An Algorithm-Based Approach to Optimize Endovascular Outcomes of Complex Infrainguinal Peripheral Arterial Disease

Clinical Review

Submitted on Sun, 05/22/2016 - 21:33

Nicolas W. Shammas, MD, EJD, MS, FACC, FASCI, FICA, FSVM
From the Midwest Cardiovascular Research Foundation and Cardiovascular Medicine, PC, Davenport, Iowa


ABSTRACT: The endovascular treatment of complex infrainguinal peripheral arterial disease continues to be challenging, with reduced rates of procedural success and poor long-term outcomes. Preparing a complex lesion prior to the delivery of an antiproliferative drug appears to improve the acute procedural success with less flow-limiting dissection and bail-out stenting. Also, there are several small randomized and observational studies that indicate that the long-term outcome may be improved after drug-coated balloon use for long and calcified disease that has been pretreated with atherectomy. Furthermore, preclinical data also support better paclitaxel diffusivity and uptake into the vessel wall following atherectomy of calcified disease. This manuscript evaluates current data and proposes an algorithm-based guideline to address the management of various lesion morphologies. This algorithm will continue to be refined based on new randomized and well-powered clinical trials that may refute or solidify these recommendations. With the rapid increase in complex endovascular interventions, vascular specialists must continue to evaluate each therapeutic modality and determine where it fits in the management of patients


Key words: complex peripheral arterial disease, calcium, thrombus, total occlusion, vessel modification, atherectomy, drug coated balloon, algorithm, infrainguinal disease, superficial femoral artery, popliteal artery


The endovascular treatment of peripheral arterial disease is expanding rapidly. The goals of optimizing acute outcome by leaving no or minimal stents behind, protecting the outflow from distal embolization, and effectively reducing neointimal smooth muscle proliferation post intervention1 are now achievable with the advent of atherectomy and specialized balloons, various embolic protection devices, and antiproliferative delivery tools such as drug-coated balloons (DCB) and drug-eluting stents (DES). In this manuscript we review complex disease and propose an algorithm (Figure 1) to tackle these lesions successfully. Many of the applications proposed herein are off label to existing technologies driven by observational or small randomized studies, and therefore the steps proposed should be considered as a guideline rather than mandatory in nature. Level A evidence is clearly and desperately needed in this field to verify and refine the steps of this algorithm. No matter what type of algorithm is proposed, patient welfare remains central to every step suggested. Although cost-effectiveness studies are still lacking for the various technologies dealing with complex disease, minimizing redundancy is important for health care dollars and patient safety. 

The treatment of simple lesions, such as nonocclusive shorter lesions (<10 cm) or less than 5 cm occlusions with no to mild associated calcification, is now relatively straightforward, with most randomized studies showing superiority of DCB when compared to plain old balloon angioplasty (POBA).2-7 Pretreatment of these lesions with POBA first then DCB have yielded excellent outcomes with improved patency and a marked reduction in target lesion revascularization (TLR). A first logical step therefore, in treating these lesions is DCB rather than atherectomy or stenting. Failure of pretreatment with POBA of these lesions prior to DCB resulting in flow-limiting type D and higher dissection (expected to be of low frequency) can now be managed with provisional DES. However, if failure occurs after the application of DCB treatment, then the placement of the shortest bare metal stent possible (“spot stenting”) to seal the dissection is reasonable. Irrespective, the treated lesion should all have been exposed to the antiproliferative drug to minimize long-term failure.

Treating complex disease is more challenging, and as of today there is no unified consensus on how to approach these lesions among operators. More interestingly, it is hard to come up with a clear high-level, evidence-based protocol based on current data. Important signals have emerged from various studies to make the preliminary recommendations illustrated in Figure 1. Although there is no uniformity in defining complex disease, the presence of severe calcification (defined here as bilateral calcium seen on high-resolution angiography at the same lesion level; or more than 180 degrees arc of calcium seen on computed tomography or intravascular ultrasound [IVUS]), long lesions exceeding 15 centimeters, chronic total occlusions exceeding 5 cm, Trans-Atlantic Inter-Society Consensus (TASC) C and D, in-stent restenosis (particularly Tosaka Class III),8 poor distal run-off and presence of significant thrombus burden are generally agreed upon to represent complex disease as they correlate with poorer outcomes and higher adverse events. It should be noted that outcomes are also determined by high-risk clinical predictors such as diabetes mellitus, critical limb ischemia, renal insufficiency, older age, and continued smoking. Complex disease leads to dissection and bail-out stenting, negatively impacts stent expansion, increases rate of distal embolization and complications, and therefore reduces the chance of procedural success and may adversely affect long-term outcomes. This manuscript will not address the problem of distal embolization but will focus on vessel preparation to optimize outcomes.

