New developments in PAD angioplasty

This article covers the latest developments in lower limb superficial femoral artery interventions using microballoon catheters

Fabrizio Fanelli MD EBIR

Alessandro Cannavale MD

Vascular and Interventional Radiology Unit,

Department of Radiological Sciences,

“Sapienza” University of Rome,

Rome, Italy

Endovascular management of femoropopliteal vascular disease is now recommended as the first approach even for TASC D (TransAtlantic Inter-Society Consensus) lesions in selected cases.1 However, late clinical failure due to restenosis, neointimal hyperplasia, or stent fractures still remain an important concern. However, percutaneous angioplasty and stenting of the superficial femoral and popliteal artery is the proposed treatment of choice in the majority of patients either with intermittent claudication (IC) or critical limb ischemia (CLI) due to reduced perioperative morbidity and mortality and reduced in-hospital stay. Generally percutaneous balloon angioplasty (PTA) should be considered as the first-line approach to femoropopliteal vascular disease. 

Over the last few years due to the advances in technology, we faced a substantial improvement of balloon platforms and endovascular techniques in both femoropopliteal and infragenicular arteries. Cutting/scoring balloons and drug-eluting balloons represent the latest developments in angioplasty. These different technologies performed differently in femoropopliteal and infragenicular area. Balloon angioplasty has recently had a major role in not only native lesions, but also in restenotic lesions and in in-stent restenosis (ISR).

Cutting/scoring balloon technology

Cutting balloons (CB) or scoring balloons (SB) have been introduced to peripheral endovascular interventions from their use in coronary angiography.  

Scoring balloons are semi-compliant nylon-blend balloons wrapped around with a nitinol scoring element with three or more (depending on the balloon diameter) spiral struts. The struts create focal concentrations of dilating force, which minimises balloon slippage and assists in the luminal expansion of stenotic arteries. The most common scoring balloon is the AngioSculpt Scoring Balloon Catheter (AngioScore, Inc., Fremont, CA) which has three to four rectangular shaped elements that encircle the balloon in a helical pattern.2 For the femoropopliteal artery (sized from 4–6mm) it usually requires a 6Fr introducer sheath.  The mechanism of action would be to concentrate radial forces along the edges of the nitinol scoring element scoring the plaque, hence aiming for complete luminal expansion and a more precise and predictable outcome. Moreover, this balloon is has no significant slippage, which would reduce the risk of damage to the normal vessel wall and therefore reduce dissection rates and elastic recoil.2–4

The great advantage of this balloon is the reduction of dissection following balloon dilatation of the plaque. Moreover the incision is also aimed to reduce the stress on the arterial surface reducing the inflammatory reaction that generally acts as the first stage of neointimal proliferation.

Cutting balloons are composed of a conventional balloon catheter with three to four atherotomes attached to the balloon surface. The mechanism of action is similar to the scoring balloons being intended to incise the plaque with blades leading to radial fissures, which can reduce the shear stress forces. Such a mechanism would lead to an enlarged lumen by plaque compression rather than vessel expansion,  hence reducing elastic recoil and vascular inflammation.5

Clinical results of cutting and scoring balloons

Suggested indications for the use of CB and SB are: highly calcified lesions (successful lesion dilatation at lower balloon pressures with less trauma/dissection leading to more predictable results); bifurcation lesions (less elastic “recoil” in ostial side-branches and no slip); in-stent restenosis and preparing vessel for stenting achieving full stent expansion/apposition.2–4

Non-enthusiastic studies and trials have been reported for CB and SB in native and ISR lesions. Amighi et al. carried out a randomised controlled trial comparing PTA versus CB in de novo femoropopliteal lesions (lesion length <5cm).6 The six-month restenosis rate determined with US-Duplex was 32%(seven patients) in the PTA group versus 62% (13 patients) in the CB group (p=0.48). Also there was no significant difference in ankle-brachial index (median, 0.83 PTA versus 0.77 CB, p=0.56) or pain-free walking distance (median, 1000m PTA versus CB 600m; p=0.17).

As well as for the treatment of ISR, CB did not show improved results over POBA: Dick et al7 found that restenosis rates at six months were 65% for POBA versus 73% for CB (p=0.73) in lesions approximately 8cm in length. Complications (dissection, peripheral emboli, early thrombotic reocclusion) and bail out stenting were not significantly different between the two groups.  Otherwise for SB there is a shortfall of reported clinical experience. 

Drug-eluting balloons technology

Drug-eluting balloon (DEB) technology aims to aid the design of devices that deliver a sufficient amount of drug into the target lesion with rapid transfer through the plaque surface to the vessel wall. Technical features of DEBs are mainly related to these features: (1) type of drug (2) coating technology (3) shaft characteristics (OTW versus RX; pushability). In general, the coated drug should have adequate properties to be quickly absorbed by the vessel wall, determining antirestenotic effect. 

