Comparison of safety and efficacy of femoropopliteal arterial disease using different dose drug-coated balloons: Systematic review and meta-analysis

Abstract

Background

Endovascular therapy with balloon percutaneous angioplasty (PTA) in the femoro-popliteal segment is frequently performed, however, long-term favorable outcomes and patency remain challenging, with restenosis rates reaching 60% post-standard balloon angioplasty. Drug-coated balloons (DCBs) have shown promise in improving these outcomes; Paclitaxel, used in DCBs, inhibits hyperplasia and smooth muscle cell proliferation, reducing restenosis; however, the optimal dose of Paclitaxel remains unclear, with high-dose (HD-DCB [>3 mg/mm²]) and low-dose (LD-DCB [<2.0 mg/mm²]) options available. This meta-analysis aims to compare the efficacy and safety of HD-DCB and LD-DCB in treating femoropopliteal arterial disease.

Methods

We followed PRISMA guidelines and conducted a comprehensive search of PubMed, EMBASE, Cochrane, Scopus, and Mendeley up to May 27, 2024. We included randomized controlled trials and cohort studies comparing HD-DCB and LD-DCB in patients with femoropopliteal arterial disease. Data were extracted on baseline characteristics, outcomes, and study quality. The Newcastle–Ottawa Scale and ROB2 tool were used for bias assessment. Outcomes included overall survival (OS), limb salvage (LS), freedom from clinically driven target lesion revascularization (CD-TLR), and major amputation.

Results

Six studies comprising 2563 patients were included. HD-DCB showed a significant benefit in limb salvage at 6 months (RR = 0.38, 95% CI = 0.18-0.78, p = .009) but not at 12 months (RR = 3.08, 95% CI = 0.14–67.13, p = .47). No significant difference was observed in overall survival between HD-DCB and LD-DCB at either 6 months (RR = 1.53, 95% CI = 0.25–9.57, p = .65) or 12 months (RR = 1.21, 95% CI = 0.17–8.84, p = .85). HD-DCB was associated with an increased risk of perioperative complications (RR = 1.90, 95% CI = 1.14–3.17, p = .01) and a higher, though not statistically significant, risk of major amputation (RR = 4.73, 95% CI = 0.54–41.52, p = .16).

Conclusion

HD-DCB may offer advantages in limb salvage over LD-DCB in the short term, but this comes with an increased risk of perioperative complications. These findings underscore the need for careful patient selection when considering HD-DCB for femoropopliteal artery disease.

Keywords

Femoropopliteal disease drug-coated balloons high-dose low-dose endovascular interventions

Introduction

Peripheral arterial disease (PAD) is a common condition whose prevalence is increasing worldwide.¹ Isolated femoropopliteal atherosclerotic disease can significantly impact patients’ quality of life, manifesting as severe chronic pain, claudication, tissue loss, and even amputation of the affected limb.² Endovascular therapies, such as drug-coated balloons (DCB), are essential for treating these lesions as they aim to restore blood flow, alleviate clinical symptoms, and preserve the limb.³ Paclitaxel is a drug used in coated balloons to inhibit hyperplasia and the proliferation of smooth muscle cells through brief exposure of the agent directly to the arterial wall.^4,5 It has been shown that DCB have a greater impact in reducing restenosis compared to standard angioplasty, which has a restenosis rate of up to 60%.^6,7 Currently, there are various devices on the market with different doses of the drug Paclitaxel. The high-dose drug-coated balloon (HD-DCB) (e.g., IN.PACT) has a dose of 3 mg/mm², while the low-dose DCB (LD-DCB) (e.g., Lutinox) has a dose of 2.0 mg/mm².^8–11 The available evidence does not conclude a significant difference in the outcomes. This meta-analysis focuses specifically on isolated femoropopliteal disease, critically evaluating the existing literature on the clinical results of low-dose and high-dose Paclitaxel-coated balloons. Which dose is more effective and safer for the treatment of this disease? Our objective is to provide a comprehensive comparison of the efficacy and safety of both therapeutic strategies, helping physicians make evidence-based decisions to optimize the treatment of isolated femoropopliteal disease.

