Drug-Eluting Technologies Below the Knee: From Current Data to Future Research

Cutting-Edge Perspectives is headed by Nicolas W Shammas, MD, Midwest Cardiovascular Research Foundation, Davenport, Iowa. Here, Dr Shammas interviews Fadi A Saab, MD, FACC, FSCAI, FASE, Associate Professor of Medicine – Michigan State College of Human Medicine, East Lansing, Michigan; Advanced Cardiac and Vascular Centers for Amputation Prevention, Grand Rapids, Michigan.

Critical limb ischemia (CLI) is an advanced form of peripheral arterial disease that has profound implications on both patients and the economy. CLI is associated with high cardiovascular mortality, amputation, disability, and impairment of the quality of life of patients. It costs our health care system billions of dollars in direct and indirect costs. Treatment of CLI patients involves strong preventative cardiovascular measures, but without revascularization of the affected limb, the amputation rate remains very high. An in-line inflow to the affected limb and foot is necessary in most patients to accelerate the healing process. Quite often, these patients have severely diseased outflow and inflow. However, in almost one-third of CLI patients, infrapopliteal arterial disease remains the main culprit. The treatment of infrapopliteal disease is challenging and involves small vessels, total occlusions, long lesions, severe calcifications, and, quite often, no clear reconstitution of the vessels at the foot level. Treatment can be tedious and time consuming, and requires dedicated CLI experts to tackle the complex disease process. We are excited to have Fadi Saab, MD, as our guest in this issue of VDM to discuss the complexity of CLI, as well as current and future treatment approaches. Dr Saab has been on the forefront of fighting this lethal disease and has dedicated his time to treating CLI. He is known for educating providers on the implications of CLI, and the endovascular techniques and tools necessary to tackle it, and he has been involved in extensive research in the field. I strongly believe you will find his insights to be extremely valuable and helpful in the fight against CLI. 

Dr Shammas: Tell us about the epidemiology and implications of CLI, and the prevalence of infrapopliteal arterial interventions.

Dr Saab: Peripheral artery disease (PAD) is a worldwide epidemic that impacts 1 in 10 patients over the age of 70 years. CLI represents the most advanced stage of PAD. Patients with CLI have a significant risk of amputation due to disruption of the distal circulation and its ability to provide oxygenated arterial blood flow to the lower extremities and plantar circulation. Patients with PAD and CLI tend to experience significant comorbidities, including cerebrovascular disease, coronary artery disease, diabetes, chronic renal failure, hypertension, dyslipidemia, and tobacco abuse. These comorbidities not only worsen the prognosis of these patients, but may also limit the ability of the patient to undergo surgical revascularization. The Peripheral Registry of Endovascular Outcomes (PRIME registry) is the first CLI registry in the United States and has helped us understand contemporary CLI disease patterns.¹ We have learned that CLI patients tend to have isolated tibial disease in 30% of cases. Multilevel disease tends to be present in up to 40% of cases. For that reason, addressing tibial plantar disease is an important part of treating any CLI patient with Rutherford class IV-VI.

Dr Shammas: How do infrapopliteal arterial interventions differ from femoropopliteal interventions?

Dr Saab:  This is an important question that highlights the significant limitations in treating tibial disease. Tibial vessels are obviously smaller in diameter in comparison to femoropopliteal segments. I believe that this point is responsible for worse outcomes, as physicians tend to undertreat tibial vessels with smaller diameter balloons. The current modality of evaluating tibial vessels depends heavily on the use of digital subtraction angiography (DSA). Other imaging modalities have significant limitations. Computed tomography (CT) angiography is a poor imaging modality in calcified tibial vessels. Duplex ultrasonography is operator dependent and reader dependent. Currently, we do not have established criteria for velocities to address high-grade stenosis. This lack of criteria will in turn lead to undertreating the disease, ultimately causing worse outcomes. Another differentiating factor between intrapopliteal and femoropopliteal interventions is the patterns of chronic total occlusions (CTO) that affect tibial vessels. The simplest forms of these patterns preserve the take-off of these vessels with adequate reconstitution above the ankle. The most extreme forms tend to have flush occlusions of the take-off with no adequate tibial reconstitution and severe plantar disease. Each of these patterns requires a different approach to crossing and treating. 

Dr Shammas: There is a problem of patency loss in infrapopliteal arterial interventions. What are potential mechanisms?

Dr Saab: One of the main reasons limiting patency is the nature of atherosclerotic disease and how it affects tibial vessels. In a pathology analysis performed by our group, we found that medial calcification tends to impact tibial vessels in a diffuse fashion.² This phenomenon, added to negative remodeling, makes our treatment modalities for tibial disease suboptimal. Unfortunately, balloon angioplasty remains a widely accepted treatment for tibial lesions. We have current evidence that suggests possible harm in comparison to other treatment modalities like drug-eluting stents (DES) and atherectomy.³ Another important issue is undersizing balloons when treating tibial vessels. In men, the distal tibial vessels have to be treated with 3.5 mm balloons and proximally with 4.0 mm diameter balloons. In women, the tibial vessels range between 3.0-3.5 mm. Upon review of many of the tibial drug-coated balloon (DCB) trials, the average diameter was between 2.1-2.4 mm. This is a far cry from what we currently practice. In a recent analysis performed by Pliagas et al⁴, a comparison between intravascular ultrasound and DSA showed that physicians tend to underestimate the diameter of tibial vessels by an average of 1.1 mm. 

Dr Shammas: Is there a role for drug-coated balloons (DCB) or drug-eluting stents (DES) in infrapopliteal interventions?

