Percutaneous Treatment of Peripheral Arterial Chronic Total Occlusions

Device Options and Clinical Outcomes

Introduction

The number of percutaneous revascularization procedures performed for symptomatic peripheral arterial disease (PAD) has significantly increased over the past several years.¹ Traditionally, the use of percutaneous techniques were limited to certain anatomic subsets, such as stenosis or focal occlusions, with surgical treatment preferred for more extensive disease.² More recently, endovascular specialists are facing the challenges of treating commonly- encountered peripheral chronic total occlusions (CTOs). Furthermore, unlike the coronary circulation, these occlusions are often long and associated with other features of complexity. The two primary issues concerning these lesions are the ability to safely achieve initial angiographic success and the longterm durability of therapy. This article will focus on the current status of treating lower extremity peripheral CTOs and expected clinical outcomes.

Distribution of Occlusive Disease

The distribution of PAD, including CTOs, varies with multiple factors, such as age and the presence of cardiovascular risk factors. Aortoiliac disease is associated with young age, females, and current smokers.^3,4 Femoropopliteal involvement in occlusive PAD is extremely common and, in one series, was present in 80% of symptomatic patients undergoing angiography.³ The predilection of disease in this segment may be due to its conduit-like nature, with no or few major branches, and torsion or stretching resulting from limb movement. These characteristics may cause relatively more damage of the vaso vasorum and endothelium than other limb segments, leading to accelerated atherosclerosis.⁵ Additionally, the flow characteristics following the development of a stenosis may promote long occlusions. Infrapopliteal disease is associated with diabetes mellitus, and diffuse and occlusive disease is common. Despite the complex nature of infrapopliteal disease, endovascular techniques have acceptable limb salvage rates.^6–8 This approach, therefore, may be increasingly used for CTOs in patients with limited surgical options, due to comorbidities or lack of bypass conduits or target vessels. Overall, CTOs are more the norm than the exception in PAD. The decision to attempt percutaneous revascularization of CTOs depends on many factors, such as severity of symptoms, and lesion characteristics, including location, calcification and length, and operator experience and institutional availability of the specialized devices discussed.

Diagnostic Considerations Prior to Intervention

The treatment of CTOs involves a fundamental understanding of the management of PAD in general. The level of occlusive disease can often be determined based on history and physical examination, including an ankle brachial index. Segmental limb pressures and duplex ultrasound are also routinely used as initial diagnostic modalities to determine the level and extent of PAD. Imaging studies, either CT or MR angiography, should be considered in patients that are candidates for revascularization. Although angiography remains the gold standard for diagnosis and allows for both anatomic and hemodynamic assessment of PAD, noninvasive imaging prior toangiography is useful in many respects. For patients with renal insufficiency, the risks of noninvasive imaging must be weighed against the potential information gained. Contrast nephropathy from CT angiography, similar to invasive angiography, can be minimized with appropriate prophylactic measures, such as intravenous hydration, sodium bicarbonate infusion, and N-acetylcycteine.

Magnetic resonance angiography (MRA) using gadolinium is much less likely to cause nephrotoxicity, but its use in patients with advanced renal disease has recently been associated with nephrogenic systemic fibrosis.⁹ This acquired condition, which has no clear treatment, causes fibrosis of the skin and other organs and results in significant morbidity and mortality. Therefore, gadolinium studies should be avoided in patients with acute renal failure or chronic kidney disease, with a glomerular filtration rate (GFR) < 30 ml/min or on dialysis. When total occlusions are identified, the length of the occlusion and, often collateral supply, can be identified. When CT angiography is used, the degree of calcification can also be gauged. These noninvasive techniques may provide incremental information about the true length of a CTO segment compared to angiography, as the retrograde filling of the distal segment is often more complete. Involvement of arterial segments that are more difficult to treat percutaneously, such as the common femoral artery and the popliteal artery, can be identified and, in some cases, surgical revascularization may be preferred to the percutaneous approach. In addition to identifying the extent of disease, preintervention imaging can be used to plan the access site(s) and determine if an antegrade or retrograde approach is more favorable. Furthermore, at the time of the intervention, a complete diagnostic angiogram may not need to be performed, shortening procedure time and decreasing contrast use. In terms of the morphologic characteristics of obstructive lesions, the TransAtlantic inter-Society Consensus (TASC) classification is commonly used to describe disease extent.² In brief, lesions are divided into four types A through D, with increasing complexity, and defined for each arterial segment: aortoiliac, femoropopliteal, and infrapopliteal. For femoropopliteal disease, a focal stenosis or occlusion < 3 cm is an example of a type A lesion. Occlusions > 5 cm or multiple lesions are type C and longer complete occlusions are type D. The recent guidelines of the management of patients with PAD that was developed by members of multiple specialties, including cardiology, vascular surgery, interventional radiology, and vascular medicine, address the endovascular treatment of claudication and critical limb ischemia (CLI).¹⁰ For patients with lifestyle- or vocation-limiting claudication and nonresponsive to exercise or pharmacologic therapy, endovascular intervention is the preferred revascularization strategy for TASC type A lesions. No specific recommendations are given based on other TASC types, but intervention is acceptable if there is a favorable risk benefit ratio. The guidelines, therefore, leave most of the decisions regarding the appropriate revascularization strategy to the treating physicians and endovascular specialists. Many of the approaches and devices discussed in this review can be used to safely and successfully treat TASC type D lesions that were previously in the domain of the surgeon. There remains an issue of durability for long CTOs, particularly infrainguinal; therefore, patient selection and close follow up with reintervention, if needed, are keys to optimal longterm patency.

