Vessel Preparation: What is the Evidence in the BTK Segment?

Reprinted with permission from VASCULAR DISEASE MANAGEMENT 2020;17(7):E142-E149.

Introduction
Critical limb ischemia (CLI) is the most severe form of peripheral artery disease (PAD), leading to a high risk of limb loss when revascularization is not attempted. Popliteal and crural artery occlusions are commonly associated with limb-threatening ischemia, mainly related to the paucity of collateral vascular pathways beyond these lesions.

Surgical revascularization for CLI has a good limb salvage rate but comes at a cost of major invasiveness. Because of its non-invasive nature with comparable technical success, the percutaneous endovascular approach has expanded considerably in recent years and has revolutionized the care of patients with CLI. With percutaneous transluminal angioplasty and other endovascular adjuncts, it is now possible to treat both simple and complex, short or long lesions.

This article will discuss the importance of lesion preparation and will review the technique and the materials to reduce the complications following inflation and deflation of the balloon with special attention to dissection in the below-the-knee (BTK) district.

Background of Balloon Angioplasty
Balloon angioplasty works by mechanical dilation and disruption of the of the atheromatous luminal ring, focal luminal dissection (ideally in a controlled fashion), and stretching of the adventitia and media, with a resultant increase in overall luminal diameter. The forced dilation in a stenotic vessel can lead to plaque fracture, intimal splitting, and localized medial dissection. The most frequent and feared complication after percutaneous transluminal angioplasty (PTA) is vessel dissection. If not only extending outward but also longitudinally, the dissection may even invade the adventitia, resulting in frank perforation.

Moreover the disrupting effect of balloon dilation can create an irregular luminal surface that contributes to the development of neointimal hyperplasia.¹ Thus, it is the basic mechanism of dilation itself that can cause vessel injury and self-maintaining of the stenosis, which negatively impacts long-term clinical outcomes. In a retrospective and multicenter analysis, Fujihara et al examined the dissection patterns after endovascular therapy of de-novo SFA lesions and found a correlation between dissections and the long-term outcomes after an endovascular intervention. Similarly to the classification system of coronary dissection according to the National Heart, Lung and Blood Institute,² they classified each lesion in increasing degree of severity: type A - minor radiolucent areas, type B - linear dissection, type C - contrast outside the lumen, type D - spiral dissection, type E - persistent filling defects, type F - total occlusion without distal antegrade flow. Among 621 patients with 748 symptomatic de novo SFA lesions, they found 42% cases of severe dissection (from grade C to F) after PTA. After 2 years, vessels that showed the most severe types of dissection had a significantly lower patency rate (P<0.001) and higher clinically driven target lesion revascularization (TLR) (P<0.001) compared to vessels with nonsevere (types A, B) or without dissections. Thus, severe dissection was demonstrated to negatively impact PTA outcomes and to represent a significant risk factor for restenosis, with an increasing risk which rises progressively from types C to F. A vessel diameter <5 mm (P=0.001), a lesion length >15 cm (P=0.001), chronic total occlusion (P<0.001), and TASC II C and D lesions were identified as additional factors related to a high prevalence of severe dissection.³

Potentially, every balloon angioplasty may create a vessel injury. Larger dissections should be prevented, but microdissections basically occur after any balloon-based intervention. There is a lack of agreement on how to optimally perform a standardized balloon angioplasty and specific guidelines are also lacking. Performance varies among medical specialties (interventional radiologists, vascular surgeons, interventional cardiologists), vessel localizations, and personal operator experience.

Dissection in below-the-knee vessels is a severe clinical problem. Its incidence (accounting for on-table and early failures) for the infrapopliteal segment is not clear. In a recent meta-analysis, the incidence of dissection in below-the-knee district varied between 5.9% and 6.4%, but in longer lesions the incidence is probably higher.⁴

Vessel preparation has become more and more important as an essential component of endovascular procedures. Currently, a clear definition of vessel preparation is lacking. Initially the principal goals of the process of vessel preparation were luminal gain and plaque modification. With the introduction of drug-eluting balloons (DEBs), these terms began to include all methods that lead to enhanced efficacy of these balloons and that help in optimizing stent deployment and drug delivery especially for calcified lesions. In severely calcified arteries, calcium represents a barrier to optimal drug absorption, and the effect of drug-coated balloons may be inhibited by calcified lesions that significantly reduce the efficacy of the drug. Fanelli et al⁵ evaluated 60 patients that underwent angioplasty of de-novo lesions of the SFA, classified into eight groups according to the distribution of calcium around the vessel circumference and length on CT-scan. They reported that the DEB effect was lower in patients with a higher degree of calcium, with a full circumferential distribution of calcium being the strongest influencing factor, especially in the presence of calcium around the entire circumference. Similar results were reported by Tepe et al⁶ who studied in a retrospective multicentric analysis the association between lesion characteristics, including calcification, with late lumen loss (LLL) after use of drug-eluting balloon therapy in patients with femoropopliteal arterial disease. It was found that LLL did differ neither based on calcium location or length; also, the severity of residual stenosis after the intervention did not have any impact on the LLL during follow-up, but there was a strong association between bilateral calcification and a higher LLL when compared to unilateral calcification. The authors concluded that a possible approach to overcome the issue of severe calcification might be plaque modification or removal prior to the use of DEB.