Calcium is highly prevalent in the peripheral vasculature. In the femoropopliteal artery calcium is likely to be found in atherosclerotic plaques, however, medial calcification (Monckeberg’s arteriosclerosis) can also present particularly in diabetic and renal failure patients.9-11 In contrast, medial calcification is highly prevalent below the knee in about 70% of cases, symptomatic or asymptomatic, with higher prevalence in men. It is usually circumferential in nature with bone formation occurring in 10% to 15% of cases. At present there is no standardized way to quantitate calcium in the peripheral vasculature. The presence of calcium reduces vessel compliance, which in return requires greater balloon pressures for arterial dilation, resulting in high barotrauma to the vessel wall, dissections, perforations, and need for bail-out stenting.12-14 Also, calcium can result in the inability to dilate a lesion, leading to stent underexpansion. In addition, stent fractures are likely to occur in areas of severe calcification, particularly in the Hunter’s canal. Finally, calcium can be a barrier to antiproliferative drug diffusion into the vessel wall, possibly diminishing the effectiveness of DCB and DES.15 

Modifying or debulking calcium is now the target of several therapeutic modalities, and studies are emerging to investigate the impact of calcium on procedural and long-term outcomes following endovascular therapies. Debulking in general has been associated with improving vessel compliance and reducing dissection and bail-out stenting, as demonstrated by the pilot single-center randomized trial of angioplasty vs directional atherectomy followed by adjunctive balloon angioplasty.12 This early observation was then tested in a multicenter randomized trial, the CALCIUM 360° study,13 which applied orbital atherectomy with balloon angioplasty vs balloon angioplasty alone in popliteal and infrapopliteal severely calcified vessels in predominantly critical limb ischemia patients. The study duplicated the same earlier findings despite the presence of severe calcification. In this study, adjunctive balloon angioplasty post orbital atherectomy led to a likely change in vessel compliance as indicated by the reduction in the average maximum balloon pressures required to obtain full balloon inflation post atherectomy (5.9 atm vs 9.4 atm, P<.001), a trend toward higher procedural success (93.1% vs 82.4%), fewer dissections (3.3% vs 11.4%) and bailout stenting (6.9% vs 14.3%), and a higher freedom from revascularization (93.3% vs 80%). Interestingly, a statistically significantly higher freedom from major adverse events in the orbital atherectomy arm (93.3% vs 57.9%, P=.006) was seen. Applying the same concept to moderately and severely calcified superficial femoral artery in the COMPLIANCE 360° trial,14 orbital atherectomy again confirmed the impact of debulking on improving vessel compliance, reducing dissection (15.8% vs 48.1%, P=.02) and bail-out stenting (5.3% vs 77.8%, P<.001) and a trend toward a higher freedom from revascularization (81.2% vs 78.3%). Several prospective registries also demonstrated the low dissection and stenting rate post debulking with various debulking devices, confirming the findings of these proof-of-concept randomized trials (Figure 2).16-18 

In addition to orbital atherectomy, there are several other devices that can modify or remove calcium. The Turbohawk catheter (Covidien) was designed to cut into calcified plaque. In the DEFINITIVE Ca study, the pivotal registry that led to the approval of the Spider Filter in calcified superficial femoral arteries when used with the TurboHawk, dissection rate was low at 0.8% (type D and higher) and stenting was only 4.1%.17 In addition, the Jetstream atherectomy device (Boston Scientific) has also been shown to be very effective in debulking calcium and fibrotic tissue. In a small, prospective, IVUS-based analysis that included moderately to severely calcified femoropopliteal arteries, Jetstream increased minimal luminal area (MLA) from 5.1 to 8.3 mm2 and reduced area stenosis from 64% to 41%, and the decrease in calcium area (2.8 mm2) at the lesion level accounted for 86% increase in the lumen area.19 In the prospective, single arm, Pathway PVD multicenter trial, 172 patients at 9 European centers were treated with the Jetstream device (early generation).16 Device success was 99% (208/210 lesions). Eighty-five percent of patients were TLR free at 6 months and 74% were TLR free at 12 months. Stenting was performed in 7% of lesions. Given the data from several small randomized trials and registries, the evidence points to atherectomy as an effective tool to modify or remove calcium, hence improving vessel compliance and reducing dissections, resulting in an overall higher procedural success without the need for bail-out stenting. Although the data suggest a trend toward improving TLR rates with debulking, this has not yet been proven in a well-powered study, and the advent of DCB is likely to make this relatively small possible gain irrelevant. 