Techniques for Crossing CTOs

Standard guidewire manipulation. Standard guidewire recanalization should initially be attempted, even for long, occlusive lesions. Although the inability to remain intraluminal or re-enter the true lumen distally are the main reasons for failure of this technique, there is still a relatively high chance of success. For aortoiliac lesions, an ipsilateral retrograde femoral approach is usually the simplest, but an alternative approach from contralateral femoral or brachialaccess may be needed. For superficial femoral artery (SFA) lesions, a contralateral femoral approach with a crossover sheath is usually needed, but for more distal lesions, such as infrapopliteal, an antegrade femoral approach may be preferable, so that device torquability and pushability is optimized. In difficult cases, an alternative access site or bilateral approach to the CTO should be considered.^11–15

The most straightforward strategy for approaching CTOs is the use of the combination of a hydrophilic guidewire and a low-profile support catheter, such as a 4-Fr or 5-Fr Glide Catheter (Terumo Medical Corporation, Somerset, New Jersey) or a .035" Quick Cross (Spectranetics, Colorado Springs, Colorado). A .035- inch Glidewire (Terumo Medical Corporation) has a hydrophilic coating and a solid core that can often penetrate the proximal cap of the occlusion. An angled Glidewire is usually preferred, due to its steerability, but a straight Glidewire in a straight or angled support catheter is another option if initial attempts fail. Once the proximal occlusion is penetrated, the wire and support catheter are advanced in a stepwise fashion, with the wire tip straight or in a narrow loop configuration. Angiography can be performed through the sheath if it is required to assess wire position in relation to the vessel distal to the CTO, but, often, vessel calcification or road map imaging can be used as a landmark. Injections through the support catheter are discouraged, as passage is often partially subintimal and contrast staining and compression of the lumen can occur. Either an intralumenal or entirely subintimal approach can be used.¹⁶ When the wire is at the distal edge of the occlusion, reentry into the true lumen is the next step. The creation of subintimal dissection distal to this point should be minimized, so as to avoid extending the lesion length or compromise collateral flow. If attempts with the .035" guidewire fail, stiff .018" or .014" wire designed for CTOs may be successful. Once the wire is in the distal true lumen, the support catheter is advanced and a contrast injection can be performed through the catheter to confirm location and measure distal pressure. The dilation component of the procedure can be completed with a number of devices, most commonly balloon angioplasty (PTA), with self-expanding nitinol stents for suboptimal PTA results. Alternatively, laser or atherectomy devices can be used, although this approach does not achieve substantial luminal enlargement in larger arteries.

The success rate for crossing CTOs with the guidewire technique varies widely. In aortoiliac and femoropopliteal disease, technical success is reported from 71–87%.^10,17 Several factors, such as lesion length, calcification, operator experience, and patency of runoff vessels may influence success rates.

