What is the Future Potential of Percutaneous Deep Vein Arterialization for No-Option Chronic Critical Limb-Threatening Ischemia?

The most advanced stage of peripheral arterial disease is chronic limb-threatening ischemia (CLTI).^1-4 CLTI is associated with a higher risk of lower limb amputation.^1-4 Current treatment options include open surgical reconstruction or endovascular interventions.¹

A Brief History of Deep Vein Arterialization

Deep vein arterialization (DVA) has existed for over 100 years, with the earliest records in humans tracing back to 1902.^6,7 One accomplishes DVA by creating an arterial-to-venous bypass, which reverses blood flow within the vein with subsequent arterialization and new distal limb perfusion.⁶ There are three categories of DVA procedures: Surgical, hybrid, and percutaneous.⁶

Surgical deep vein arterialization involves open surgery, creating a proximal anastomosis of the great saphenous vein with the popliteal or superficial femoral artery. Complications include postoperative venous thrombosis, bleeding, leg swelling, and wound infections at the incision site.⁶ The limb salvage rate at one year is 57 to 79%, with a low 30-day mortality rate (0 to 10%).^6,8 Poor long-term outcomes, however, made this procedure unpopular.⁶ In the early 2000s, adding valvulotomes to the procedure to help reverse distal venous flow improved the patency rate and limb salvage outcomes.^6,8,9

The first recording of hybrid deep vein arterialization was in 2011 and combines open bypass surgery with subsequent endovascular valvulectomy of the distal vein.^6,10 Using open surgery, one anastomoses the popliteal or common femoral artery to the posterior tibial vein or medial marginal vein using either graft from the great saphenous vein or one made from polytetrafluoroethylene. Valvulectomy then takes place via an endovascular technique of the distal anastomosed vein immediately or in the weeks following the original procedure.

One also embolizes the proximal foot venous collaterals to improve caudal blood flow. Hybrid DVA has a limb salvage rate of 68 to 73% at one year.^6,10,11

Recently, percutaneous deep vein arterialization has gained popularity.⁶ Kum and colleagues reported the first pilot study for percutaneous DVA (using the LimFlow device) in 2017.^6,12 This technique involves using an ultrasound detection device to assist the endovascular arterial-venous puncture. The original study has a one-year limb salvage rate of 71%.^6,12

A Closer Look at a Percutaneous DVA Technique

The LimFlow system utilizes arterial and venous catheters, an antegrade over-the-wire valvulotome, and self-expanding stent grafts. The design of grafts divert blood flow from the donor tibial artery into the recipient tibial and pedal venous system.¹³ It is important to note, however, that at this time, the LimFlow technology is only approved for investigational use in the United States.

The procedure starts with ultrasound venous mapping and/or venography to confirm adequate pedal venous anatomy. Once confirmed, one achieves ultrasound-guided venous catheter access through the plantar foot. The venous catheter then advances proximally through the venous system to the level of the intended crossover point. Next, an ipsilateral antegrade common femoral artery access is obtained, before advancing an arterial crossing through the artery to the crossover point. Using the ultrasound system, one confirms the longitudinal and radial orientation of the artery and vein. The snaring mesh of the venous catheter deploys within the vein, and the crossing needle from the arterial catheter deploys through the artery wall into the target vein/snaring mesh. One then advances a guidewire from the artery into the vein. A small angioplasty balloon allows the passage of more devices by dilating the crossover point.¹³

The valvulotome then advances through the artery into the vein. Activation of the valvulotome renders all of the venous valves incompetent from the crossing point distally to the midfoot level. The forward pressure will engage and lyse the valve cups. This will allow reversal of blood flow within the vein, allowing oxygenated blood into the foot. Self-expanding polytetrafluoroethylene (PTFE)-covered stent grafts then deploy from the level of the calcaneus to the crossover point within the vein. To bridge the vein to the artery, one places a tapered covered stent across the crossover point. Balloon angioplasty of the new stent graft then confirms nominal diameter and lack of restrictive lesions. The procedure is complete after arteriography confirms the adequacy of blood flow into the stent graft conduit and through the pedal venous loop from the donor artery.¹³

What Can We Learn From Early Trial Results?