Paclitaxel is the most studied and used drug due to its lipophilic-hydrophobic properties that both facilitate drug cellular uptake, showing high tissue concentrations after single-dose with a balloon inflation time of 30–45 seconds without any related side effects.8 Paclitaxel stops the cellular cycle in phase M, without allowing re-entry into the cell cycle and therefore leads the cell to apoptosis.  In order to achieve this effect the appropriate dose needs to be delivered during inflation to the smooth muscle cells. Several preclinical and clinical studies showed optimal results by using a balloon coated with 3μm/mm2,9 nevertheless there is some evidence that even lower dose balloons coated with 2μm/mm2 of paclitaxel may have comparable effectiveness.10

The main aim during the transfer/release of the drug is to minimise loss of the drug in systemic circulation as well as to allow a homogeneous coating of the balloon surface and uniform drug release. Paclitaxel may be loaded on the balloon surface either on a folded/wrapped state (mainly for smaller balloons used for crural arteries) or when it is inflated (commonly used femoropopliteal arteries), the latter providing more durable coating and uniform, higher dosage. To bind paclitaxel on the balloon surface and facilitate the outward transfer, various hydrophilic carriers have been used: iopromide (a renowned contrast substance), urea (a natural inert substance), polysorbate/sorbitol, biodegradable polymers, or a nanoparticle formulation of paclitaxel.

Clinical results of DEBs

DEBs are currently the most investigated devices in both native peripheral arterial lesions and restenosis/in-stent restenosis.

Native lesions

Clinical success of DEBs in femoropopliteal native stenoses is currently supported by several trials and studies. A recent meta-analysis11 found DEBs as the most cost-effective device as compared to drug-eluting stents, bare-metal stents and plain angioplasty.

The main indicators of clinical and angiographic success of DEBs are primary patency (PP), target lesion revascularisation (TLR) rate, binary restenosis (BR), Rutherford/Fontaine stage and ankle-brachial index (ABI).

The following data that report on the clinical success of DEBs in native lesions are available: PP rate at one year resulted between 83.7% and 92.1% and TLR rate is comprised of between 4% at six months and 15% at 24 months. BR ranged between 9.1% and 19.0% at six months. At one year it was 14.5%. LLL was similar at six months in several studies: 0.4±1.2 and 0.5±1.4. 

Rutherford class or Fontaine stage improvement have been observed in patients treated with DEBs, for example Micari et al. reported a consistent improvement of Rutherford class from 28% to 65% of RC III and RC II (0% RC I) to 65.0% RC I and 18.0% of RC II at 12 months of follow-up (p<0.001). ABI improvement has been described by most of the studies considered. It ranged from +0.1 (ABI at 6 months of DEB and POBA resulted not significantly different; p=0.1) to +0.4 (baseline ABI of 0.5 to 0.9 at six months; DEB versus POBA, p>0.05).

Micari et al. also analysed the quality of life of 105 patients with 114 treated lesions with DEB. The percentage of patients reporting any problem across the five dimensions of health-related quality of life was statistical significantly reduced at three, six and 12 months after treatment.12

Restenotic/in-stent restenotic lesions

Interventional cardiologists have published the initial studies and trials regarding the use of DEBs in the treatment of ISR. The use of DEB in femoropopliteal ISR is being described in dedicated studies either alone or in combination with atherectomy.13–17 The aim of combining DEB and atherectomy is to reduce the plaque thickness and the calcium burden and to improve the diffusion of the drug through the intima to the media layer of the vessel wall.

The first prospective study assessing DEBs in the treatment of ISR was published in 201212 and included a two-year follow-up.13 The authors included relatively long lesions (length 82.9±78.9mm) and 20.5% were in-stent occlusions (Class III).  Treatment included the use of almost two DEBs per patient; excimer laser atherectomy was also applied in four cases. The angioplasty technique consisted of performing POBA with a smaller size balloon to remodel the lesion (0.8:1 to the reference vessel diameter (RVD)) for at least 60 seconds and then the DEB angioplasty (1:1 to the RVD) for 180 seconds. In four cases dissection developed at the stent edges and was treated with stenting.  Post-procedure patients received thienopiridines for 30 days in combination with aspirin. Primary patency at one year was 92.1%. After two years, PP was 70.3% and freedom from TLR was 78.4%. In this study Class II and III ISR lesions were associated with higher risk of restenosis compared to Class I ISR (33.3% and 36.3% versus 12.5%, p=0.05).