Therefore, currently the goal of vessel preparation includes removing impediments to local drug delivery, avoiding drug loss on the way to lesion, ensuring that a 1:1 sized DEB does not dissect the vessel, maximizing DEB expansion and vessel contact. Most peripheral interventionalists currently use an aggressive lesion preparation strategy in an effort to “leave nothing behind”.

Optimal Percutaneous Transluminal Angioplasty
When performing a percutaneous angioplasty, especially below the knee, the residual plaque burden can result in a dissection or can lead to an early restenosis, influencing patency negatively, as described earlier. There are several ways to optimize outcomes of PTA.

Importance of inflation technique
One of the first trials that intended to prove the efficacy of a progressive dilation during coronary angioplasty (in the pre-stent era) to reach a high rate of successful procedures with a low risk of complication or restenosis was published in 1993.⁷ The authors hypothesized that by avoiding a mismatch between balloon and vessel size and with a progressive balloon dilation of the vessel, there could be a more controlled injury of the artery. This involved stenosis dilation at a lower pressure range and the primary use of smaller diameter (undersized) balloons, followed by properly (1:1) sized balloons. A success rate of 98.7% out of a total of 1248 stenotic vessels, and 88% in occluded vessels was obtained, with an incidence of major and minor dissection of 1.3% and 5.4%, respectively. This is significantly less than what is commonly observed following traditional coronary balloon angioplasty.

Successive research on the biochemical responses of cells to mechanical loading led to understand that vessel injury during angioplasty is related to the rate at which the vessel wall is stretched, the so-called strain rate. In their study, Barbee et al⁸ applied 10-psi loads to endothelial and smooth muscle cells either as an impulse (8 ms) or over a period of 1.75 s. They observed that even if the amount of strain was the same, a long period of slow load application reduced the strain rate. The higher the strain rate, the more significant the injury to the cells was.

Subsequently, many authors published trials in which they applied the principle of slow inflation of the balloon to prepare the vessel. Ilia et al⁹ randomized 103 patients to either a gradual or rapid inflation protocol. The inflation protocol consisted of an initial balloon inflation at 3 atm, then an increase of the pressure by 1 atm every 20 seconds until the nominal pressure was reached. In the rapid inflation protocol the nominal pressure was reached at the initial inflation. Although there was a satisfying success rate in both groups and the baseline characteristics were the same in the two groups, the dissection frequency was higher in patients with rapid inflation (59% vs 36%, P<0.01).

Therefore, acute complications like dissection and early restenosis may be lowered by using a progressive dilatation strategy that employs predilatation with a small balloon followed by dilatation with an optimally sized balloon.

In a study reporting 1-year data from a trial evaluating long femoropopliteal lesions treated with paclitaxel-coated balloons, Micari et al¹⁰ obtained a high primary patency rate at 12 months (83%) in very long femoropopliteal lesions (251 +/- 71mm) using a similar approach: after a 2-minute pre-dilation with an undersized uncoated balloon (0.5 to 1 mm smaller than the reference vessel diameter), the target lesion is dilated by a DCB of appropriate size and length (1:1) based on a visual estimate) with an inflation time of 3 min at 6 to 12 atm; an additional long (at least 3 min) inflation with an adequate (same size or 1 mm larger than the DCB) uncoated balloon is performed if there is a persistent stenosis of >50% or dissection. Not only was the 12-month patency rate high, but also the bailout stent rate was low (10.9%), especially when compared to other studies.

Another important issue that often causes problems during angioplasty is plaque morphology and composition, since lumen enlargement depends on cracking of the plaque. The stress applied by the balloon can lead to inadequate and unpredictable acute results in complex lesions, because of the heterogeneous characteristics of the plaque. High balloon inflation pressures are often required to provide enough stress to crack the plaque. However, when a plaque subsides only at high inflation pressures, the balloon typically expands to its full size rapidly and the vessel wall expands at a high strain rate, leading to a significant injury, with the deleterious effect on long-term patency described before.^11-13

This is the reason why a slow and progressive inflation can reduce the degree of arterial trauma, and, hence, the incidence of major acute complications such as dissection and restenosis. Some authors suggest to dilate the stenosis with an undersized balloon and to maintain inflation for 180 seconds.¹⁴ This leads to improved immediate results as compared to a 30-second dilation strategy. The results in the POBA arm in the ILLUMENATE RCT (Primary patency per Kaplan-Meier estimates at day 365 for PTA of 70.9%) underscore the potential of PTA when performed in a ‘state-of-the-art’ fashion.¹⁵

In case of a focal residual stenosis, a short 1:1 balloon can be inflated at a specific point to obtain a focused force angioplasty. This system was applied by Solar et al¹⁶ and Miller et al¹⁷ who studied a balloon specifically designed to apply a high focal stress along the surface of the balloon itself. Focused force angioplasty is a technique in which the forces resulting from inflating an angioplasty balloon in a stenosis are concentrated and focused at one or more locations within the stenosis. While the technique has been shown to be useful in resolving resistant stenoses, its real value may be in minimizing the vascular trauma associated with balloon angioplasty and subsequently improve outcomes.

Importance of inflation time
Some studies¹⁸ have shown that prolonged balloon inflation with a perfusion balloon catheter effectively improves poor initial results of coronary angioplasty. In 1997, Manninen et al¹⁹ conducted a trial in which it was proven that prolonged dilation is a feasible and effective method for improving unsatisfactory primary results of femoropopliteal artery PTA. In their study, they performed balloon inflations of up to 3 hours.

