20167 
Drug-coated balloon (DCB) angioplasty of femoropopliteal TASC II A and B (Trans Atlantic interSociety Consensus conference) lesions has shown promising mid-term results in randomised controlled trials.1–4 However, depending on lesion complexity, bail-out stent placement is indicated in a significant percentage of interventions and patency failures occur in calcified lesions, in particular.5,6 DCB angioplasty has the same limitations as plain balloon angioplasty, specifically acute recoil including undilatable calcified lesions and severe dissections requiring provisional bare metal stenting.5 Vessel preparation with debulking devices or plaque modulation devices might improve acute and longer-term technical outcomes of DCB angioplasty in native femoropopliteal arteries as suggested in small single-centre studies.7–9 Even less is known with regard to vessel preparation for femoropopliteal instent restenosis, in particular in-stent reocclusions, which have been shown to be at high risk for developing recurrent instent restenosis or reocclusion following plain balloon angioplasty, cutting balloon angioplasty and even DCB angioplasty.10,11
Vessel preparation for native femoropopliteal arteries
After DCB angioplasty, approximately 15% of the paclitaxel transfers from the balloon surface into the vessel wall.12 Intimal intraluminal calcification can increase the loss of antiproliferative drug when advancing the coated balloon into the lesion, in particular if the lesion is not or insufficiently pre-dilated, and can impair drug uptake.13 The role of Mönckeberg medial calcification – a common manifestation in patients with diabetes and end-stage renal insufficiency14 – on the biological efficacy of drug-coated balloons is still unknown. Fanelli et al6 and Tepe et al5 reported a significant drop in primary patency and increase in late lumen loss following DCB angioplasty of femoropopliteal lesions with circumferential calcification independent of lesion length (Figure 1).
Atherectomy mechanically recanalises the vessel without overstretch, removes the perfusion barrier for a following anti-restenotic therapy with a DCB, and reduces the likelihood of bail-out stenting even in calcified lesions and as a result preserves the native vessel. The DEFINITIVE Ca++ (Determination of Safety and Effectiveness of the SilverHawk™ Peripheral Plaque Excision System for Calcium (SilverHawk LS-C) and the SpiderFX™ Embolic Protection Device for the Treatment of Calcified Peripheral Arterial Disease in the Superficial Femoral and/or the Popliteal Arteries) single arm trial demonstrated calcified disease can be treated effectively with directional atherectomy using an embolic protection device.16 Directional atherectomy related lumen gain was 2.2mm, the bail-out stent rate was as low as 4.1%, flow-limiting dissections were found in 1.5% only.
In a prospective, single-centre study including 30 patients suffering from peripheral vascular disease, Rutherford categories 3-6 heavily calcified femoro-popliteal lesions, defined as fluoroscopic calcification on both sides of vessel wall longer than 1cm in length, were treated with directional atherectomy.8 All procedures included distal protection with the SpiderFX™ Filter and IVUS-guided atherectomy with the TurboHawk™ Peripheral Plaque Excision System. Once <30% residual stenosis was achieved confirmed by IVUS and angiography, a DCB was used for post-dilation. A <30% residual stenosis was achieved in all cases without procedure-related adverse events, the bail-out stenting rate was 6.5%. After one year, the duplex-derived primary patency rate was 90% (27/30) and freedom from major adverse events was 87% (26/30). The authors concluded that directional atherectomy and DCB angioplasty may represent a potential alternative strategy for the treatment of femoropopliteal severely calcified lesions. These very promising data and the considered hypothesis have to be confirmed in a multicentre randomised trial.
The investigator initiated DEFINITVE AR (Directional AthErectomy Followed by a PaclItaxel-Coated BallooN to InhibiT RestenosIs and maintain Vessel PatEncy: A Pilot Study of Anti-Restenosis Treatment) trial to assess and estimate the effect of treating a vessel with directional atherectomy followed by DCB angioplasty compared with treatment with DCB alone. The randomised study arm was supplemented by a registry arm treating severely calcified lesions with the combination therapy using the Turbohawk atherectomy catheter in conjunction with a distal protection filter. Overall, 121 patients were enrolled at 10 centres in Europe; 102 patients in the randomised study arm and 19 patients into the calcium registry. Mean lesion length in both study cohorts was approximately 10cm.
The technical success defined as ≤30% residual stenosis following the protocol-defined treatment at the target lesion as determined by the angiographic core laboratory was achieved in 89.6% in the combination therapy cohort as compared with 64.2% in the DCB angioplasty cohort (p=0.004). The stent rate was 0% in the combination therapy cohort and 3.7% in the drug coated balloon cohort, grade C and D dissections were significantly reduced in the combination cohort (2% vs 19%; p=0.009). At one year, there was no significant benefit for vessel preparation prior to DCB angioplasty, the primary outcome of angiographic percent diameter stenosis was 33.6±17.7% for directional atherectomy plus DCB angioplasty vs. 36.4±17.6% for DCB angioplasty only (p=0.48). Clinically-driven target lesion revascularisation was 7.3% for the combination therapy vs 8.0% for DCB angioplasty only. Duplex ultrasound patency was 84.6% for the combination therapy and 81.3% for DCB angioplasty only. The study was not powered to show significant differences between the two methods of revascularisation in one-year follow-up. A larger adequately-powered randomised trial is warranted.
The REALITY trial (The REALITY Study: Directional Atherectomy + Drug-Coated Balloon To Treat Long, Calcified Femoropopliteal Artery Stenoses) will evaluate the performance directional atherectomy plus DCB angioplasty in a larger study cohort. However, the study is limited by its single arm study design.
