[Abstract].
This review reviews new advances and evidence in the field of endoluminal therapy for peripheral arterial disease (PAD) over the past year. These new advances include various new techniques for endoluminal therapy, such as stent design, further improvements in plaque removal devices, and the development and application of drug-coated balloons, with the aim of improving the success rate of treatment with endoluminal techniques, particularly for the treatment of long-segment occlusive lesions. Numerous clinical studies continue to provide new evidence to test the immediate and long-term effects of various treatments and provide an important reference for clinical work, but most of them are still flawed for various reasons.
In the past year, endoluminal therapy in peripheral arterial disease (PAD) has continued the momentum of previous rapid advances, with new technologies and devices being developed and put into clinical use. There has also been much progress in the field of evidence-based medicine, with a series of multicenter randomized controlled clinical studies being conducted and new findings being published to further guide clinical work and decision making, driving the paradigm shift from empirical medicine to evidence-based medicine.
Evidence for endovenous treatment of PAD
The question of whether patients with PAD with mild to moderate claudication should be treated conservatively or surgically, and which approach has better long-term outcomes, has long been controversial. The famous MIMIC31 is an international multicenter randomized controlled study designed to address this issue. The study was divided into two parts, with mild to moderate claudication in combination with main iliac or femoral N artery lesions, and was designed to compare whether endoluminal treatment of PTA had better medium to long-term outcomes than conservative treatment, including supervised exercise and best medical treatment. The final results of the study were published in 2008 and showed significant efficacy in the intraluminal PTA group over the conservative treatment group, with a 38% (p = 0.04) increase in walking distance in the femoral N artery lesion group and a 78% (p = 0.05) increase in walking distance in the main iliac artery group at 24 months follow-up compared to the conservative treatment group. Unfortunately, however, only 127 of the 340 subjects originally planned for this study were actually enrolled, including 93 in the femoral N artery group and 34 in the main iliac artery group. A significant number of subjects were originally randomized to the PTA group but did not undergo PTA as planned because their symptoms subsequently resolved on their own; in addition, 15% of the subjects were unable to complete the scheduled follow-up because their physical condition was too poor (e.g., poor cardiopulmonary function to be evaluated with the Treadmill test). The final conclusion of the MIMIC3 study is that, despite the efficacy of PTA, the aggressive use of endoluminal therapy in patients with mild to moderate claudication, especially in patients with severe co-morbidities, needs to be carefully considered in view of its complications and relatively expensive medical costs.
In patients with severe claudication and critical limb ischemia (CLI), it is generally accepted that open bypass surgery has good long-term results but relatively high surgical trauma and risk, while endoluminal treatment is relatively less invasive but has relatively poor long-term results. However, this view has long lacked convincing evidence to support it. The multicenter randomized controlled study BASIL (Bypass versus Angioplasty in Severe Ischemia of the Leg) was designed to address this controversial point.2 The study lasted for 5.5 years, with 452 subjects randomized to the study, and focused on comparing the intermediate and long-term outcomes of open bypass surgery and PTA in patients with CLI. The results of this study were also published in 2008. The results of this study, also published in 2008, showed no significant difference in long-term limb-preserving survival between the open surgery and PTA groups (HR 1.07, 95% CI 0.72-1.6), which seems inconsistent with the expected results of the study design. Upon deeper analysis of the reasons, the BASIL study had the same shortcomings as other RCT studies, such as small sample size, inconsistent inclusion criteria (degree of limb ischemia, severity of arterial lesions), and difficulty in adherence to follow-up leading to discontinuous data. In the present study, only 48% of the subjects were followed up to 3 years, and only 22% were followed up to 4 years, and the overall survival rate of subjects at 4 years was only 50-60%, which may lead to biased results due to the small sample size. The results were not representative.
Drug eluting stent (Drug eluting stent)
The SIROCCO multicenter clinical study3,4 concluded in 2006, comparing drug-eluting nitinol stents with bare stents for the treatment of SFA lesions, showed a slightly higher patency rate with drug-eluting stents than with bare stents at 6-month follow-up, but the results at 24-month follow-up were not significantly different, at 24% and 25%, respectively. This result differs significantly from previous coronary treatment data, which may be due to factors such as anatomical and physiological differences between SFA and coronary arteries and differences in stent drug coating concentrations. The ongoing ZILVER uncontrolled clinical study5 evaluating the efficacy of the novel drug-eluting nickel-titanium alloy stent Zilver PTX (COOK) for the treatment of supraclinoid artery lesions is planned to enroll 480 participants, including multiple centers in the United States, Germany, and Japan, and preliminary results are encouraging, with a total of 435 participants followed up for 6 months, a free from TLR rate (Free from TLR (free from TLR) rate of 96% and stent fracture rate of 1%, and 200 participants at 12-month follow-up with a free from TLR rate of 88% and stent fracture rate of 2%.