Zorger et al¹⁴ conducted the first human study evaluating morphological outcome after short and long inflation time of angioplasty in peripheral vessels. Randomizing seventy-four infrainguinal atherosclerotic lesions to undergo balloon dilation for 30 seconds (group I) or 180 seconds (group II), they found a significantly lower rate of dissection in the group of prolonged inflation, and a lower incidence of additional interventions, with better acute results (long-term follow-up was not considered). The difference in major residual stenosis was not statistically significant, but a long dilation did not cause a worsening of the morphology of the lesions.

Söder et al²⁰ in 2002 also carried out a trial in which they tested the additional value of prolonged balloon inflations. They performed femoropopliteal PTA in 112 limbs of 97 patients and used prolonged balloon dilation in those cases of unsatisfactory primary results after standard dilation for 1-3 minutes: the prolonged dilation consisted in a mean time of inflation of 31 minutes with use of the same balloon catheter or a perfusion balloon catheter. Primary success was achieved in 92.9% of cases; however, the better acute results did not translate into better long-term outcomes. This indicates that a long-inflation time can overcome elastic recoil but will not be able to affect the occurrence of neo-intimal hyperplasia.

Specialty Balloons
Currently available specialty balloons are: AngioSculpt (Philips), Chocolate (Medtronic), VascuTrak (Bard), and Scoreflex (OrbusNeich). Data about VascuTrak^®, AngioSculpt^® and Chocolate^® balloons will be discussed below. There is currently no published data on Scoreflex.

Scoring balloons
One of the tools for vessel preparation is the so-called scoring balloon. This type of balloon can modify or crack the plaque to achieve luminal gain during dilatation itself and potentially reduce the rate of dissections or bail-out stenting, thus overcoming the limitations of conventional balloon angioplasty. It may be considered in calcified or very fibrotic lesions. The rationale behind this technology is that the entire force is focused on a wire or blade edge mounted on the balloon: the plaque is fractured at low inflation pressures, before the balloon is fully inflated, and further expansion during dilatation is facilitated. This setup leads to a controlled plaque incision or a controlled dissection with less barotrauma to the entire lesion. Subsequently a gradual increase of pressure will slowly stretch the vessel. Scoring or cutting balloons may be the first choice in bifurcation and ostial lesions with the intention to minimize an expected plaque shift and make bail-out stenting less likely. Moreover, scoring balloons decrease elastic recoil, which is one of the most important factors negatively influencing the acute results of angioplasty, being responsible for a significant loss of luminal area immediately after the procedure.²¹ This is of importance in the BTK segment. Potentially scoring balloons can increase penetration of anti-proliferative drug of paclitaxel-coated tools in presence of calcium deposits.²²

The VascuTrak balloon catheter is a peripheral balloon angioplasty catheter that incorporates two external focal force wires to introduce high focal stresses longitudinally along the luminal surface of the lesion at low balloon inflation pressures. It is also referred to as a pressure-focused expanding balloon catheter or double-wire balloon catheter. In the DCB-Trak registry,²³ a total of 32 symptomatic femoropopliteal lesions were treated. Vessel preparation was performed with the VascuTrak balloon for 60-120 seconds and subsequently a DEB-angioplasty with an inflation time of 60 seconds was performed. A 100% freedom of target lesion revascularization at 6 and 12 months was reported, therewith demonstrating safety of the combined treatment of SBA and DEB-angioplasty avoiding the use of a stent. These results may be related to improved antiproliferative effect of paclitaxel in DEB after plaque modification done by scoring-balloon, thus highlighting the importance of an adequate lesion preparation before using a DEB.

The AngioSculpt^® device (Philips) received FDA approval in 2005 as an adjunctive scoring balloon catheter in the treatment of PAD. It consists of a double lumen catheter with a semicompliant, nylon balloon surrounded by 3 laser-cut external nitinol scoring elements with a helical configuration. The expansion properties of the spiral struts are influenced by a fixed distal end and a semiconstrained proximal end in relation to the balloon. This design allows for a controlled and uniform expansion of the balloon and nitinol cage, potentially preventing significant device sliding while scoring the plaque. The first in-man-study with this device in the infrapopliteal segment was conducted in 2007 by Scheinert et al.²⁴ They evaluated a cohort of 42 patients with 56 lesions, 73% of which were complex, including moderate to severe calcification. The AngioSculpt^® demonstrated to be highly effective in a broad range of complex lesion morphologies (long lesions, bifurcation or ostial lesions, moderate/severe calcification), in most cases as stand-alone therapy. A low peri-procedural complication rate with 10.7% of dissections (6/56; 1 severe dissection). In 2009, Bosiers et al²⁵ collected data of 31 patients treated with AngioSculpt balloon for CLI with infra-popliteal disease (36 lesions, mean lesion length 32.4 mm) and single-vessel runoff to the ankle. In 20 patients (64.5%) AngioSculpt scoring balloon angioplasty was performed as a stand-alone procedure. They reported a low incidence of minor dissections (9.7%) that had to be addressed with stenting. One-year primary patency as estimated by Kaplan-Meier analysis was 61.0 ± 9.3%, secondary patency was 79.5 ± 7.4% and limb salvage was 86.3 ± 6.4%. These results leave room for  improvement.