LimFlow’s feasibility, safety, and effectiveness underwent testing with a prospective, multicenter, single-arm, early feasibility study for treating no-option CLTI (conducted under investigational device exemption from the United States Food and Drug Administration) between July 2017 and April 2019. The authors defined “no-option” as being ineligible for surgical or endovascular arterial revascularization.¹³ They followed 32 patients for 12 months. At 30 days, 6 months, and 12 months, patient assessments took place for clinical status, pain, wound healing, and they performed a duplex ultrasound. Amputation-free survival (AFS) was the primary endpoint analysis, which they defined as freedom from above-the-ankle amputation and all-cause mortality. Secondary endpoints included wound healing at 6 and 12 months, as well as the technical success of the procedure.¹³

The investigators saw technical success in 31 cases (96%) at the time of procedure. Procedural success was 24/32 (75%) with 1 failed procedure, 4 re-interventions, 3 amputations, and 0 deaths. AFS rates were 91%, 74%, and 70% at 30 days, 6 months, and 12 months, respectively. For the 21 patients who met the study endpoint at 6 months, 67% exhibited wound healing. Additionally, for the 20 patients who remained alive and amputation-free at 12 months, 75% had the wound healing status of “fully healed” or “healing.”¹³

Within the group of patients with limb salvage, 15 patients underwent 19 minor amputations (7 toe amputations, 2 ray amputations, and 10 transmetatarsal amputations). In addition, 52% of the patients underwent reintervention, with 75% involving the arterial inflow tract proximal to the LimFlow circuit, with no in-stent stenosis noted. Limitations of the study include the small size, 12-month follow-up duration, and lack of a control group.¹³

There is currently a second trial underway, PROMISE II, a multicenter, prospective, single-arm study being conducted at multiple sites in the US. Using an adaptive statistical design, the study has enrolled 105 no-option CLTI patients. Endpoints of the study include amputation-free survival at six months, limb salvage, and wound healing. The patients will be followed for three years.¹⁴

Other Emerging Endovascular DVA Techniques

Surgeons in Taiwan recently crafted an endovascular DVA technique similar to that described above.⁶ However, there are two main differences. The Taiwanese surgeons utilize the Outback (Cordis) reentry device for the arterial-venous puncture. This is advantageous, per their report, as it is a more popular and more familiar device for most interventionists. They also use a Viabahn (Gore Medical) heparin bonding graft stent, replacing the valvulotome.⁶ In their study, oral anticoagulation and antiplatelet therapy were given for six months. One year after the procedure, peripheral sonography showed continued posterior tibial vein arterialization with a patent Viabahn stent-graft. More studies for this technique are necessary to fully assess the benefits and risks.

What Does the Cost Analysis Data Reveal?

A recent exploratory cost-effectiveness analysis of percutaneous deep vein arterialization (pDVA) suggests that the incremental costs are justified for no-option CLTI patients. This is due to emerging consensus that avoiding major amputation should always be the treatment goal in patients with CLTI due to its associated high costs, loss of functional status, lowered quality of life, and high mortality. The analysis suggests that utilizing pDVA may provide significant clinical and health-economic value. They note that the analysis should be updated and further refined as more clinical data becomes available.¹

Concluding Thoughts

One must keep in mind that the LimFlow technology is approved for investigational use only in the United States. The LimFlow System received the CE Mark and is currently available commercially in Europe. The LimFlow System has not been approved for sale in the US, Canada, or Japan at this time.

After seeing the results firsthand earlier this year with one of my own no-option CLTI patients, I feel as though this technique has tremendous potential to help heal lower extremity wounds and prevent amputations. 

