Comparative Efficacy and Safety of Different Balloon Angioplasty Procedures for Infrapopliteal Artery Lesions in Chronic Limb-Threatening Ischemia Patients: A Systematic Review and Network Meta-Analysis

Abstract

Background:

The optimal endovascular method to treat infrapopliteal chronic limb-threatening ischemia (CLTI) remains to be determined, given the limitations of stent use in infrapopliteal artery disease. We performed a network meta-analysis (NWM) of randomized controlled trials (RCTs) to simultaneously compare the outcomes of different balloon angioplasty procedures for infrapopliteal artery lesions in CLTI patients.

Methods:

We searched the Cochrane Central Register of Controlled Trials, Embase, and PubMed. 8 eligible RCTs involving 3 endovascular modalities or combinations (plain old balloon angioplasty [POBA], drug-coated balloon [DCB], orbital atherectomy plus plain old balloon angioplasty [OA+POBA]) were included. Primary outcomes were efficacy (12-month clinically driven target lesion revascularization [CDTLR]) and safety (12-month major amputation and all-cause mortality). We used random-effects models based on the frequentist framework.

Results:

Plain old balloon angioplasty had a higher 12-month CDTLR rate than DCB (relative risk [RR]: 2.11, confidence interval [CI]: 1.33, 3.34) in the NWM and this result was still statistically significant (RR: 0.47, CI: 0.30, 0.75) in subgroup analyses. According to the SUCRA value, in terms of 12-month CDTLR, OA+POBA was considered the best treatment (SUCRA=72.2), while POBA was considered the worst treatment (SUCRA=8.9). In terms of 12-month all-cause mortality, OA+POBA was considered the best treatment (SUCRA=95.0), while DCB was considered the worst treatment (SUCRA=12.8). In terms of 12-month major amputation, POBA was considered the best treatment (SUCRA=72.0), while DCB was considered the worst treatment (SUCRA=23.0).

Conclusions:

In infrapopliteal CLTI disease, DCB showed a significantly lower 12-month CDTLR in comparison to POBA. There is no statistically significant evidence to suggest that DCB raises safety concerns. The SUCRA values of OA+POBA indicate that it might offer a superior treatment option compared to DCB or POBA in terms of CDTLR and mortality. This advantage, however, was not sustained when major-amputation rates were analyzed. Consequently, further RCTs are required to examine the potential benefits of OA and other forms of atherectomy for managing infrapopliteal CLTI disease.

Clinical Impact

The findings of this study provide further evidence for the safety of DCB in the application of infrapopliteal CLTI disease and suggest preliminary benefits of atherectomy. These results are likely to encourage further research and application of these treatment modalities in managing infrapopliteal CLTI.POBA has been a traditional approach for treating infrapopliteal artery disease. The current evidence supports clinicians in exploring and utilizing DCB and atherectomy as better treatments.We focused on the performance of different balloon angioplasty procedures in infrapopliteal CLTI, considering the characteristics of infrapopliteal CLTI.

Keywords

peripheral arterial disease infrapopliteal artery chronic limb-threatening ischemia endovascular procedures angioplasty network meta-analysis

Introduction

More than 200 million people worldwide suffer from peripheral arterial disease (PAD), with chronic limb-threatening ischemia (CLTI) being the most severe type.¹ Clinically, CLTI is characterized by rest pain, lower limb ulcers, or gangrene (lasting more than 2 weeks).² CLTI resulting from infrapopliteal artery occlusive disease (IPOD) is often accompanied by numerous comorbidities, higher mortality rates, and increased amputation rates, posing significant challenges to clinical treatment and socioeconomics.³

Infrapopliteal blood vessels have distinct anatomical characteristics, such as smaller diameter, slower blood flow, and often severe calcification accompanying lesions. These characteristics impose limitations on the application of stents in IPOD.⁴ Besides, using stents in long lesions may be unwise as it increases the chances of restenosis and jeopardizes the long-term patient prognosis.⁵ For a long time, ordinary balloon angioplasty has been regarded as the standard treatment for IPOD, but it leads to high restenosis rate due to elastic recoil and intimal hyperplasia. This has prompted the use of novel balloon and vessel preparation methods for angioplasty, most notably drug-coated balloons (DCB) and atherectomy devices. We included existing eligible randomized controlled trials (RCTs) and conducted a network meta-analysis (NWM) to evaluate the efficacy and safety of different balloon angioplasty procedures for infrapopliteal artery lesions in CLTI patients.