The PANTHER study²⁶ enrolled 101 patients with 124 SFA lesions. In 34.7% of cases, patients presented with CLI. The average lesion length was 7.4 ± 5.9 cm, and the mean degree of stenosis was 85.5%, with 16.1% total occlusions. Treated lesions were under 5 cm in length (41.9%), 5 to 10 cm in length (38.7%), or over 10 cm in length (19.4%). The AngioSculpt^® balloon was used in each case: in 37.1% of patients it was used for vessel preparation in stand-alone PTA, and in 32.3% it was used in combination with a DEB angioplasty; an adjunctive placement of a bare-metal stent was performed in 30.6% of lesions. At 12 months, the primary patency rate was 81.2%. It did not significantly differ between the various treatment strategies. When stratified by calcification severity (mild, moderate, severe), there was no significant difference between patency rates. The strongest predictor of patency was the length of the lesion. Although limited in sample size, this study is encouraging for the use of scoring balloons in calcified lesions, supporting the role of plaque scoring for vessel preparation in calcific lesions and the hypothesis that the degree of calcium does not influence patency.

Other specialty balloons
The Chocolate^® balloon is a special over the wire balloon device, compatible with 0.018- and 0.014-inch guidewires, where the balloon is encased in a nitinol-constraining, cage-like, structure. The balloon is semi-compliant and requires 1:1 vessel sizing. The design allows a homogeneous inflation and deflation that reduces  vessel wall trauma. When inflated, the nitinol cage around the balloon forms segments called “pillows” that apply a focal and atraumatic force that reduces the amount of damage and stress to the vessel wall. The grooves of the balloon allow for plaque modification. The device is available in sizes to treat both above- (ATK) and below-the-knee (BTK) lesions and renal arteries, with balloon diameters of 2.5 to 6 mm, balloon lengths of 40 to 120 mm, and catheter lengths that range from 120 to 150 cm.

A large postmarket study evaluating the efficacy of the Chocolate^® Balloon is the Chocolate^® Bar Study, published by Mustapha et al in 2018,²⁷ which enrolled a total of 488 patients with either above-the-knee (n=264) or below-the-knee (n=226) lesions and at least 1 vessel runoff. It represents one of the largest studies ever conducted of interventions in patients with below-the-knee arterial disease. The SFA data have been published,²⁷ while the BTK cohort data have been presented at the LINC Meeting in 2018. Considering the below-the-knee group of patients, the results were very encouraging, with a high rate of peri-procedural success. The reported freedom from flow-limiting dissection was 99%, with 84.6% of lesions that obtained a grade of stenosis less than 30% and a freedom from bail-out stenting of 99.1%, while the rate of freedom from major unplanned amputation was 96.7% in BTK patients at 6 months. The long-term clinical outcomes (primary patency at 12 months in the ATK cohort of 64.1%) remain however disappointing. Sirignano et al²⁸ reported their experience with 68 limbs (SFA lesions) treated by a standard angioplasty with the Chocolate^® balloon catheter followed by drug coated balloons (Ranger). All patients had a Rutherford category class 3. In 65.5% of patients an occlusion was present and the 21.4% of the lesions were occlusions longer than 150 mm; average stenosis length was of 64.9 ± 30 mm. At 3-month follow-up, only two patients presented a re-occlusion and one had a severe restenosis. At 12-month follow-up, 56% of patients were completely asymptomatic, with an improvement of 2 or more Rutherford Classification categories in 85.4% of patients, and only two out 48 treated limbs had a recurrence of severe intermittent claudication. The overall primary patency at 1 year was 98.8%. Thus, this protocol seems to be safe and effective in treating SFA and PA lesions in claudicants with satisfactory early and 12-month results. Results of the drug-coated Chocolate^® balloon (Chocolate^® TOUCH;  ENDURE study) in treatment of femoropopliteal lesions have been recently published.²⁹ Seventy lesions in femoropopliteal arteries of 67 patients with a mean lesion length of 7.3 cm were evaluated. Moderate or severe calcification was seen in in 54.3%. No flow-limiting dissections were seen and only in 1 case a residual stenosis (>50% diameter loss) was noted, because of an undersized balloon. The angiographically measured late lumen loss (primary endpoint) at 6 months was 0.16 mm. The primary patency for patients treated per protocol was 90% at 6 months and 82% at 12 months. According the ENDURE study, the combination of the Chocolate^® platform with the paclitaxel coating offers the possibility to avoid stents.

Atherectomy
The reshaping of the plaque from peripheral arterial lesions is essential when preparing vessels for adjunct therapies such as DEBs and drug-eluting stents. Atherectomy reduces the plaque burden through debulking: this allows to obtain a more uniform subsequent angioplasty of the vessel at a lower pressure, in order to diminish the barotrauma that overstretches the vessel wall during the angioplasty. Moreover, atherectomy can also disrupt heavily calcified lesions, thus optimizing drug delivery when a DEB is used.³⁰

Catheter-based atherectomy achieves atherosclerotic plaque clearance by means of directional plaque excision, rotational plaque removal (high speed or orbital rotation) or laser plaque ablation. Directional atherectomy (SilverHawk, TurboHawk, HawkOne, Medtronic) works by a single or multiple cutting rotation blades without a system of active aspiration; plaque is removed by directing the cutter towards the plaque, which is especially of advantage when treating eccentric lesions. Rotational atherectomy (Pathway Jetstream Pv [Boston Scientific], Peripheral Rotablator [Boston Scientific], Phoenix [Philips] and Rotarex [BD]) removes the plaque by a high-speed rotation of a burr at the tip of catheter, with or without aspiration; luminal gain usually matches the size of the tip/burr used. This system is effective and fast, but it cannot control the depth of the atherectomy. Orbital atherectomy (Diamondback 360° [CSI]) is based on the high-speed rotational spin of the shaft and the orbital rotation of a specially designed debulking, diamond-coated crown. The debulking area increases with the increase of the rotational speed of the crown. There is no aspiration function, so distal embolization cannot be prevented if a filter is not used.