Removing or modifying calcium may also lead to enhancing DCB effectiveness by allowing more drug diffusivity into the vessel wall, meaning higher concentration and deeper penetration. Data from Fanelli et al have shown that a 270° arc of calcium when compared to mild calcium (less than 90° arc) is associated with poor patency rate and reduced TLR at 1 year in 60 patients with superficial femoral artery occlusion or stenosis treated with DCB.20 Also, recent data from Tepe et al showed that bilateral calcification on angiographic imaging is associated with a higher late lumen loss post DCB in 91 patients with superficial femoral or popliteal artery disease.21 In this study, the depth of calcium (intimal, medial, or adventitial) and the length of calcium had no impact on late lumen loss. Bilateral calcification on angiography seen at the same lesion level is essentially the equivalent of over 180° arc of calcium. These data are consistent with Fanelli’s data and indicate that higher degrees of calcium (typically more than 180° arc) need to be the main target for treatment or modification for clinical benefit to be seen. Therefore, a simplified classification of calcium severity in the periphery can be proposed in the era of DCB, which could be as simple as severe (more than 180° calcium seen on any imaging modality) vs mild to moderate (less than 180°), irrespective of length or depth. Testing this hypothesis in a prospective large study will be of great interest. 

In a preclinical model of five fresh human lower limbs confirmed by computed tomography to have severe calcification and included both femoropopliteal and tibial vessels, the distal segments were treated with orbital atherectomy, then the arteries explanted and infused with radiolabeled or fluorescent paclitaxel and incubated 1h at 37°C.15 In the orbital atherectomy treated segment, paclitaxel uptake increased by 20% in the femoropopliteal segment and by 400% in tibial arteries, with an average increase of drug deposit above 50%. Furthermore, fluorescent microscopy revealed a more diffuse and extended paclitaxel in the atherectomy-treated segments. Enhanced drug uptake may explain why, in the DEFINITIVE AR feasibility study, there was a trend toward higher patency in long (>10 cm) and severely calcified disease in the directional atherectomy and DCB arm when compared to DCB alone.22 Another small observational study (n=30) examined severely calcified lesions in patients with advanced peripheral arterial disease (mean Rutherford-Becker category of 4.2) that underwent IVUS-guided directional atherectomy followed by DCB under embolic protection. In this study, bail-out stenting was needed only in 6.5% of patients, and at 1-year follow-up, limb salvage and TLR rates were 100% and 10%, respectively.23 These data signal the importance of calcium modification in optimizing antiproliferative drug uptake to enhance the effectiveness of DCB. Larger randomized trials are needed to validate this concept.  

Thrombus is another barrier to drug diffusion. The presence of thrombus in peripheral arterial disease is quite often underdiagnosed by angiography. Depending on its composition, thrombus can significantly affect drug diffusion into the vessel wall and therefore lead to a heterogeneous and unpredictable milieu for DCB and DES.24 Red blood cells (RBC) have a high affinity to paclitaxel. The higher the concentration of RBC in a thrombus, the less drug would be available to enter the vessel wall. Removal of thrombus is therefore a logical step before deploying DCB or DES, and atherectomy devices such as laser and Jetstream have been shown to remove thrombus effectively. Therefore the choice of these devices is relevant in thrombotic lesions and adds another argument to why vessel prepping prior to DCB may be necessary. 