Re-entry catheters. In cases where the true lumen cannot be reentered distally from the subintimalspace with the guidewire, re-entry devices may be an option. Two devices are available, the Pioneer catheter (Medtronic Vascular) and the Outback (Cordis Corporation, Miami, Florida). Both devices are best suited for vessels that are not heavily calcified and have a well-visualized distal vessel. Briefly, the Pioneer has two .014" wire ports, one with a hollow core nitinol needle. The needle is rotated towards the vessel lumen using intravascular ultrasound guidance (Volcano Corporation, Rancho Cordova, California). The needle is advanced into the lumen and a .014" wire is advanced and secures intraluminal position as the device is withdrawn. With the Outback catheter, fluoroscopic imaging is used to direct a 22-gauge cannula for distal vessel entry. Orthogonal angiography and a fluoroscopic marker provide orientation of the tip toward the reentry site and an angled nitinol needle is advanced into the vessel into the true lumen.

Early small series showed favorable outcomes with procedural success in the absence of complications for both devices.^18–20 A retrospective review of 52 consecutive peripheral CTO cases at a single institution showed that procedural success was 100% with the availability of the Pioneer catheter, compared to 76% prior to having a re-entry device with similar complication rates.²¹ Re-entry devices are also very effective for lesions that failed prior guidewire attempts. In a study of 87 previously attempted CTOs (58 iliac and 29 SFA), a re-entry device, either Pioneer or Outback, resulted in procedural success in 24 lesions that could not be reentered with a wire onsecond attempt. No bleeding was reported at the site of lumen reentry, although 4 cases of PTA site bleeding were observed, all in iliac interventions. These were treated with covered stents in 2 cases and uncovered stents in the others.²² In summary, the re-entry catheters will allow endovascular specialists to pursue more difficult CTOs. A caveat is that caution must be exercised, particularly in the aortoiliac vessels, due to the possibility of perforation. The ultrasound-guided device may be preferable in this circumstance and covered stents should be readily available.

Alternative Crossing Approaches

There are CTOs that have characteristics that are not favorable for the standard wire or subintimal approach. They include occlusions that are flush with a major sidebranch or collateral supply, such as the ostial SFA, vessels with heavy calcification, those with diffuse disease in the reconstituted segment, and those involving segments, such as the common femoral or popliteal artery, where stenting is best avoided. In these cases, other device options can be considered and are discussed below.

Blunt microdissection. The Frontrunner catheter (Cordis Corporation) is a blunt microdissection device that can penetrate the hard caps of fibrocalcific plaques and is approved for both coronary and peripheral CTOs. The device is advanced into the occlusion and the actuating jaws are opened to create plaque fracture planes. The catheter is slightly withdrawn and the jaws are allowed to close. Then, the catheter is advanced further into the occlusion. If successful, a .014" wire can ultimately be passed into the distal lumen. The ability of this device to increase overall success rates for CTO cases is unclear, but some cases of success following guidewire failure have been reported.²³

Radiofrequency ablation. The Safe-Cross wire (IntraLuminal Therapeutics, Menlo Park, California) combines a forward-looking optical coherence reflectometer with radiofrequency energy that is delivered from the wire tip. The near-infrared sensor can detect differences in the vessel wall, plaque and lumen, based on tissue characteristics. Green and red signals identify an intraluminal versus near endoluminal position, respectively and radiofrequency is delivered if the reflective signal is green. Theoretically, this capability allows the wire to remain intraluminal, which may be desired for occlusions near large collateral vessels, or that lead to diffusely disease vessels. Registries have shown promising results with the device. In 75 lower-extremity CTOs that failed guidewire attempts, 76% were successfully crossed with the device with no clinical perforations or distal embolizations.²⁴ In another small series, the Safe- Cross wire was successfully used in 18 lower extremity CTOs, with a mean length of 22.4 cm that previously failed with conventional guidewires.²⁵

Excimer laser. The 308-mm excimer laser (Spectranetics) ablates tissue without thermal injury by utilizing fiber-optic catheters to deliver ultraviolet energy in short pulse durations. A theoretical advantage of the laser is its ability to ablate plaque and thrombus and therefore, minimize embolic complications. The laser has also been shown to reduce platelet aggregation.²⁶ Excimer laser atherectomy, of both peripheral and coronary arteries, has been used in clinical practice and has several potential uses in peripheral CTOs. For lesions that cannot be crossed with conventional wires, a wireless laser-assisted technique can be used. In this technique, the laser is used to create a channel and then the wire and laser are advanced in a stepwise fashion.²⁷ For long CTOs, the laser may be used to identify critical segments requiring further PTA or stenting.