The following overview of data underlines the importance of atherectomy with calcified plaque modification in order to enhance the effectiveness of drug-coated balloons.

A small observational, single-arm, prospective study examined severely calcified lesions in 30 patients with intermittent claudication (n=18) or CLI (n=12) with baseline Rutherford class 4.2 ± 1.2.³¹ Calcium was defined as 1 cm on both sides of lesion. All of the patients underwent angioplasty of the lesions with intravascular ultrasound guided distal atherectomy (TurboHawk) and DCB (In.PACT ADMIRAL, Medtronic) with an inflation time of 180 seconds. All procedures were performed using an embolic protection device. Less than 30% residual stenosis was achieved in all cases. Bail-out stenting was performed only in 2 patients (6.5%) for flow-limiting dissection. TLR at 12 months was 10% and secondary patency rate was 100%, while a limb-salvage rate of 100% was seen. The result of this study shows that combined use of DA and paclitaxel-coated ballons may represent a potential alternative strategy for the treatment of femoropopliteal severely calcified lesions.

The DEFINITIVE AR (Atherectomy Followed by a Drug-Coated Balloon to Treat Peripheral Arterial Disease) used a similar protocol³² and analyzed 121 subjects in a multicenter, randomized, controlled trial, comparing atherectomy with the TurboHawk or SilverHawk plaque excision systems followed by drug-eluting balloon angioplasty (DAART; n=48) versus a drug-eluting balloon (Cotavance [Bayer Healthcare Pharmaceuticals]) alone (n=54), in patients with Rutherford 2 to 4 disease and 7- to 15-cm long superficial femoral and/or popliteal lesions. Technical success was superior in the DAART arm (89.6% vs 64.2%), there was no need for bailout stenting and a significantly lower flow-limiting dissection rate was achieved (2% vs 19%, P=0.01). Nevertheless, at 1 year no statistically significant difference in angiographic stenosis, clinically driven-TLR and duplex ultrasound patency was found (93.4% of stenosis-free in DAART vs 89.6% in DCB; P>0.05). In a post-hoc analysis it was seen that in the DAART arm, patients that were treated with DA until a <30% residual stenosis was achieved, a higher 1-year patency rate was reported, both by angiography or duplex measurement (88.2% and 84.2%). The investigators concluded that, given the excellent performance of DCB alone in TASC II A and B femoropopliteal lesions — provided they are not severely calcified—the DA+DCB strategy should be reserved to more complex, calcified, and long lesions in which they potentially have a better outcome, following this initial experience.

In a recent study, Stavroulakis et al.³³ performed a comparison between DAART and DCB in 72 symptomatic patients with isolated popliteal, mainly de novo lesions. Both groups had a similar calcium score. Seventy-two patients were treated with DCB angioplasty alone (n=31) or with DAART (n=41). Four atherectomy devices were used: Turbohawk (Medtronic), Silverhawk (Medtronic), Panteris (Avinger Inc) and HawkOne (Medtronic). Several DCBs were used: The technical success rate in both groups was similar. The 12-month primary patency rate was significantly higher in the DAART group (82% vs 65%). A greater need for bail-out stenting in the DCB only group was observed, although the difference was not statistically significant (16% vs 5%, P=0.13). Distal embolization was reported in 1 patient in the DCB only group and in 2 patients in the DAART group (P=0.99); 3 false aneurysms occurred that required surgical treatment, 1 following DCB angioplasty and 2 after DAART. In the DAART group 2 arterial injuries and 3 cases of popliteal aneurysm formation were seen.

The most recent study is the LIBERTY 360 trial.³⁴ It was conceived as an observational study to examine predictors of clinical outcomes in symptomatic PAD patients undergoing lower extremity endovascular revascularization with different devices, aiming to give an overview about optimal revascularization strategies. There were multiple prespecified outcome measures, including procedural and lesion success, major adverse events (MAEs), duplex ultrasound, change in self-reported quality of life (QoL), wound status, and economic analysis. As previously mentioned, not a single endovascular strategy has been studied, but a panel of different methods. Examining 1204 enrolled patients, investigators found that endovascular therapies are a viable treatment option for patients with claudication, CLI, or patients in Rutherford Class 6, for whom primary amputation becomes not necessarily mandatory. They observed an improvement in all QoL measures and, most importantly, in amputation prevention after endovascular interventions in both claudicant and CLI patients. A high number of patients in all RC groups reached a final residual stenosis <50% maintaining a low significant rate of angiographic complications. Early patency of the target lesion was 95.5% in the RC 2 and 3 subjects (n=355) at 30 days, while the patency at 6 and 12 months was over 80%. There was an overall improvement of the Rutherford Class. Finally, there was a good outcome in terms of 30-day and 12-month freedom from major adverse events and amputation: 99.2% and 82.6%, respectively in RC2.3; 96.1% and 73.2% in RC4.5; and 90.8% and 59.3% in RC6. Specifically, the sub-analysis of patients treated with orbital atherectomy showed that this system is essential in patients with CLI. There was excellent freedom from MAEs in the Rutherford 4, 5, and 6 classes. In particular, in the Rutherford 6 class, orbital atherectomy proved to be very effective due to its low profile and ability to access more vascularization distal, combined with a mechanism of action specifically designed for hard calcified plaque. In this class, the rate of freedom from major amputation at 12 months was 91%. LIBERTY 360 has demonstrated that endovascular treatment is safe and effective in patients with symptomatic PAD. Most importantly, this study consists of real-world data: most of the lesions included here are often excluded from studies. This trial represents a step forward towards developing a more aggressive treatment strategy for challenging lesions and patients with CLI.