Stavroulakis et al published a retrospective single centre experience comparing DCB angioplasty versus directional atherectomy with DCB angioplasty for isolated lesions of the popliteal artery.9 Seventy-two patients were treated with either DCB angioplasty alone (n=31) or with the combination therapy (n=41). The technical success rate following DCB angioplasty was 84% vs 93% (p=0.24) after combination therapy. Bailout stenting was more common after DCB angioplasty group (16% vs. 5%; p=0.13). The 12-month primary patency rate was significantly higher in the combination therapy group (82% vs. 65%, p=0.021), while freedom from target lesion revascularisation (TLR) did not differ between the two treatment strategies (94% vs. 82%, p=0.072).
Vessel preparation for femoropopliteal instent restenosis
Very little is known about the value of vessel preparation of instent restenosis prior to DCB angioplasty. It is well known that the main limitation of the treatment of instent restenosis is instent reocclusion according to the Tosaka classification, which defines instent restenosis lesion morphology by angiographic presentation into class I, being focal lesions (stenosis ≤50 mm in length), class II diffuse lesions (stenosis >50 mm in length) and class III total occlusions.17
The EXCITE ISR study (EXCImer Laser Randomised Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis) compared plain balloon angioplasty with laser-assisted balloon angioplasty in instent restenotic lesions with a mean lesion length of 19cm.18 The combination therapy demonstrated superior procedural success (93.5% vs. 82.7%; p=0.01) with significantly fewer procedural complications. The combination therapy resulted in a significant higher six-month freedom from TLR of 73.5% versus 51.8% (p<0.005) and was associated with a 52% reduction in TLR (hazard ratio: 0.48; 95% confidence interval: 0.31–0.74). However, the patency and freedom from TLR was mainly driven by the higher acute treatment success for the laser group. Laser debulking resulted in the highest benefit in TOSAKA class III lesions.
To date, the only published study comparing plain DCB angioplasty with vessel preparation using the excimer laser is a small single centre randomised study including 24 patients with diabetes mellitus and instent reocclusion into each study arm.19 Patients in the laser plus DCB group demonstrated patency rates at six and 12 months of 91.7% and 66.7%, which were significantly higher than in the DCB-only patients (58.3% and 37.5%, respectively). The secondary outcome measure, TLR, was 16.7% at 12 months in the laser plus DCB angioplasty group and 50% in the DCB angioplasty-only group.
Theoretically, devices offering combined thrombectomy and atherectomy capabilities, such as Jetstream (Boston Scientific) and Rotarex (Straub Medical), should be most effective in preparing instent re-occlusions prior to DCB angioplasty due to the unique composition of the occlusive material containing thrombus and neointima.
Conclusions
Vessel preparation prior to DCB angioplasty using atherectomy for the treatment of femoropopliteal artery disease improves biological efficacy of drug release and reduces the provisional stent rate. According to the DEFINITIVE AR study, vessel preparation using directional atherectomy prior to DCB angioplasty seems to be safe.
Lesion calcification and lesion length greater than 10cm were identified as potential predictors for superior outcomes for the combination therapy. A larger scale randomised controlled study, focusing on such complex lesion types, is warranted.
A small single-centre randomised study comparing plain DCB angioplasty with laser debulking prior to DCB angioplasty in in-stent reocclusions resulted in significantly better acute outcomes and one-year primary patency rate but no significant benefit for freedom from target lesion revascularisation. These study results need confirmation by a larger scale multicentre controlled trial.
References
1 Tepe G et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358(7):689–99.
2 Werk M et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118(13):1358–65.
3 Tepe G et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015;131(5):495–502.
4 Rosenfield K et al. Trial of paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med 2015;373:145–53.
5 Tepe G et al. Predictors of outcomes of drug-eluting balloon therapy for femoropopliteal arterial disease with a special emphasis on calcium. J Endovasc Ther 2015;22(5):727–33.
6 Fanelli F et al. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. Cardiovasc Intervent Radiol 2014;37(4):898–907.
7 Sixt S et al. Drug-coated balloon angioplasty after directional atherectomy improves outcome in restenotic femoropopliteal arteries. J Vasc Surg 2013;58(3):682–6.
8 Cioppa A 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 Revascularization Med 2012;13(4):219–23.
9 Stavroulakis K et al. Directional atherectomy with antirestenotic therapy vs drug-coated balloon angioplasty alone for isolated popliteal artery lesions. J Endovasc Ther 2016:1526602816683933.
10 Dick P 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.
11 Grotti S et al. Paclitaxel-eluting balloon vs standard angioplasty to reduce restenosis in diabetic patients with in-stent restenosis of the superficial femoral and proximal popliteal arteries: Three-year results of the DEBATE-ISR Study. J Endovasc Ther 2016;23(1):52–7.
12 Schnorr B et al. Paclitaxel-coated balloons – Survey of preclinical data. Minerva Cardioangiol 2010;58(5):567–82.
13 Schnorr B, Albrecht T. Drug-coated balloons and their place in treating peripheral arterial disease. Expert Rev Med Devices 2013;10(1):105–14.
14 Jude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes – a review. Diabet Med 2010;27(1):4–14.
15 Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: Prevalence, mechanism, detection and clinical implications. Catheter Cardiovasc Interv 2014;83:E212–20.
16 Clair DG, Roberts DK. Treatment of severely calcified femoropopliteal lesions with plaque excision and embolic protection – DEFINITIVE Ca++. J Vasc Interv Radiol 2011:22:1785.e2.
17 Tosaka A et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol 2012;59:16–23.
18 Dippel EJ 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: Cardiovascular Interventions 2015;8:92–101.
19 Gandini R et al. Treatment of chronic SFA in-stent occlusion with combined laser atherectomy and drug-eluting balloon angioplasty in patients with critical limb ischemia: a single-center, prospective, randomized study. J Endovasc Ther 2013;20:805–14.