Regarding the use of drug-eluting stents in infrapopliteal artery lesions, Scheinert6,7 et al. published the results of a randomized controlled clinical study comparing Cypher (CORDIS) and balloon-expandable bare stents for infrapopliteal artery lesions. The inclusion criteria were lesion length less than 3 cm and only one stent placement. The study was divided into two groups of 30 cases each, with a total of 60 cases and a mean follow-up time of 9.3 months, with cumulative major adverse event rates of 10% and 46.6% in the two groups, restenosis rates of 1.8% and 53% in the two groups, and TLR of 0 and 23.3%, respectively, with favorable results for drug-eluting stents. Another multicenter randomized controlled study comparing the efficacy of another drug-eluting stent, Xience V (everolimus eluting stent, ABBOTT), with the balloon-expandable bare stent Multilink vision (ABBOTT) in infrapopliteal artery lesions was initiated this year in Europe and is ongoing.
Self-expanding stents for the infrapopliteal artery
Although drug-eluting balloon-expandable stents have shown good results in the infrapopliteal artery, there are still concerns about the potential for stent fracture if the stent is used in a tortuously calcified artery (e.g., anterior tibial artery) or in a proximal ankle artery that is susceptible to compression. small, compatible with the 018 guidewire system, can be used in arteries as small as 2 mm in diameter, and has a small delivery profile that allows passage through a 4F sheath. Recently published clinical studies8,9 have shown a 20.9% in-stent bidirectional restenosis rate and a maximum cumulative limb preservation rate of 95.9% at 1 year postoperative follow-up.
Stented vessel (Stentgraft)
Viabahn is a self-expanding nickel-titanium alloy stent lined with PTFE grafts, formerly known as Hemobahn, and is currently the only stent vessel approved by the FDA for use in SFA lesions. Its advantages include complete coverage of the lesioned segment, which isolates plaque and appendage thrombus and reduces intimal hyperplasia, and the overall flexibility of the stent, which is less likely to fracture. In a recently published clinical study,10 the average lesion length of the enrolled cases was 25.6 cm, the average stent vessel diameter was 5.7 cm, and the average number of stent vessels applied per limb was 2.3; at 1-year postoperative follow-up, the first- and second-stage patency rates were 73.5% and 83.9%, respectively, almost as high as that of the above-knee artificial vessel bypass. Another global multicenter RCT, VIBRANT11, comparing Viabahn and self-expanding nitinol bare stents for SFA efficacy, is currently underway.
Drug coated ballon
Following the success of coronary applications, drug-coated balloons are also being tried in PAD lesions, and preliminary results from several published clinical studies12.13 are satisfactory, suggesting that this approach may reduce the incidence of postoperative restenosis in the femoral N and infrapopliteal arteries. In Europe, a multicenter randomized controlled clinical study investigating the efficacy of drug-coated balloons for BTK lesions in patients with CLI has just been initiated (PICCOLO).
Excimer laser-assisted angioplasty (ELA)
The excimer laser emits short-wave UV pulses to penetrate and destroy atherosclerotic plaques, with the advantage of using photochemical effects to break molecular bond structures rather than thermal effects to remove the lesion, thus minimizing the thermal effects on the vessel wall. It can be mainly used to treat long segment stenotic lesions, remove the attached plaque, reduce the volume load and improve the long-term efficacy; it can also be applied to chronic occlusive CTO lesions that cannot be passed by using conventional methods, which is also called Step by step technique, that is, the laser probe follows the opening guidewire and uses the laser to clear the lesions deposited in the vessel to ensure the passage in the true lumen, but in actual operation, it is difficult to However, in practice, it is difficult to ensure that the guidewire is completely inside the true lumen and often enters partially into the subendothelium. The largest excimer laser catheter currently available is 2.5 mm in diameter, so balloon dilation is often required to achieve the desired lumen diameter after laser treatment. The recent advent of the Turbo Booster controlled laser system allows for adjustment of the direction of the laser beam, thus broadening its application to 4 mm to 7 mm diameter arteries. The recent LACI (Laser Assisted Angioplasty for Critical Limb Ischemia) study, the results of which were published by Laird JR et al.14,15 is a multicenter clinical study evaluating excimer laser (Spectranetics, USA) assisted angioplasty in 127 subjects. A total of 155 severely ischemic limbs were treated with an average of 2.4 lesions per procedure. The results showed a 93% limb salvage rate at 6 months follow-up, a Free from TLR rate of 86% at 6 months, and a 72% technical success rate with the Step by step technique for chronic occlusive lesions where the guidewire could not be passed. However, laser treatment alone was applied in only 4% of all cases, and the vast majority required balloon-assisted dilatation shaping.