These data highlight the additional benefit of performing debulking atherectomy prior to the use of a drug-eluting balloon. The marriage of atherectomy and DCB (effective plaque modification / debulking paired with sustained drug presence) may be a useful union of technologies, at least in the SFA.

Lithoplasty
Extensive calcifications of the tunica media make the vessel wall rigid and difficult to dilate. Such calcified arteries require high pressure to dilate effectively, and this often results in a vessel wall injury and contribute to recoil and restenosis. As shown by Fanelli et al and as mentioned above, circumferential distribution of calcium is the most influential factor with the worst effect after revascularization.⁵

Lithoplasty represents a novelty in plaque modifying devices. It adopts a method already widely used for the treatment of urinary stones, lithotripsy, in which calcifications are fragmented by high-power acoustic shockwaves. Intravascular lithoplasty (IVL) involves the use of localized circumferential high-speed sonic pressure waves through an inflated balloon catheter. The Shockwave^® (Shockwave Medical, Inc) uses a semi-compliant balloon catheter with 5 lithotripsy emitters along the length of the balloon that create sound pressure waves to deal with calcification. The balloon is inflated at low pressures (4 to 6 atm) to minimize the damage to the artery, and subsequently the acoustic energy delivers significant shearing forces that selectively target the high-density calcium deposits. Such high pulsatile energy is able to fracture the calcium and allows the subsequent dilation of a peripheral artery stenosis by means of low balloon pressure.³⁵ IVL does not rely on mechanical tissue injury by physical interaction (in comparison to balloon angioplasty and rotational/orbital atherectomy). In fact, acoustic pulses can differentiate calcium from soft tissue and address both intimal and deep calcium with minimal injury to other tissues, thus resulting in fewer complications. The capacity to preferentially disrupt calcium in a controlled manner may optimize stent delivery while maintaining the integrity of surrounding soft tissue.³⁶ The device is available in Europe since 2015 and was approved by the US Food and Drug Administration in late 2016.

The first study demonstrating reliability and effectiveness of this system used in lower limbs is the DISRUPT PAD, a case series by Broadmann et al that enrolled a total of 95 patients, 60 of which followed for 12 months. They applied the lithoplasty catheter in the treatment of femoropopliteal lesions, with an initial stenosis of 77.8 ± 13.5%, a mean lesion length of 71.9 ± 36.4 mm, and a mean calcium burden that was moderate in 44.2% of cases and severe in 54.7%. Procedural success was achieved in all cases, the post-treatment residual stenosis was 23.8 ± 5.7% with an acute man lumen gain of about 3.0 mm. They obtained an immediate vessel patency of 100% and of 76.7% at 6 months and reported just one major adverse event (a type D dissection requiring stent).^37,38,39

The DISRUPT PAD III Observational Study⁴⁰ is the first study conducted in a real-world setting and reports the data about daily clinical practice, in which IVL is used in combination with other devices for the treatment of patients with strong calcified vessel lesions. The study is a prospective, nonrandomized, multicenter, single-arm study that enrolled 200 patients. The majority of adjunctive tools used were balloon-based technologies (ie, conventional, drug-coated, and specialty balloons). No infrapopliteal lesions were considered. The mean acute luminal gain at the end of the procedure was 3.4 ± 1.2 mm and the final mean residual stenosis was 23.6% ± 9.7%. There were 2 type D dissections and a single perforation. There were no major adverse events. A very interesting feature emerging from this analysis is the potential synergic effects when using IVL combined with atherectomy. In fact, IVL modifies concentric arterial calcium because sonic pressure waves are delivered spherically; catheter-based atherectomy is used to mechanically debulk the superficial calcium. It means that atherectomy may facilitate IVL to treat areas of medial calcification or areas of angulation or bifurcation in which atherectomy may not be effective or have a high risk of complications.

The only study that concerns below-the-knee artery lesions is the DISRUPT BTK study. It is a prospective, nonrandomized, multicenter, feasibility, and safety trial that enrolled 20 patients. The characteristics were similar to those previously mentioned. The group obtained a post-treatment mean diameter stenosis of 26.2%, with an acute mean lumen gain of 1.5 ± 0.5 mm. Vascular complications were represented by only 1 grade B dissection reported (no flow-limiting). There were no major adverse events. Unfortunately, the follow-up was only 30 days.⁴¹ The DISRUPT PAD III randomized controlled trial will directly assess safety and effectiveness outcomes in IVL plus DCB compared with balloon angioplasty plus DCB and that will follow patients through 2 years.

A 2019 review³⁶ synthesizes the early outcomes and shows that lithoplasty appears to achieve low residual stenosis, sustained patency with minimal vascular wall injury and not any relevant vascular complications or MAEs. Such equivalence in terms of safety and efficacy may take lithoplasty to have a growing role as an adjunctive therapy to percutaneous intervention. This could be particularly true for long tibial artery calcifications, which are otherwise difficult to treat and that predict a poor outcome in patients with critical limb ischemia, especially in diabetics.⁴² A recent individual patient level data analysis of five prospective studies evaluating the use of IVL in significantly calcified PAD lesions, demonstrates this treatment strategy to be both effective and safe.⁴³ In summary, the Shockwave Peripheral IVL System^® demonstrated a high rate of procedural success and an excellent safety profile. It can be used as a stand-alone treatment or in adjunction to other specific tools.