The safety and efficacy of excimer laser-assisted angioplasty for peripheral CTOs was investigated in a series of 318 consecutive patients with 411 SFA CTOs, averaging 19.4 ± 6.0 cm in length. The initial attempt to cross the occlusion was successful in 83.2% of limbs. A secondary attempt increased the technical success rate to 90.5%. Complications included acute closure in 1.0%, perforation in 2.2%, and distal embolization in 3.9% of limbs.²⁸ The excimer laser has also been used successfully for patients with occlusive disease and CLI.²⁹

Thrombolytic Therapy

Although shown to be effective and routinely used for acute and subacute arterial and graft occlusions, thrombolytic therapy is rarely used for CTOs because of the availability of multiple alternative techniques, bleeding risks, and the inconvenience of local intraarterial infusions and questionable effectiveness. Although thrombolyic therapy has been used for peripheral CTOs for over 30 years,^30,31 it is more successful for subacute than chronic occlusions, shorter occlusion, and lesions in larger arteries, such as the iliac.^32,33 Using thrombolytic therapy as an adjunct to PTA may increase procedural success by reducing the thrombotic component of the CTO. Local thrombolytic infusion, however, may require being continued for several days to achieve success. At the least, thrombolytic therapy should be considered part of the CTO armamentarium and may be useful when other strategies are ineffective.³⁴

Ultrasound Therapy

In the near future, a new CTO device that utilizes high-frequency mechanical vibration to penetrateatherosclerotic plaque material to cross coronary and peripheral CTOs should be available. The CROSSER system (Flowcardia Inc., Sunnyvale, California) is an investigational, monorail catheter delivered over a .014" or .018" wire. The Peripheral Approach To Recanalization In Occluded Totals (PATRIOT) trial is an 85-patient US trial to determine the safety and efficacy of the device for lower extremity CTOs. This device may be useful in smaller vessels where re-entry devices cannot be used. A feasibility study in 55 coronary CTO lesions showed clinical success of 76%, without any perforations.³⁵

Durability of Peripheral CTO Interventions

Acute procedural success for peripheral CTOs has greatly increased with the use of the specialized devices described above, with low reported complication rates. Now the challenge in treating patients with long CTOs, or TASC type C and D lesions is maintaining patency over the long term. Unfortunately, PTA alone for CTOs is usually suboptimal, due to the large plaque burden and calcification, which leads to high dissection rates and significant vessel recoil. Also rates of restenosis due to neointimal hyperplasia of total occlusions are typically substantially higher than those of subtotal lesions. In femoropopliteal lesions, PTA primary patency is lower for CLI than for claudication, 40.8% versus 64.8%, and lower for TASC type C and D lesion, compared to TASC A and B lesions.36 The 3-year patency rates for PTA are very poor and are as low as 20% for long lesions and in patients with poor runoff.^37,38 Due to the limitations of PTA, both stenting and non-stent treatment options have emerged.

Stents. Self-expanding nitinol stents have become an important component of the treatment of CTOs. The ability to prevent elastic recoil and stabilize PTA or other device-induced dissections has improved upon acute success rates. Stenting, however, still has limitations with regards to long-term patency, particularly in the SFA. Although restenosis rates appear lower with current nitinol stents, treatment of restenosis remains an unsolved problem. There is also an issue with stent fracture that may be variable with specific stent designs, but it has been associated with restenosis rates as high as 67%.³⁹ Patency rates for stenting in CTO lesions vary depending on several factors, such as location. In iliac occlusions with a mean length of approximately 9 cm and treated with excimer laser and stenting, primary patency rates were 84% at 1 year and 76% at 4 years.⁴⁰

Evaluations of drug-eluting stents in the peripheral arterial circulation have been performed but are limited. In the SIROCCO I and II trials comparing bare metal to sirolimus-eluting stents in obstructive SFA disease, 57% and 66.7% of patients had occlusions. The bare-metal nitinol self-expanding stent arm had a binary restenosis rate of 7.7% at 6 months and overall no benefit was observed with the drug-eluting stent.^41,42 Late follow up of TASC type C lesions in these studies showed binary restenosis of 21.1% by duplex ultrasound in the bare metal stent arm and again no benefit in the sirolimus stent arm.⁴³

Another option in the future may be the use of stent grafts. The Hemobahn stent-graft was prospectively evaluated in 52 patients with mainly occlusions of the SFA. The mean length of vessel segments covered was 10.9 cm. Technical successful was 100%, but distal embolization was observed in 4 patients and an arteriovenous fistula in one. Primary patency rates at 24 months were favorable at 74.1%, with an assisted patency of 80.3%.⁴⁴ Further data are needed to determine if stent grafts offer an advantage over uncovered stents.