Atherectomy devices (plaque removal devices)
This type of device is used to remove or reduce intimal plaque by cutting, rotating, or grinding. similar to excimer laser, this device can theoretically reduce intimal plaque volume, reduce the possibility of entrapment and elastic retraction, thus increasing the effectiveness of balloon dilation, avoiding the need for stenting, and may reduce restenosis and improve long-term outcomes. silverhawk is the most commonly used type of plaque removal device with controlled orientation, but a review Zellar et al16,17 reported a group of 36 patients with 49 distal inguinal lesions with a mean length of 46 mm, a mean diameter stenosis rate of 89%, occlusion in 22%, and in-stent restenosis in 18%, and balloon dilatation after treatment with the Silverhawk in 38% and stent placement in 4% due to entrapment formation. Stents were placed in 4% due to entrapment. In this group, the patency rates were 67% and 91% for stage I and stage II, respectively, at 1-year follow-up, and 60% and 80%, respectively, at 2-year follow-up. The authors concluded that Silverhawk treatment was most effective for first-time lesions, non-calcified lesions, and relatively short lesions. Most of the literature reports a low incidence of distal embolization with Silverhawk; however, Suri et al18 made a different finding when they treated 10 femoral N artery lesions with Silverhawk while applying a distal thrombus protection device (filterwire) and found that each case could capture plaque debris ranging from 0.5 mm to 10 mm in diameter, which suggests that the incidence of distal embolism may have been greatly underestimated.
Cryoballoon (Cryoplasty)
The principle of the cryoballoon technique is to deliver cryogenic energy to the arterial wall via an intraluminal balloon, which, combined with radial dilatation forces, performs angioplasty and has been preliminarily shown to be effective in reducing clot formation and preventing vascular retraction, thereby avoiding the application of stents.19,20 A multicenter clinical study published by Das TS et al19,20 included a total of 108 patients with CLI, and the application of cryoballoons for the treatment of infrapopliteal arterial lesions resulted in an immediate procedural success rate ( successful dilatation and shaping with less than 50% residual) was 97%, with only 1 case (0.9%) producing a clamping affecting blood flow, 2 cases with residual stenosis greater than 50%, and 3 cases in which stents were applied due to unsatisfactory results (2.7%). At 180 days postoperative follow-up, 93% of patients avoided high level amputation and 85% avoided high level amputation at 365 days follow-up, but 21% of limbs required secondary intervention.
Overall, although endoluminal techniques have been used for PAD for nearly four decades, with a variety of new techniques and devices emerging and a series of clinical studies evaluating various treatments, there is still a lack of authoritative evidence to support the superiority or inferiority of any one revascularization technique. Most of the current PAD clinical study designs have numerous shortcomings, such as too small sample size, inability to achieve complete randomized control, inconsistent clinical assessments, and interference from commercial interests.
The most common problem is that the sample size is too small or the follow-up information is not continuous, leading to biased analysis of the results. Since most patients with PAD have numerous comorbid medical conditions, the natural course and overall prognosis are relatively poor, and local intrathecal treatment cannot fundamentally improve the systemic condition, which can greatly increase the difficulty of clinical study enrollment and follow-up. The complexity of comorbid diseases makes it difficult to standardize and randomize treatment protocols, and often requires individualized protocols for different patients. Another common problem is the inconsistent selection of lesion severity and clinical efficacy assessment indexes, which leads to a lack of comparability between studies and thus makes it difficult to provide convincing evidence. In recent years, some investigators have started to introduce assessment metrics for coronary studies, such as TLR (Target lesion revascularization) and Binary Restenosis, to replace the traditional patency rate (including primary, assisted, secondary patency). Of course, the classical limb preservation rate and survival rate are still used as the primary endpoint for outcome assessment.