Conclusion
Nowadays, endovascular techniques have significantly improved with the advent of crossing, debulking, and DCB devices. Algorithms that encompass vessel preparation allow for treatment of complex lesions, while minimizing acute complications, the risk of dissection and the need for stenting at the same time. Little data is available on the use of vessel preparation in the BTK segment, but in the SFA and popliteal artery committing to this algorithm, an adequate lesion pre-treatment is a key step to optimize acute outcomes and facilitate drug delivery into the lesion, and thus enhance the antirestenotic properties, thus leading to better long-term outcome. Safety has been demonstrated, and the algorithm leaves future therapy options open. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. They report no conflicts of interest regarding the content herein.

Address for correspondence:
Jos C. van den Berg, MD, PhD
Head of Service of Interventional Radiology
Centro Vascolare Ticino, Ospedale Regionale di Lugano, sede Civico
Via Tesserete 46, 6903 Lugano, Switzerland
Email: jos.vandenberg@eoc.ch
 

REFERENCES
1.    Picchi A, Micheli A, Limbruno U. Images in cardiology. The traumatic effect of balloon dilatation on neointimal hyperplasia: what we did not see before optical coherence tomography. Heart. 2011;97(3):265-266.

2.    Rogers JH, Lasala JM. Coronary artery dissection and perforation complicating percutaneous coronary intervention. J Invasive Cardiol. 2004;16(9):493-499.

3.    Fujihara M, Takahara M, Sasaki S, et al. Angiographic dissection patterns and patency outcomes after balloon angioplasty for superficial femoral artery disease. J Endovasc Ther. 2017;24(3):367-375.

4.    Razavi MK, Mustapha JA, Miller LE. Contemporary systematic review and meta-analysis of early outcomes with percutaneous treatment for infrapopliteal atherosclerotic disease. J Vasc Interv Radiol. 2014;25(10):1489-1496.

5.    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.

6.    Tepe G, Beschorner U, Ruether C, et al. Drug-eluting balloon therapy for femoropopliteal occlusive disease. J Endovasc Ther. 2015;22(5):727-733.

7.    Banka VS, Kochar GS, Maniet AR, Voci G. Progressive coronary dilation: An angioplasty technique that creates controlled arterial injury and reduces complications. Am Heart J. 1993;125(1):61-71.

8.    Barbee KA, Macarak, EJ, Thibault LE. Strain measurements in cultured vascular smooth muscle cells subjected to mechanical deformation. Ann Biomed Eng. 1994;22(1):14-22.

9.    Ilia R, Cabin H, McConnell S, Cleman M, Remetz M. Coronary angioplasty with gradual versus rapid balloon inflation: Initial results and complications. Cathet Cardiovasc Diagn. 1993;29(3):199-202.

10.    Micari A, Vadalà G, Castriota F, et al. 1-year results of paclitaxel-coated balloons for long femoropopliteal artery disease: Evidence from the SFA-Long Study. JACC Cardiovasc Interv. 2016;9(9):950-956.

11.    Solar RJ, Meany DF, Miller RT, Rahdert DA, Radcliff MB, Rieß G, Ischinger TA. Technical realization and results of a new angioplasty balloon for application of increased focal stress. Germ J Cardiol. 1995;84(4,Suppl 1):227.

12.    Solar RJ, Meany DF, Miller RT, Rahdert DA, Radcliff MB, Ischinger TA. Use of a new focused force angioplasty device to facilitate low pressure PTCA. J Invasive Cardiol. 1995;7(Suppl 1):56C.

13.    Solar RJ, Meany DF, Miller RT, Rahdert DA, Radcliff MB. Enhanced lumen enlargement with new focused force angioplasty device. Circulation. 1995;92(8):I-147.

14.    Zorger N, Manke C, Lenhart M, et al. Peripheral arterial balloon angioplasty: Effect of short versus long balloon inflation times on the morphologic results. J Vasc Interv Radiol. 2002;13(4):355-359.

15.    Krishnan P, Faries P, Niazi K, et al. Stellarex drug-coated balloon for treatment of femoropopliteal disease: Twelve-month outcomes from the randomized ILLUMENATE pivotal and pharmacokinetic studies. Circulation. 2017;136(12):1102-1113.

16.    Solar RJ, Ischinger TA. Focused force angioplasty: theory and application. Cardiovasc Radiat Med. 2003;4(1):47-50.

17.    Miller RT, Rahdert DA, Radcliff MB, Solar RJ. Finite element analysis of balloon angioplasty: mechanism of plaque expansion. AHA Sci Conf Func Struct Asp Vasc Wall. 1995.

18.    Ohman EM, Marquis JF, Ricci DR, et al. A randomized comparison of the effects of gradual prolonged versus standard primary balloon inflation on early and late outcome: Results of a multicenter clinical trial. Perfusion Balloon Catheter Study Group. Circulation. 1994;89(3):1118-1125.

19.    Manninen HI, Söder HK, Matsi PJ, et al. Prolonged dilation improves an unsatisfactory primary result of femoropopliteal artery angioplasty: Usefulness of a perfusion balloon catheter. J Vasc Interv Radiol. 1997;8(4):627-632.