The DEBATE-ISR15 study was performed in 44 diabetic patients with femoropopliteal ISR. Angioplasty technique and post-procedure medication was similar to the study of Stabile et al.13 Freedom from TLR was 86% at one year in the DEB group (69% for POBA group), TLR was 13.6% and BR was 19.5%. Distal embolisation occurred in two patients after pre-dilation of occlusive lesions (Class III). Additional stenting was required in five patients (seven stents in total implanted). A multivariate analysis showed that Class III lesions treated only with DEB are exposed to four-times higher risk of re-occlusion. In those lesions the authors advised the use of atherectomy devices. 

Excisional and laser atherectomy devices have been further used in combination with DEBs in the treatment and prevention of femoropopliteal ISR.16,17 A retrospective study by Sixt et al15 reported higher 1-year freedom of restenosis in the DEB group 84.7% (range 70.9–98.5%) versus POBA 43.8% (range 30.5–57.1%) after mechanical atherectomy debulking. Stenting was performed in similar rates in both cohorts (eight cases POBA versus three cases DEB; p>0.99). Notably five cases (19%) of peripheral embolisation occurred in the DEB group. 

Van den Berg et al17 also investigated the efficacy of (excimer laser) atherectomy associated with DEBs in the treatment of femoropoliteal ISR.16 Their endovascular approach was to cross the lesion with a guide wire and then advance the excimer laser catheter through the lesion. Subsequently a predilation with an undersized balloon (1mm smaller than the RVD) was performed and then DEB angioplasty in a nominal size to the RVD. In this study 11 out of 14 patients (78.6%) presented with a total in-stent occlusion (Class III; mean lesion length was 161.8mm), the other three out of 14 were Class I.  Primary patency was 91.7% and the mean follow-up was 14.3 months (range 9–19). 

References

1. European Stroke Organisation et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011;32(22):2851–906. 
2. Kiesz RS et al. Results From the International Registry of the AngioSculpt Scoring Balloon Catheter for the Treatment of Infra-Popliteal Disease. J Am Coll Cardiol 2008;51(10) Supplement B: 75.  
3. Scheinert D et al. Results of the multicenter first-in-man study of a novel scoring balloon catheter for the treatment of infra-popliteal peripheral arterial disease. Catheter Cardiovasc Interv 2007;70(7):1034–9. 
4. de Ribamar Costa J Jr et al. Nonrandomized comparison of coronary stenting under intravascular ultrasound guidance of direct stenting without predilation versus conventional predilation with a semi-compliant balloon versus predilation with a new scoring balloon. Am J Cardiol 2007;100(5):812–7.
5. Canaud L et al. Infrainguinal cutting balloon angioplasty in de novo arterial lesions. J Vasc Surg 2008;48(5):1182–8.
6. Amighi J et al. De novo superficial femoropopliteal artery lesions: peripheral cutting balloon angioplasty and restenosis rates–randomized controlled trial. Radiology 2008;247(1):267–72.
7. Dick P et al. Conventional balloon angioplasty versus peripheral cutting balloon angioplasty for treatment of femoropopliteal artery in-stent restenosis: initial experience. Radiology 2008;248:297–302. 
8. Krokidis M et al. Peripheral applications of drug-coated balloons: past, present and future. Cardiovasc Inter Radiol 2013;36:281–91.
9. Biondi-Zoccai G et al. Drug-eluting balloons for peripheral artery disease: a meta-analysis of 7 randomized clinical trials and 643 patients. Int J Cardiol 2013;168(1):570–1.
10. Scheinert D 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;7:10–19.
11. Pietzsch JB et al. Economic analysis of endovascular interventions for femoropopliteal arterial disease: a systematic review and budget impact model for the United States and Germany. Catheter Cardiovasc Interv 2014;84(4):546–54.
12. Micari A et al. Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12-month results from a multicenter Italian registry. JACC Cardiovasc Interv 2012;5(3):331–8.
13. Stabile E et al. Drug-eluting balloon for treatment of superficial femoral artery in-stent restenosis. J Am Coll Cardiol 2012;60:1739–42. 
14. Virga V et al. Drug-eluting balloons for the treatment of the superficial femoral artery in-stent restenosis: 2-year follow-up. JACC Cardiovasc Interv 2014;7:411–5.
15. Liistro F 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;21:1–8.
16. Sixt S et al. Drug-coated balloon angioplasty after directional atherectomy improves outcome in restenotic femoropopliteal arteries. J Vasc Surg 2013;58:682–6.
17. van den Berg JC et al. In-stent restenosis: mid-term results of debulking using excimer laser and drug-eluting balloons: sustained benefit? J Invasive Cardiol 2014;26:333–7.