Excimer laser. The excimer laser was discussed above as an alternative technique for crossing CTOs. The laser can also be used for debulking. As a standalone therapy for SFA CTOs, the excimer laser resulted in a 1-year primary patency of 33.6% in one study, with assisted primary patency of 65.1%.²⁸ In the randomized controlled Peripheral Excimer Laser Angioplasty (PELA) trial, laser debulking followed by PTA was compared to PTA alone for the treatment of long SFA occlusions. The laser group less often underwent stenting and had lower complication rates with less embolization, however, 1-year patency rates were equivalent. Overall, use of the excimer laser does not appear to improve procedural durability over PTA and stenting.

Excision atherectomy. Debulking can also be accomplished with the SilverHawk atherectomy catheter (FoxHollow, Redwood City, California). The SilverHawk is a monorail catheter, requiring a .014" guidewire, with a forward-cutting carbide cutting blade that rotates at 8,000 rpm when turned on. As the catheter is advanced through the lesion, plaque is excised and collected into a nose cone. The SilverHawk can remove a large amount of tissue, but long lesions may be time consuming to treat, as they require multiple passes across the lesion with intermittent clearing of the nosecone. The potential for distal embolization has also been recognized. Atherectomy alone can be performed with this device. To date, there are no randomized trials comparing atherectomy alone or with adjunctive PTA to PTA and/or stenting. Data are available from the Treating Peripherals with SilverHawk Outcomes Collection (TALON) registry, which is a multicenter, prospective, observational database of 601 consecutive patients (748 limbs) with symptomatic lowerextremity PAD treated by plaque excision with the SilverHawk catheter. Mean lesion lengths above and below the knee were 62.5 ± 68.5 mm and 33.4 ± 42.7 mm, respectively. Procedural success was 97.6%, 73.3% of lesions were treated with atherectomy alone, and only 6.3% were stented. The 12-month rate of survival, free of TLR, was 80%. Increasing lesion length predicted higher TLR rates.⁴⁵

Cryoplasty

Cryoplasty, angioplasty and cold therapy, was developed to target mechanical injury-induced arterial restenosis. The potential advantages are a less medial injury and the stimulation of smooth muscle cell apoptosis, which may lead to positive vessel remodeling. Cryotherapy with liquid nitrous oxide is delivered via the PolarCath balloon (Boston Scientific, Natick, Massachusetts). During balloon inflation, the liquid nitrous oxide expands into gas and the balloon surface temperature is lowered to a temperature of -10°C. Following a brief treatment, the gas is removed and the balloon is warmed prior to removal. Limited data are available on the use of cryoplasty for CTOs at this time, but in a prospective registry of 102 patients with SFA PAD, 14.7% had total occlusions (< 10 cm). Overall, 85.3% were treated with cryoplasty alone (67% of CTO patients) and the remainder received stents. The clinical patency rate at 9 months was 82.2%, with primary assisted patency of 94%.⁴⁶ A 3-year follow up of a subset of these patients showed maintained durability.⁴⁷ It is unclear if cryotherapy is effective at treating longer or more complex CTOs and how it compares to therapy with PTA and/or stenting.

Conclusion

In summary, peripheral CTOs remain one of the most challenging lesions for the endovascular specialist. The device armamentarium continues to expand with the availability of re-entry devices, microdissection catheters, excimer lasers, and potential additions, such as ultrasound therapy. In addition to devices, subintimal angioplasty and utilization of multiple arterial access sites have continued to increase the rate of crossing a CTO. Although durability remains an issue, particularly in the SFA, we need to design trials that will determine optimal therapy, including the possible use of debulking with laser or atherectomy or vascular remodeling with cryoplasty. The roles of drug-eluting and covered stents are also unknown at this time. Although treatment of CTOs remains challenging and requires patience and knowledge of many devices, clinical success leads to significant improvement in the quality of life and, for some, limb salvage, and is therefore rewarding.