Methods

Our study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines⁶ and was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42023475769).

Search Strategy and Selection Criteria

We searched the Cochrane Central Register of Controlled Trials, Embase, and PubMed from the date of their inception to Oct 8, 2023. We used the search terms “Angioplasty,” “Atherectomy,” “Endovascular Procedures,” “Drug-Coated Balloon,” “Tibial Arteries,” “Peroneal Artery,” “Peripheral Arterial Disease,” “Chronic Limb-Threatening Ischemia,” “Atherosclerosis” and “Randomized Controlled Trial.” We used the mesh words and free words of these entries to construct search terms and search in the titles and abstracts. The full search strategy was written in the Supplementary material. We also performed a gray literature search and examined the reference lists of the included studies and relevant reviews to identify other valuable articles.

The following selection criteria were employed to perform the analysis according to Population-Intervention-Comparison-Outcome-Study design (PICOS) principles. Participants(P): the inclusion criteria for the RCTs were Rutherford grade of at least 4. Intervention(I) and control(C): different types of balloon angioplasty without primary stenting. Outcome(O): 1-year result of clinically driven target lesion revascularization (CDTLR), major amputation, and all-cause death. RCTs should include at least one of the above outcomes. Study(S): RCTs published in English. When multiple articles were published by the same RCT, only one article containing the required data was included.

Data Extraction and Quality Assessment

After identifying the articles to be included in the study, we extracted the main data of the articles, including: author, year, inclusion criteria, follow-up time, patients’ age, gender, comorbidities, indicators representing efficacy and safety, etc. We used the Cochrane Collaboration Tool to assess the risk of bias of the included RCTs and performed a quality assessment for each outcome measure.⁷ Two investigators independently selected the studies, extracted the relevant information from the included trials, and assessed the risk of bias. Discrepancies were resolved by consensus, and a third investigator was consulted if necessary.

Outcomes and Data Analysis

Our outcomes were 12-month CDTLR, defined as repeat percutaneous or surgical intervention because of angiographic evidence of restenosis (≥50%) with recurrence of pain in the foot and/or the presence of a nonhealing foot lesion; 12-month major amputation, defined as amputation above the ankle; and 12-month all-cause mortality.

Before performing NWM, a network evidence map is constructed to display the name of each treatment method and the number of included studies. Each outcome is associated with its own network evidence map. Inconsistency can be analyzed using the node-splitting model and the loop-specific method.⁸ Heterogeneity at each outcome level is measured using prediction interval plots. In evaluating the similarity assumption, we comprehensively assessed the research design standards of each RCT, the basic characteristics of the patients, the definition of the primary outcome indicators, follow-up time, and loss to follow-up to determine the similarity assumption.⁸

A “comparison-adjusted” funnel plot was structured to assess the small-study effects and publication bias in each meta-analysis.

We employed a random-effects model to compute RR (Relative Risk) values and 95% confidence intervals. The results of the pairwise comparisons were presented in a league table, and RR>1 or <1 was considered to favor 1 of the 2 treatments. For each outcome, we calculated the SUCRA (surface under the cumulative ranking curve) value and created a cumulative ranking curve plots to assess the efficacy and safety of various treatment methods. SUCRA value is a statistical indicator used to evaluate the effectiveness of interventions. It quantifies the effect of interventions by calculating the area under the cumulative ranking curve, thereby comparing the pros and cons of different interventions. A higher SUCRA indicates a potentially superior treatment method. We also performed a subgroup analysis of the studies discussing DCB and plain old balloon angioplasty (POBA).

All of the analyses were performed using Stata statistical software, version 16.0.

