Infrapopliteal peripheral arterial disease (PAD) has a high rate of limb loss within 6 months when untreated (1, 2). The overall morbidity of PAD is in the range of 3-10%, and increases to 15-20% in persons over 70 years. With the trend of the aging, the social and economic burden of PAD is considerable. Endovascular intervention, such as angioplasty, debulking, and stenting offer a less invasive method, but evidence of safety and efficacy is heterogenous (3). Infrapopliteal arterial disease is often accompanied by extensive severe calcification, lumen narrowing, and poor distal outflow tracts, significantly increasing the difficulty of endovascular therapy and resulting in high likelihood of restenosis and the need of revascularization.

Recent reports have indicated considerable results of angioplasty for the treatment of infrapopliteal artery occlusion and benefited equivalent clinical limb salvage rates to bypass surgery (4). However, plain of balloon angioplasty (POBA) has a high rate of reocclusion, revascularization and complications (embolization, dissection, bailout stenting). Theoretically, excimer laser removes biologic tissue by photochemical desorption and the injected energy would convert the tissue to vaporized fragments (5). Cool excimer laser-assisted angioplasty (CELA) can decrease the rate of residual stenosis, thromboembolization, perforation to some extent (6). Traditionally, underdeveloped application of laser resulted in poor immediate and mid-term outcomes (7, 8), while recent studies have reported satisfactory clinical outcomes in high-volume centers with refinement of laser techniques (1, 9). However, clinical efficacy of CELA for infrapopliteal arterial occlusion is inconclusive.

We aim to determine the safety and efficacy of CELA for infrapopliteal arterial occlusion by carried out this meta-analysis of prospective and retrospective cohort studies and randomized controlled trials.

Our study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for meta-analysis (Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement).

Our meta-analysis evaluated the efficiency and safety of CELA therapy vs. PTA alone for treatment of patients suffering infrapopliteal artery occlusion disease for the first time. Comparing with conventional PTA alone, CELA therapy showed a significantly higher patency of 6 months and 1 year in target lesion, offered the advantages of an increase rate free from TLR, meanwhile not increased surgery complication (embolization, bailout stenting, dissection). However, CELA could not reduce major amputation and amputation-free survival. These data provide evidence that CELA maybe a more effective and safer therapetic strategy for infrapopliteal artery occlusion.

Laser-assist angioplasty was firstly applied for vascular intervention since the early 1980s in coronary disease (14). Initially, underdevelopment use of the laser resulted in high rate of complications (perforation, dissection, and thermal injure) (15, 16). With the advance of equipment and technology, recent studies have reported some convincing result supporting laser for the treatment of peripheral artery disease. There have many meta-analyses compare the efficacy and safety between laser-assist angioplasty and POBA in iliofemoral artery occlusion, however, no meta-analysis summarized laser effectiveness on infrapopliteal artery occlusion. Our finding verified showed that CELA therapy shows superior clinical outcome over PBOA.

The importance of infrapopliteal artery patency upon clinical outcomes was recently reported by some studies (17–20). Tibial arterial patency was mandatory during the process of wound healing (4, 21, 22). Baumann F observed a prolong time of wound healing in tibial restenosis patients and a significant corroboration with TLR and POBA (20). Target lesion revascularization was necessary in 48% of patients with restenosis of the tibial artery in 73% at 12-month follow-up. Restenosis was observed in 68.8 and 74% of limbs in CLI patients undergoing tibial artery POBA after 3 months and 1 year, respectively (23, 24). In our analysis, three studies recorded the patency of target vessel during 6-month and 12-month follow-up and 3-year freedom from TLR verified that CELA has a higher patency rate and free from TLR over POBA alone. This may be due to the excimer laser can selectively ablate atherosclerotic plaques and thrombi, while reducing subintimal angioplasty (25, 26). Our findings are in accordance with the results of the study of Laird et al. that CELA can be used for complex anatomic lesions with a high technical success and admirable short-term success rates (27).

However, our finding also verified that there is no advantage of AFS and major amputation rate to CELA compared with POBA alone. Higher patency of infrapopliteal artery did not translate into high limb salvage rate. This is very similar to other studies' conclusion. Michael C represented this result as a case-selection bias, accounting that CELA was not usually used on cases where a guidewire could not be successfully access to the occlusion lesion and suggested a randomized trial to verify the result (28). Our findings are in accordance with the results of the study of Romiti et al. that significant differences in patency rate did not result in significant difference in clinical outcomes (limb salvage) (4). Based on these findings, we assumed that the increased perfusion to the target lesion was mandatory to wound healing but not for keeping tissue integrity.

Theoretically, the excimer laser can vaporize intravascular plaques, effectively remove hyperplastic tissue (29), thereby reducing the risk of ectopic embolism. Laser atherectomy can reduce the probability of dissection after PTA, the implantation of bail-out stents and avoidance of subintimal technique. Previous studies reported embolism after PTA occurred in 2.6% of the cases (30) and laser atherectomy related distal embolization occurred in 3-10% of the cases (27, 31–35). However, our findings suggested that there is no significant advantage to CELA compare to POBA in surgery complications (dissection, embolization, bail-out stenting). We represented the result as case-selection bias. Patients with CELA therapy have more probabilities to accompany by severe calcifications. Calcification lesions are related to the dissection post-PTA, ectopic embolization and bailout stents, resulting in the finding that CELA has no obvious advantage in surgical complications compared with POBA. Without a randomized clinical trial, this result is difficult to address, but admittedly the datasets are not positive.

Limitations of our analysis included the retrospective studies other than Randomized Controlled Trial (RCT) trial and relatively small samples size. Retrospective nature could lead to various biases, resulting more determinants for outcome, however, currently there is no RCT study on laser treatment of the infrapopliteal artery. The relatively small samples size magnifies the result of analysis process. The current evidence is not sufficient to represent a real-world application of CELA technology for infrapopliteal artery occlusion revascularization, however, our findings tend to mirror contemporary revascularization studies.

Our meta-analysis showed that CELA has superior patency rate (6 months and 12 months) and freedom from TLR. However, comparing to POBA therapy, CELA did not decrease amputation rate and AFS, meanwhile had no advantage in surgery complications. Considering the retrospective nature of our analysis and inherent bias shortcomings, there is no any indication for revascularization. Large-scale RCTs are needed to verify the safety and efficiency of CELA therapy to infrapopliteal artery occlusion.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

MZ and YG designed the methods, analyzed the data, and results. MZ and LQ wrote the manuscript and prepared figures. All authors have read and agreed to the published version of the manuscript.

This study was supported by the National Key Research and Development Program of China (No. 2017YFC1104100).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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