Femoropopliteal in-stent restenosis (FP ISR) is another challenging problem to treat. It occurs in 20% to 30% of stented patients at 1 year and up to 49% at 2 years.25-30 Treatment of FP ISR with balloon angioplasty carries a high rate of TLR at 1 year (37% to 47%; bail-out stent included as TLR) and reduced patency rates (28% to 37%).31-33 New therapies, including laser atherectomy,32 Viabahn (W. L. Gore) graft stenting,33 and DCB34 have shown superiority over balloon angioplasty in treating FP ISR. It is unclear whether aggressive debulking leads to better outcomes than less debulking. However, there are some data to suggest that the Turbo-Tandem laser (Spectranetics) has better TLR rates at 6 months and 1 year than the Turbo-Elite (Spectranetics) despite similar treated lesion length, suggesting that aggressive debulking can improve TLR.32,25-37 Also, the off-label use of the Jetstream device in ISR shows promising results with low TLR rate at 6 months comparable to the Turbo-Tandem laser.38 The Jetstream has been shown to be effective in debulking neointimal hyperplasia of smooth muscle cell very effectively in preclinical39 and clinical models of FP ISR40 and showed no device-stent interaction as evaluated by core laboratory analysis.39 Jetstream currently has a CE marking (European Conformity) approval in Europe (i.e. “complies with the essential requirements of the relevant European health, safety and environmental protection legislation”) but is off label in the United States. Although Silverhawk (Covidien) is also effective in neointimal tissue ablation, it is contraindicated in the United States in treating FP ISR because of potential interaction between the cutter and stents. It is unclear at this time whether atherectomy has a significant added value to DCB in treating FP ISR. However, based on current randomized trials, atherectomy does at least improve the acute procedural success in complex lesions as was seen in the EXCITE ISR trial.32 Balloon angioplasty in these complex lesions carries a higher rate of procedural failure with more residual narrowing and a higher need for restenting. Therefore the application of atherectomy in long complex FP ISR disease may improve the acute procedural success obtained with DCB and could improve tissue drug penetration. Whether this may contribute to improving long-term outcomes will need to be proven in a well-powered randomized trial. Early observational studies with DCB41 or combining atherectomy with DCB42 in ISR has shown promising results compared to historic control, and these data are encouraging. 

Current guidelines have recommended a surgical approach to TASC D disease.43 However, these lesions are quite often treated with endovascular techniques, which have significantly improved with the advent of crossing devices, debulking, and DCB. Currently no trials exist to compare surgery to current endovascular treatment of TASC D lesions. The success of an endovascular approach, however, may well rely on ensuring good vessel preparation to minimize the risk of acute procedural failure, dissection, and stenting. Coupling this with DCB, long-term outcomes could improve to make this approach a cost-effective one. Currently, TASC D lesions have been included in most DCB trials, but no one study has been designed and powered specifically for these lesions. 

We conclude that vessel modification is an essential tool at present to improve the acute procedural success of complex disease, minimize dissections, and reduce the need for stenting, including DES. Its utility in simple, non-occlusive or non-calcified disease may still be valuable, however, considering that even in these simple lesions, dissections and stenting remain a problem, albeit at a lower frequency. The added cost, however, may be problematic and harder to justify in noncomplex disease. 

Given the above, an algorithm-based approach is proposed as a guideline (Figure 1) where simpler disease is treated initially with DCB and vessel preparation is considered in more complex disease. Drug eluting stenting remains an important tool for subintimal disease and bailout situation. Also, it may be considered as a first line treatment in proximal and mid superficial femoral artery disease where forces on this segment of the artery are not as pronounced. Finally, and although the focus of this manuscript is on procedural outcomes, it should be noted that the treatment of the peripheral arterial disease patient is more complex and requires an individualized approach to treatment. n

Editor’s note: Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Shammas reports training for and consultancy to Boston Scientific, speakers’ bureau membership with Boston Scientific; training for Covidien; educational grants from Boston Scientific, Medtronic and CSI; and research grants from Boston Scientific. 

Manuscript received January 30, 2016; provisional acceptance given March 28, 2016; manuscript accepted April 11, 2016.

Address for correspondence: Nicolas W. Shammas, MD, MS, FACC, FASCI, Research Director, Midwest Cardiovascular Research Foundation, 1622 E. Lombard Street, Davenport, Iowa 52722. 