Dr. Swain is a board-certified wound specialist physician (CWSP) of the American Board of Wound Management, and a Diplomate of the American Board of Podiatric Medicine. He is the Medical Director of the St. Vincent’s Wound Care and Hyperbaric Center at St. Vincent’s Southside Hospital in Jacksonville, FL, on faculty at the HCA/Mercer University School of Medicine/Orange Park Medical Center Program Cardiology Fellowship, and is in private practice at the First Coast Cardiovascular Institute in Jacksonville, FL.

References
1.    Pietszch JB, Ederhof M, Geisler BP, Schneider PA. Cost-effectiveness of percutaneous deep vein arterialization for patients with no-option chronic limb-threatening ischemia: an exploratory analysis based on the PROMISE I study. J Crit Limb Ischem, 2021;1:E148-E157.
2.    Bosma J, Vahl A, Wisselink W. Systematic review on health-related quality of life after revascularization and primary amputation in patients with critical limb ischemia. Ann Vasc Surg. 2013;27(8):1105-1114.
3.    Dua A, Lee CJ. Epidemiology of peripheral arterial disease and critical limb ischemia. Tech Vasc Interv Radiol. 2016;19(2):91-95.
4.    Duff S, Mafilios MS, Bhounsule P, Hasegawa JT. The burden of critical limb ischemia: a review of recent literature. Vasc Health Risk Manag. 2019;15:187-208.
5.    Lindeman JHN, Zwaginga JJ, Kallenberg-Lantrua G, et al. No clinical benefit of intramuscular delivery of bone marrow-derived mononuclear cells in nonreconstructable peripheral arterial disease: results of a phase-III randomized-controlled trial. Ann Surg. 2018;268(5):756-761.
6.    Chang HW, Hsu CH, Jhang YC, Wang CC, Chang CT, Chen HC. Percutaneous deep vein arterialization for a chronic limb-threatening ischemia patient in Taiwan. Acta Cardiol Sin. 2021 Jul;37(4):434-437.
7.    Pozzi G. Arteriovenous anastomosis in the treatment of gangrene of the extremities caused by arterial obliteration. Ann Ital Chir. 1954;31(8):640–664.
8.    Schreve MA, Vos CG, Vahl AC, et al. Venous arterialisation for salvage of critically ischaemic limbs: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2017;53(3):387–402.
9.    Engelke C, Morgan RA, Quarmby JW, et al. Distal venous arterialization for lower limb salvage: angiographic appearances and interventional procedures. Radiographics. 2001;21(5):1239–1248; discussion 1248-1250.
10.    Alexandrescu V, Ngongang C, Vincent G, et al. Deep calf veins arterialization for inferior limb preservation in diabetic patients with extended ischaemic wounds, unfit for direct arterial reconstruction: preliminary results according to an angiosome model of perfusion. Cardiovasc Revasc Med. 2011;12(1):10–19.
11.    Ferraresi R, Casini A, Losurdo F, et al. Hybrid foot vein arterialization in no-option patients with critical limb ischemia: a preliminary report. J Endovasc Ther. 2019;26(1):7–17.
12.    Kum S, Tan YK, Schreve MA, et al. Midterm outcomes from a pilot study of percutaneous deep vein arterialization for the treatment of no-option critical limb ischemia. J Endovasc Ther. 2017;24(5):619–626.
13.    Clair DG, Mustapha JA, Shishehbor MH, Schneider PA, Henao S, Bernardo NN, Deaton DH. PROMISE I: Early feasibility study of the LimFlow System for percutaneous deep vein arterialization in no-option chronic limb-threatening ischemia: 12-month results. J Vasc Surg. 2021 Nov;74(5):1626-1635.
14.    LimFlow Completes Enrollment in PROMISE II U.S. Pivotal Trial of Breakthrough Device Designed to Prevent Amputations in No-Option Patients with Chronic Limb-Threatening Ischemia. Published 3/15/2022. Accessed 7/3/2022. https://limflow.com/us-pivotal-study-and-clariti-complete-enrollment/