20.    Söder HK, Manninen HI, Räsänen HT, Kaukanen E, Jaakkola P, Matsi PJ. Failure of prolonged dilation to improve long-term patency of femoropopliteal artery angioplasty: Results of a prospective trial. J Vasc Interv Radiol. 2002;13(4):361-369.

21.    Baumann F, Fust J, Engelberger RP, et al. Early recoil after balloon angioplasty of tibial artery obstructions in patients with critical limb ischemia. J Endovasc Ther. 2014;21(1):44-51.

22.    Mehrotra S, Paramasivam G, Mishra S. Paclitaxel-coated balloon for femoropopliteal artery disease. Curr Cardiol Rep. 2017;19(2):10.

23.    Baumhäkel M, Chkhetia S, Kindermann M. Treatment of femoro-popliteal lesions with scoring and drug-coated balloon angioplasty: 12-month results of the DCB-trak registry. Diagn Interv Radiol. 2018;24(3):153-157.

24.    Scheinert D, Peeters P, Bosiers M, O’Sullivan G, Gershony G. 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):1034-1039.

25.    Bosiers M, Deloose K, Cagiannos C, Verbist J, Peeters P. Use of the AngioSculpt Scoring Balloon for infrapopliteal lesions in patients with critical limb ischemia: 1-year outcome. Vascular. 2009;17(1):29-35.

26.    Lugenbiel I, Grebner M, Zhou Q, et al. Treatment of femoropopliteal lesions with the angiosculpt scoring balloon – Results from the Heidelberg PANTHER Registry. Vasa. 2018;47(1):49-55.

27.    Mustapha JA, Lansky A, Shishehbor M, et al. A prospective, multi-center study of the chocolate balloon in femoropopliteal peripheral artery disease: The Chocolate BAR registry. Catheter Cardiovasc Interv. 2018;91(6):1144-1148.

28.    Sirignano P, Mansour W, d’Adamo A, Cuozzo S, Cappocia L, Speziale F. Early experience with a new concept of angioplasty nitinol-constrained balloon catheter (Chocolate®) in severely claudicant patients. Cardiovasc Intervent Radiol. 2018;41(3):377-384.

29.    Binyamin G, Orosz K, Konstantino E & Holden A. Early results for the Chocolate Touch paclitaxel-coated PTA balloon catheter for the treatment of femoropopliteal lesions. Ital J Vasc Endovasc Surg. 2018;25(4):302-308.

30.    Katsanos K, Spiliopoulos S, Reppas L, Karnabatidis D. Debulking atherectomy in the peripheral arteries: Is there a role and what is the evidence? Cardiovasc Intervent Radiol. 2017;40(7):964-977.

31.    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.

32.    Zeller T, Langhoff R, Rocha-Singh KJ, et al. Directional atherectomy followed by a paclitaxel-coated balloon to inhibit restenosis and maintain vessel patency. Circ Cardiovasc Interv. 2017;10(9):e004848.

33.    Stavroulakis K, Schwindt A, Torsello G, et al. Directional atherectomy with antirestenotic therapy vs drug-coated balloon angioplasty alone for isolated popliteal artery lesions. J Endovasc Ther. 2017;24(2):181-188.

34.    Mustapha J, Gray W, Martinsen BJ, et al. One-year results of the LIBERTY 360 study: Evaluation of acute and midterm clinical outcomes of peripheral endovascular device interventions. J Endovasc Ther. 2019;26(2):143-154.

35.     Kokkinidis DG,  Armstrong EJ. Emerging and future therapeutic options for femoropopliteal and infrapopliteal endovascular intervention. Interv Cardiol Clin. 2017;6(2):279-295.

36    Khan S, Li B, Salata K, et al. The current status of lithoplasty in vascular calcifications: A systematic review. Surg Innov. 2019;26(5):588-598.

37.    Brinton T, Brodmann M, Werner M, et al. Safety and performance of the shockwave medical Lithoplasty® system in treating calcified peripheral vascular lesions: 6-month results from the two-phase DISRUPT PAD Study. JACC. 2016;68(18):B314.

38.     Brinton TJ, Illinda U, Brodmann M. Lithoplasty for the treatment of calcified SFA lesions: the DISRUPT PAD study program. Cardiovascular and Interventional Radiological Society of Europe. CIRSE 2016. Spain. 2016;39:S157.

39.    Brodmann M, Werner M, Brinton TJ, et al. Safety and performance of lithoplasty for treatment of calcified peripheral artery lesions. J Am Coll Cardiol. 2017;70(7):908-910.

40.    Adams G, Shammas N, Mangalmurti S, et al. Intravascular lithotripsy for treatment of calcified lower extremity arterial stenosis: Initial analysis of the Disrupt PAD III Study. J Endovasc Ther. 2020;27(3):473-480.

41.    Brodmann M, Holden A, Zeller T. Safety and feasibility of intravascular lithotripsy for treatment of below-the-knee arterial stenoses. J Endovasc Ther. 2018;25(4):499-503.

42.    Norgren L, Hiatt WR, Dormandy JA, et al. The next 10 years in the management of peripheral artery disease: Perspectives from the ‘PAD 2009’ conference. Eur J Vasc Endovasc Surg. 2010;40(3):375-380.

43.    Madhavan MV, Shahim B, Mena-Hurtado C, Garcia L, Crowley A, Parikh SA. Efficacy and safety of intravascular lithotripsy for the treatment of peripheral arterial disease: an individual patient-level pooled data analysis. Catheter Cardiovasc Interv. 2020;95(5):959-968.