  1. Shammas NW. An overview of optimal endovascular strategy in treating the femoropopliteal artery: mechanical, biological, and procedural factors. Int J Angiol. 2013;22(1):1-8.
  2. Scheller B, Speck U, Abramjuk C, Bernhardt U, Bohm M, Nickenig G. Paclitaxel balloon coating, a novel method for prevention and therapy of restenosis. Circulation. 2004;110(7):810-814.
  3. Scheinert D, Duda S, Zeller T, 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. 2014;7(1):10-19. 
  4. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358(7):689-699.
  5. Werk M, Albrecht T, Meyer DR, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv. 2012;5(6):831-840.
  6. Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation. 2008;13(13):1358-1365.
  7. Liistro F, Grotti S, Porto I, et al. Drug-eluting balloon in peripheral intervention for the superficial femoral artery: the DEBATE-SFA randomized trial (drug eluting balloon in peripheral intervention for the superficial femoral artery). JACC Cardiovasc Interv. 2013;6(12):1295-1302.
  8. Tosaka A, Soga Y, Iida O, et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol. 2012;59(1):16-23. 
  9. Bishop PD, Feiten LE, Ouriel K, et al. Arterial calcification increases in distal arteries in patients with peripheral arterial disease. Ann Vasc Surg. 2008;22(6):799-805.
  10. Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Catheter Cardiovasc Interv. 2014;83(6):E212-E220.
  11. Kashyap VS, Pavkov ML, Bishop PD, et al. Angiography underestimates peripheral atherosclerosis: lumenography revisited. J Endovasc Ther. 2008;15(1):117-125. 
  12. Shammas NW, Coiner D, Shammas GA, Dippel EJ, Christensen L, Jerin M. Percutaneous lower-extremity arterial interventions with primary balloon angioplasty versus Silverhawk atherectomy and adjunctive balloon angioplasty: randomized trial. J Vasc Interv Radiol. 2011;22(9):1223-1228. 
  13. Shammas NW, Lam R, Mustapha J, et al. Comparison of orbital atherectomy plus balloon angioplasty vs. balloon angioplasty alone in patients with critical limb ischemia: results of the CALCIUM 360 randomized pilot trial. J Endovasc Ther. 2012;19(4):480-488. 
  14. Dattilo R, Himmelstein SI, Cuff RF. The COMPLIANCE 360° Trial: a randomized, prospective, multicenter, pilot study comparing acute and long-term results of orbital atherectomy to balloon angioplasty for calcified femoropopliteal disease. J Invasive Cardiol. 2014;26(8):355-360.
  15. Tzafriri AR, Nikanorov A, Zani B, et al. TCT-794. Lesion preparation with an orbital atherectomy system enhances paclitaxeldeposition in calcified peripheral arteries. J Am Coll Cardiol. 2015; 66(15 Suppl B):B323.
  16. Zeller T, Krankenberg H, Steinkamp H, et al. One-year outcome of percutaneous rotational atherectomy with aspiration in infrainguinal peripheral arterial occlusive disease: the multicenter pathway PVD trial. J Endovasc Ther. 2009;16(6):653-662. 
  17. Roberts D, Niazi K, Miller W, et al; DEFINITIVE Ca+ Investigators. Effective endovascular treatment of calcified femoropopliteal disease with directional atherectomy and distal embolic protection: final results of the DEFINITIVE Ca+ trial. Catheter Cardiovasc Interv. 2014;84(2):236-244. 
  18. McKinsey JF, Zeller T, Rocha-Singh KJ, Jaff MR, Garcia L; DEFINITIVE LE Investigators. Lower extremity revascularization using directional atherectomy: 12-month prospective results of the DEFINITIVE LE study. JACC Cardiovasc Interv. 2014;7(8):923-933. 
  19. Maehara A, Mintz GS, Shimshak TM, et al. Intravascular ultrasound evaluation of JETSTREAM atherectomy removal of superficial calcium in peripheral arteries. EuroIntervention. 2015;11(1):96-103.
  20. Fanelli F, Cannavale A, Gazzetti M, et al. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. Cardiovasc Intervent Radiol. 2014;37(4):898-907.
  21. Tepe G, Beschorner U, Ruether, et al. Drug-eluting balloon therapy for femoropopliteal occlusive disease: predictors of outcome with a special emphasis on calcium. J Endovasc Ther. 2015;22(5):727-733.
  22. Zeller T et al. DEFINITIVE AR. Presented at VIVA 2014, Las Vegas, NV.
  23. Cioppa A, Stabile E, Popusoi G, et al. Combined treatment of heavy calcified femoro-popliteal lesions using directional atherectomy and a paclitaxel coated balloon: One-year single centre clinical results. Cardiovasc Revasc Med. 2012;13(4):219-223.