Results

Study Selection and Assessment

803 citations were identified by the search and 8 potentially eligible articles were retrieved in full text (Figure 1).^9
–18 The 8 RCTs included 3 different balloon angioplasty methods: POBA, DCB and orbital atherectomy plus plain old balloon angioplasty (OA+POBA). Table 1 summarizes the characteristics of the included studies: 8 double-armed RCTs included 1046 subjects. The average age of the participants was 71.3 years, and 72.2% were male (one study did not report specific gender data). Four of the 8 studies were multicenter studies. Inclusion criteria of all studies are patients presenting with CLTI (Rutherford class of at least 4) and stenosis or occlusion of peroneal and/or tibial arteries. The quality evaluation charts and the prediction intervals for each outcome have been placed in the Supplementary materials (Supplementary Figures 1 and 2).

Table 1.

Characteristics of the eligible randomized controlled trials included in the network meta-analysis.

Study	Treatment arms	Number of included patients	Major inclusion criteria	Age	Lesion length (mm)	Lesionstenosis (%)	Follow-up (year)
Liistro, 2022	DCB vs POBA	23 vs 27	CLTI (Rutherford class ≥4): stenosis ≥50% or occlusion of at least 40 mm by visual estimation, located in BTK arteries with distal runoff	73.1 vs 69.6	215.4 vs 218.2	97.6 vs 96.3	1
Patel, 2021	DCB vs POBA	70 vs 68	critical limb ischemia (Rutherford category 4, 5, or 6) and stenosis of 50% or more (at visual angiographic assessment) or occlusion of at least one native infrapopliteal artery)	61 vs 64	90.3 vs 81.8	77.2 vs 78.8	1
Jia, 2021	DCB vs POBA	61 vs 59	single or sequential de novo or restenotic lesions with >70% diameter stenosis in the infrapopliteal arteries, at least 1 patent runoff vessel to the foot, Rutherford category 4 to 6 ischemia	70.7 vs 70	170.0 vs 179.9	95 vs 97	1
Liistro, 2020	DCB vs POBA	52 vs 53	CLTI (Rutherford class ≥4): stenosis ≥50% or occlusion of at least 40 mm by visual estimation, located in BTK arteries with distal runoff	75.4 vs 74.8	168.0 vs 187.0	91.5 vs 90.9	1
Haddad, 2017	DCB vs POBA	48 vs 45	patients presenting with CLI (Rutherford class 4 or greater), stenosis or occlusion ≥30 mm of at least one tibial artery	52-74 vs 53-77	/	/	1
Zeller, 2014	DCB vs POBA	239 vs 119	infrapopliteal arteries in Rutherford class 4-5-6 symptomatic critical limb ischemia patients	73.3 vs 71.7	101.5 vs 128.6	83.9 vs 86.6	5
Liistro, 2013	DCB vs POBA	65 vs 67	CLI (Rutherford class 4 or greater), stenosis or occlusion ≥40 mm of at least 1 tibial vessel with distal runoff to the foot	74 vs 75	129.0 vs 131.0	97.2 vs 97.1	5
Shammas, 2012	OA+POBA vs POBA	25 vs 25	Rutherford class 4–6 in popliteal, peroneal, and/or tibial arteries.	70.7 vs 71.8	/	/	1

DCB, drug-coated balloon; POBA, plain old balloon angioplasty; OA, orbital atherectomy, CLTI, chronic limb-threatening ischemia; CLI, critical limb ischemia; BTK, Below-The-Knee.

Figure 2 shows the network of eligible comparisons for each outcome, with the 3 treatment methods being POBA, DCB, and OA+POBA. All studies are double-armed RCTs. Because there is a lack of RCT comparing the efficacy between OA+POBA and DCB, there is no closed loop in the NWM of this article. The results comparing the above 2 treatment methods only come from indirect comparisons. We cannot use the ring inconsistency detection method to measure its inconsistency.

Network Meta-Analysis

12-month CDTLR

The results of 12-month CDTLR rates were reported in 7 RCTs.^{9,10,12
–14,16,17} We found POBA had a higher 12-month CDTLR rate than DCB (RR: 2.11, CI: 1.33, 3.34), while no significant differences were identified among the other comparisons (Figure 3). The SUCRA plot for 12-month CDTLR is shown in Figure 4. OA+POBA had the highest SUCRA values (SUCRA=72.2), followed by DCB (SUCRA=68.9), POBA (SUCRA=8.9). This suggests that OA+POBA may have a lower 12-month CDTLR, while POBA may have the highest 12-month CDTLR. The comparison-adjusted funnel plot for 12-month CDTLR was visually symmetrical, suggesting no evidence of the publication bias and small-study effect (Supplementary Figure 3B).

