14-21.

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