  24. Hwang CW, Levin AD, Jonas M, Li PH, Edelman ER. Thrombosis modulates arterial drug distribution for drug-eluting stents. Circulation. 2005;111(13):1619-1626.
  25. Schillinger M, Sabeti S, Loewe C, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med. 2006;354(18):1879-1888.
  26. Laird JR, Katzen BT, Scheinert D, 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. 2010;3(3):267-276.
  27. Schillinger M, Sabeti S, Dick P. Sustained benefit at 2 years of primary femoropopliteal stenting compared with balloon angioplasty with optional stenting. Circulation. 2007;115(21):2745-2749.
  28. Laird JR, Katzen BT, Scheinert D, et al; RESILIENT Investigators. Nitinol stent implantation vs. balloon angioplasty for lesions in the superficial femoral and proximal popliteal arteries of patients with claudication: three-year follow-up from the RESILIENT randomized trial. J Endovasc Ther. 2012;19(1):1-9.
  29. Iida O, Nanto S, Uematsu M, Ikeoka K, Okamoto S, Nagata S. Influence of stent fracture on the long-term patency in the femoro-popliteal artery: experience of 4 years. JACC Cardiovasc Interv. 2009;2(7):665-671.
  30. Laird JR. Limitations of percutaneous transluminal angioplasty and stenting for the treatment of disease of the superficial femoral and popliteal arteries. J Endovasc Ther. 2006;13 Suppl 2:II30-II40.
  31. Dick P, Sabeti S, Mlekusch W, et al. Conventional balloon angioplasty versus peripheral cutting balloon angioplasty for treatment of femoropopliteal artery in-stent restenosis: initial experience. Radiology. 2008;248(1):297-302.
  32. Dippel EJ, Makam P, Kovach R, et al; EXCITE ISR Investigators. Randomized controlled study of excimer laser atherectomy for treatment of femoropopliteal in-stent restenosis: initial results from the EXCITE ISR trial (EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis). JACC Cardiovasc Interv. 2015;8(1 Pt A):92-101.
  33. Bosiers M, Deloose K, Callaert J, et al. Superiority of stent-grafts for in-stent restenosis in the superficial femoral artery: twelve-month results from a multicenter randomized trial. J Endovasc Ther. 2015;22(1):1-10.
  34. Krankenberg H, Tübler T, Ingwersen M, et al. Drug-coated balloon versus standard balloon for superficial femoral artery in-stent restenosis: the randomized Femoral Artery In-Stent Restenosis (FAIR) Trial. Circulation. 2015;132(23):2230-2236. 
  35. Shammas NW, Shammas GA, Hafez A, Kelly R, Reynolds E, Shammas AN. Safety and one-year revascularization outcome of excimer laser ablation therapy in treating in-stent restenosis of femoropopliteal arteries: A retrospective review from a single center. Cardiovasc Revasc Med. 2012;13(6):341-344.
  36. Shammas NW. Commentary: excimer laser in treating femoropopliteal in-stent restenosis: can early success be maintained over long-term follow-up? J Endovasc Ther. 2015;22(4):514-517.
  37. Armstrong EJ, Thiruvoipati T, Tanganyika K, Singh GD, Laird JR. Laser Atherectomy for Treatment of Femoropopliteal In-Stent Restenosis. J Endovasc Ther. 2015;22(4):506-513. 
  38. Shammas NW, Shammas GA, Park H, Banerjee S, Mohammad A, Jerin M. Safety and in-Hospital Outcomes of JetStream Atherectomy in Treating In-Stent Restenosis of Femoropopliteal Arteries. J Endovasc Ther. 2016;23(2):339-346. 
  39. Shammas NW, Aasen N, Bailey L, Budrewicz J, Farago T, Jarvis G. Two blades-up runs using the Jetstream Navitus atherectomy device achieve optimal tissue debulking of nonocclusive in-stent restenosis: observations from a porcine stent/balloon injury model. J Endovasc Ther. 2015;22(4):518-524.
  40. Shammas NW, Shammas GA, Aasen N, Jarvis G. Number of blades-up runs using JetStream XC atherectomy for optimal tissue debulking in patients with femoropopliteal artery in-stent restenosis. J Vasc Interv Radiol. 2015;26(12):1847-1851.
  41. Liistro F, Angioli P, Porto I, et al. Paclitaxel-eluting balloon vs. standard angioplasty to reduce recurrent restenosis in diabetic patients with in-stent restenosis of the superficial femoral and proximal popliteal arteries: the DEBATE-ISR study. J Endovasc Ther. 2014;21(1):1-8.
  42. van den Berg JC, Pedrotti M, Canevascini R, Chimchila Chevili S, Giovannacci L, Rosso R. In-stent restenosis: mid-term results of debulking using excimer laser and drug-eluting balloons: sustained benefit? J Invasive Cardiol. 2014;26(7):333-337.
  43. Norgren L, Hiatt WR, Dormandy JA, et al; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg. 2007;33 Suppl 1:S1-S75.