12-month major amputation

The results of 12-month major-amputation rates were reported in 8 RCTs.^{9
–14,16,17} We did not find any endovascular modality that had a significantly lower rate of 12-month major amputation compared to the others (Figure 3). The SUCRA plot for 12-month major amputation is shown in Figure 4. POBA had the highest SUCRA values (SUCRA=72.0), followed by OA+POBA (SUCRA=55.0), DCB (SUCRA=23.0). This suggests that POBA may have a lower 12-month major amputation, while DCB may have the highest 12-month major amputation. The comparison-adjusted funnel plot for 12-month major amputation was visually symmetrical, suggesting no evidence of the publication bias and small-study effect (Supplementary Figure 3C).

12-month all-cause mortality

The results of 12-month all-cause mortality rates were reported in 8 RCTs.^{9
–14,16,17} We did not find any endovascular modality that had a significantly lower rate of 12-month all-cause mortality compared to the others (Figure 3). The SUCRA plot for 12-month all-cause mortality is shown in Figure 4. OA+POBA had the highest SUCRA values (SUCRA=95.0), followed by POBA (SUCRA=42.2), DCB (SUCRA=12.8). This suggests that OA+POBA may have a lower 12-month all-cause mortality, while DCB may have the highest 12-month all-cause mortality. The comparison-adjusted funnel plot for 12-month all-cause mortality was visually symmetrical, suggesting no evidence of the publication bias and small-study effect (Supplementary Figure 3A).

Subgroup analysis

We conducted subgroup analyses of 7 studies on POBA and DCB based on 3 outcome measures.^{10
–14,16,17} The results of pairwise comparisons are consistent with the results of NWM. The result that DCB had a lower 12-month CDTLR rate than POBA is still statistically significant (RR: 0.47, CI: 0.30, 0.75), yet there is no statistical difference in 12-month all-cause mortality rates (RR: 1.17, CI: 0.80, 1.73) and 12-month major-amputation rates (RR 1.59, CI 0.92 2.75). Forest plots of comparison were placed in the Figure 5.

Discussion

The infrapopliteal blood vessels carry significant importance as they serve as the direct outflow tract of the femoropopliteal artery and provide direct blood supply to the foot. The patency of the infrapopliteal artery is crucial for the survival of the distal limbs. Advancements in various emerging endovascular treatment technologies have led to an increase in the intraluminal patency rate of the infrapopliteal artery. However, due to the characteristics of the IPOD, maintaining long-term patency remains challenging with the current technology. The commonly used technique, POBA, manifested satisfactory clinical outcomes for focal lesions,¹⁹ but had a higher restenosis rate when treating diffuse, long-segment, or completely occlusive lesions, with a 1-year restenosis rate possibly reaching 70%.¹² Therefore, CLTI occurring in the infrapopliteal artery presents a special challenge for endovascular treatments. Studies on below-the-knee lesions using stents and balloon-type devices have great differences in characteristics such as lesion length. We collected data from stent-related studies on below-the-knee CLTI and compared lesion lengths with those in our study. The average lesion length in the stent group was 17.1 mm,^20
–22 whereas the average lesion length in our study was 150.1 mm. Furthermore, in a study comparing PTA and primary stenting, PTA group had longer median lesion lengths (78.48 mm) compared to the stent group (27.86 mm; p<0.001).²³ Despite this, the benefits of the stent group were not greater than those of the PTA group. To provide a more accurate description of treatment methods for infrapopliteal arteries, this article focuses on 3 primary endovascular treatment methods according to the literature research: POBA, DCB, and OA+POBA.