Dr Saab: The data for DCB below the knee have been disappointing. The reasons are discussed above and ultimately, undersizing is a main modality of failure. DES have shown promise. While the results are encouraging, the type of lesions included are very short in comparison to what we deal with in our daily practice. The average lesion length in DES trials ranges from 4-6 cm, with patency dropping significantly in those lesions exceeding 10 cm. In addition, the distal tibial vessels remain a significant challenge. In a recent publication, the use of Lutonix DCB balloons (BD) below the knee in comparison to balloon angioplasty showed very favorable results at 6 months follow-up.⁵ We believe these promising results are related to appropriate tibial vessel sizing. Currently, the SAVAL trial (Saval DES BTK vascular stent system [Boston Scientific] vs PTA in subjects with CLI) is a global, prospective, multicenter, randomized investigation designed to evaluate the safety and effectiveness of an infrapopliteal DES in patients with CLI. The primary objective of the randomized study is to demonstrate superior effectiveness and acceptable safety of infrapopliteal DES treatment versus balloon angioplasty in patients with CLI.

Dr Shammas: What insights do you have about the optimal strategy for atherectomy, atherectomy + DCB, or DES?

Dr Saab: Vessel preparation is an important part of the optimal strategy for revascularization of tibial vessels. While DCB and DES enjoyed a limited success with relatively short lesions, the use of atherectomy in real-world CLI lesions will offer a better outcome. We definitely need more trials to address this question. Currently the OPTIMIZE BTK (Orbital Vessel Preparation to Maximize DCB Efficacy in Calcified Below the Knee Lesions) is trying to tackle this issue. More importantly, registry data will have to be an important part in understanding and tailoring treatment in tibial disease. The average lesion length of chronic total occlusions in the CTOP (Chronic Total Occlusion Crossing Approach based on the Plaque Cap Appearance) trial was greater than 200 mm.⁶ Lesion length remains a major cause for exclusion in randomized trials. A clear advantage was seen when atherectomy was compared to balloon angioplasty. The difference is driven by lower rates of mechanical complications in the atherectomy arm. In addition, the use of plaque modification (ie, atherectomy) within the distal tibial and plantar vessels theoretically offers a better solution than just balloon angioplasty and all of its related mechanical complications.

Dr Shammas: What is in the pipeline for infrapopliteal arterial interventions?

Dr Saab: Distal tibial vessels and the plantar circulation are an important area that definitely commands our attention. One of the exciting new technologies to provide a possible solution for distal tibial disease is the Spur Stent System (Reflow Medical). This is a metal stent with spike-like projections that penetrate the intima into the media and help interrupt the medial calcium layer that acts as a constraining structure in many of these cases. This device provides a temporary scaffold that can deliver medication such as immunosuppressive therapy. The device can be retrieved and removed during the intervention. Plaque modification within the plantar circulation may also offer some advantage, especially in relation to pedal loop reconstruction. Another promising technology would be deep vein arterialization, performed primarily via percutaneous approach.⁷ Early results in patients with end-stage plantar disease showed some encouraging results. These are patients with end-stage plantar disease where the plantar vessels, including the dorsalis pedis, medial plantar, and lateral plantar, become completely obliterated with negative remodeling and destruction of the lumen calcific occlusions. Typically, these patients will have preserved proximal tibial vessels. We access the distal tibial vein and use a re-entry device to cross from the tibial artery into the tibial vein. This approach will ultimately divert the arterial blood flow into the plantar venous circulation.

Disclosure: Dr Saab reports he is a consultant to BD, Boston Scientific, Cardiovascular Systems, Inc., Medtronic, Philips, and Terumo. Dr Saab can be contacted at fsaab@acvcenters.com

Disclosure: Dr Nicolas W Shammas receives educational and research grants from Intact Vascular, Phillips, Boston Scientific, VentureMed Group and BD. Dr Shammas can be contacted at shammas@mchsi.com

REFERENCES

1. Mustapha JA, Saab F, Diaz-Sandoval LJ, Beasley R. The Peripheral RegIstry of Endovascular Clinical OutcoMEs (The PRIME Registry): interim analysis of the first 328 subjects with critical limb ischemia. Vascular Disease Management. 2017;14(3): E55-E66.

2. Mustapha JA, Diaz-Sandoval LJ, Saab F. Infrapopliteal calcification patterns in critical limb ischemia: diagnostic, pathologic and therapeutic implications in the search for the endovascular holy grail. J Cardiovasc Surg (Torino). 2017;58(3):383-401.

3. Mustapha JA, Katzen BT, Neville RF, et al. Propensity score-adjusted comparison of long-term outcomes among revascularization strategies for critical limb ischemia. Circ Cardiovasc Interv. 2019;12(9):e008097.

4. Pliagas G, Saab F, Stavroulakis K, et al. Intravascular ultrasound imaging versus digital subtraction angiography in patients with peripheral vascular disease. J Invasive Cardiol. 2020 Mar;32(3):99-103.

5. Mustapha JA, Brodmann M, Geraghty PJ, et al. Drug-coated vs uncoated percutaneous transluminal angioplasty in infrapopliteal arteries: six-month results of the Lutonix BTK Trial. J Invasive Cardiol. 2019;31(8):205-211.

6. Saab F, Jaff MR, Diaz-Sandoval LJ, Engen GD, et al. Chronic total occlusion crossing approach based on plaque cap morphology: the CTOP classification. J Endovasc Ther. 2018;25(3):284-291. 

7. Mustapha JA, Saab FA, Clair D, Schneider P. Interim results of the PROMISE I trial to investigate the LimFlow system of percutaneous deep vein arterialization for the treatment of critical limb ischemia. J Invasive Cardiol. 2019;31(3):57-63.