This NWM demonstrated that DCB had a lower 12-month CDTLR than POBA. This result was statistically significant in both NWM and subgroup analysis, suggesting that DCB may have a better efficacy than POBA in infrapopliteal CLTI disease. In the analysis of mortality and major-amputation rates, we did not obtain statistically significant data proving that DCB has safety issues. OA+POBA did not produce statistically significant results, which may be attributed to the limited number of eligible articles included in the analysis. Nevertheless, OA+POBA showed promising findings as indicated by the SUCRA values, ranking highest in 12-month CDTLR and mortality. This suggests that OA+POBA may have a lower CDTLR and mortality. However, OA+POBA has a lower SUCRA value than POBA in 12-month major-amputation rate. Overall, there are no statistically significant results validating the superiority of OA+POBA compared to the other treatments. While the SUCRA value of OA+POBA showed promising outcomes in CDTLR and mortality, its advantage was diminished in the major-amputation rate analysis. Thus, the necessity for high-quality RCTs to validate these findings and accurately assess the actual benefits and amputation risks associated with atherectomy remains imperative.

Although POBA is the commonly used treatment, it has some disadvantages, including early vascular elastic recoil, intimal hyperplasia, and poor efficacy in treating calcified lesions. These issues are particularly pronounced in the infrapopliteal artery.²⁴ DCB mitigate the incidence of intravascular restenosis by inhibiting the proliferation of vascular smooth muscle cells and reducing intimal hyperplasia.^25,26 In our study, the results that DCB is more effective than POBA were statistically significant in both direct and mixed comparisons. However, DCB do not address the shortcomings of early vascular elastic recoil and the poor treatment of calcified lesions. With regard to the safety of DCB, on July 11, 2023, the U.S. Food and Drug Administration (FDA) issued a new opinion on paclitaxel drug-coated devices, stating that based on current research data and analytical review, there is no longer support for the idea that paclitaxel-coated devices carry excess risk of death in the treatment of PAD.²⁷ This is consistent with our conclusion, because the SUCRA value only suggests one possibility, and we did not obtain statistically significant data to prove that DCB increases the risk of death. Besides, in the two 5-year studies included in our study, their results both suggested that compared with POBA, there was no significant difference in the overall survival rate and major-amputation rate of patients with below-the-knee CLTI treated with DCB.^11,18 During the 5-year follow-up, paclitaxel was not associated with increased rates of major amputation or all-cause mortality.

Drug-coated balloon functions primarily by pushing solid paclitaxel particles into the vessel wall,²⁸ where it acts to inhibit proliferation. The effectiveness of DCB can be influenced by the drugs, the use of excipients and the coating technologies. The low water solubility of paclitaxel enables it to remain in the blood vessel wall for several months^29,30 and exert anti-proliferative effects at lower concentrations.³¹ Despite research indicating that only 5-20% of paclitaxel is transferred to the vessel wall,²⁸ its pharmacological effects are still evident. Excipients are essential for the efficient release and absorption of paclitaxel, with paclitaxel-only coatings demonstrating reduced effectiveness.^32,33 The coating process varies among different DCBs. In the IN.PACT DEEP trial, the IN.PACT Amphirion DCB platform is manually coated after it is folded, resulting in a distinctly inhomogeneous distribution after inflation. Most of the drug is in an exposed position, potentially leading to excessive drug loss on the way to the target lesion.³⁴ The potential for paclitaxel particles to cause embolisms in the distal vessels may explain the increased amputation rate associated with this device.³⁵ Hence, the efficacy of DCB is influenced by multiple factors, indicating the need for continuous improvement to enhance their efficacy and safety.

Severe calcification of the infrapopliteal artery poses challenges for endovascular treatment. Neither balloon angioplasty nor stenting can effectively remove calcified lesions in the arterial wall. Instead, they primarily rely on mechanical destruction to alter the compliance of the artery and increase the artery lumen.³⁶ However, for hard, eccentric lesions and severe calcified plaque, the efficacy of balloon angioplasty and stenting is very limited, which can lead to issues such as dissection, acute thrombosis, stent fracture, and restenosis.³⁷ Patients with below-the-knee CLTI have a high probability of restenosis in the early stage of intervention (within 3 months) due to elastic recoil and other reasons. Therefore, regardless of the treatment method, sufficient lumen acquisition is necessary. Endovascular atherectomy offers an effective method of lesion preparation. Currently, various endovascular atherectomy devices are used in infrapopliteal artery interventions, including directional, rotational or orbital, laser atherectomy devices, and chronic total occlusion (CTO) recanalization devices.³⁸

In Rastan’s RCT, the efficacy of directional atherectomy (DA) combined with DCB was compared to DCB alone for the treatment of long infrapopliteal lesions.³⁹ The results indicated that DA+DCB was equally effective as DCB alone. Another RCT investigating OA+DCB for calcified infrapopliteal lesions demonstrated a numerically superior primary patency rate for the OA+DCB group, with similar safety profiles between the OA+DCB and DCB groups.⁴⁰ According to current evidence, research on this type of combined therapy has demonstrated its safety and effectiveness in treating lower extremity arteries, but there is still a lack of high-quality data to prove its significant impact on reducing restenosis rates.^41,42 A retrospective study indicated a 1-year mortality rate of 18.6% and a 2-year mortality rate of 32.3% for CLTI patients undergoing endovascular treatment. The main causes of death were infectious disease (33.3%) and cardiovascular disease (30.9%).⁴³ Therefore, reducing major amputations and enhancing the quality of life for patients is the end goal to treat this disease. In our study, CDTLR and mortality SUCRA values of OA+POBA suggest that it may be the best treatment method, but it shows a lower major-amputation SUCRA value compared to POBA. This could be due to the limited sample size in the experimental group and the technical limitations at the time.

Our study has several limitations. The number of studies we included was still small, which may weaken the validity of the findings. In addition, we only selected 3 outcomes, which may result in a single and 1-sided evaluation method. It is important to establish a comprehensive evaluation system from multiple perspectives and apply it to future RCTs. We chose CDTLR rather than patency as the primary efficacy endpoint of the study, which may have an impact on the evaluation of the effectiveness of the treatment. It is also worth noting that we were unable to study the long-term efficacy of the 3 treatments in this article. Therefore, caution should be exercised regarding the long-term efficacy of positive results, and our information cannot serve as a reference for the long-term results of the treatment modality.

In conclusion, in infrapopliteal CLTI disease, DCB demonstrates a significantly lower 12-month CDTLR in comparison to POBA. This effectiveness of DCB has been verified through both NWM and subgroup analysis. There is no statistically significant evidence suggesting that DCB poses safety concerns. The SUCRA values of OA+POBA indicate that it might offer a superior treatment option compared to DCB or POBA in terms of CDTLR and mortality. This advantage, however, was not sustained when major-amputation rates were analyzed. Consequently, further RCTs are required to examine the potential benefits of OA and other forms of atherectomy for managing infrapopliteal CLTI disease.

Supplemental Material

sj-docx-1-jet-10.1177_15266028241292954 – Supplemental material for Comparative Efficacy and Safety of Different Balloon Angioplasty Procedures for Infrapopliteal Artery Lesions in Chronic Limb-Threatening Ischemia Patients: A Systematic Review and Network Meta-Analysis

Supplemental material, sj-docx-1-jet-10.1177_15266028241292954 for Comparative Efficacy and Safety of Different Balloon Angioplasty Procedures for Infrapopliteal Artery Lesions in Chronic Limb-Threatening Ischemia Patients: A Systematic Review and Network Meta-Analysis by Zelin Guo, Julong Guo, Sensen Wu, Fan Zhang, Xixiang Gao and Lianrui Guo in Journal of Endovascular Therapy

Footnotes

Correction (December 2024):

Article updated online to correct Figure 2.

Author Contributions

ZG, JG, SW, and FZ collected the data. ZG and JG contributed to the study design and interpretation of the results. JG, ZG, and SW analyzed the data and prepared the figures. ZG prepared the manuscript. ZG, JG, LG and XG revised the manuscript. All authors contributed to the article and approved the submitted version.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Key Research and Development Projects (grant nos. 2022YFC3602400 and 2022YFC3602404).

ORCID iDs

Zelin Guo

Julong Guo

Supplemental Material

Supplemental material for this article is available online.

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