Methods

This meta-analysis was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.¹² All study stages were performed following the Cochrane Handbook for Systematic Reviews of Interventions, version 6.3.¹³ The protocol for this meta-analysis was registered in PROSPERO on August 9th, 2024, with the protocol ID: CRD42024574228.

Criteria of the selected studies

Specific inclusion criteria were established to identify relevant studies for this meta-analysis. The study population comprised patients diagnosed with de novo or restenotic femoropopliteal lesions. Included studies were required to compare groups utilizing DCB (drug-coated balloon) angioplasty with either high-dose and low-dose paclitaxel coating. To ensure the robustness of results, included studies were limited to comparative clinical trials or observational cohort studies with a minimum of 10 participants. Studies were excluded if they did not report outcomes pertaining to DCB angioplasty with high-dose or low-dose paclitaxel coating, as well as those that involved procedures using non-drug-coated balloon angioplasty or stents. Excluded study designs included cross-sectional studies, systematic reviews, meta-analyses, case reports, and review articles. No restrictions were applied based on language or publication date.

Literature search strategy

An extensive search of the following electronic databases—PubMed (Medline), EMBASE (Excerpta Medica DataBASE), COCHRANE,¹⁴ Scopus, and Mendeley—was conducted up to May 27, 2024. The search strategy utilized specific keywords and MeSH terms related to “drug-coated balloons,” “‘femoropopliteal artery disease,” “low-dose,” and “high-dose.” Only randomized controlled trials (RCTs) and cohort studies that compared low-dose and high-dose DCBs in patients with symptomatic femoropopliteal artery disease were included.

Duplicate entries were meticulously removed using Zotero. Initially, the retrieved references underwent a screening process where titles and abstracts were evaluated. Full-text reviews were conducted as necessary. Two independent authors (M.E. and B.B.) rigorously assessed each paper for eligibility and quality, with any disagreements resolved by a third author (N.C). Furthermore, references cited within the included studies were examined and incorporated if they satisfied the eligibility criteria.

Data extraction

The process of trial selection adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹² The reference lists of all retrieved articles were additionally assessed for potential inclusion. Two authors conducted the systematic review with support from programs/platforms such as Rayyan and Zotero;¹⁵ they analyzed each article individually and independently extracted all duplicated data.

Excel spreadsheets were used to extract the following data: (1) Baseline characteristics of the studied population; (2) Summary of the characteristics of the included studies; (3) Outcome measures; and (4) Quality assessment domains.

Assessing the risk of bias

To evaluate the risk of bias in the included observational cohort studies, we utilized the Newcastle–Ottawa Quality Assessment Scale Cohort Studies.¹⁶ For the randomized controlled trial (RCT), we employed Version 2 of the Cochrane risk-of-bias tool for randomized trials (ROBS 2) from the Cochrane Handbook of Systematic Reviews of Interventions 6.3.^13,17 The evaluation of study quality was carried out in accordance with the guidelines outlined by these established tools.

Outcome measures

In this study, we performed a thorough assessment of relevant outcomes to determine the comparative efficacy of the interventions. The following outcomes were included for our analysis:

1. Overall survival (OS): The duration from the angioplasty procedure using DCB to the occurrence of death from any cause. The OS outcome was assessed using risk ratios (RR) derived from multivariate Cox regression analyses, as well as the mean difference (MD) in OS measured in months.

2. Limb Salvage (LS): Assesses the effectiveness of the intervention in maintaining the viability and function of the limb, thereby avoiding the need for amputation.¹⁸ LS was represented as HR and MD in months.

3. Freedom from clinically driven target lesion revascularization (CD-TLR): The measure of time during which patients do not require additional revascularization procedures at the target lesion site due to clinical symptoms.¹⁹ It was represented as HR and MD in months.

Statistical analysis

To assess dichotomous data, we evaluated event frequencies and totals from each study group to calculate the risk ratio (RR) and its 95% confidence interval (CI), such as overall survival, limb salvage, and freedom from clinically driven target lesion revascularization, we applied appropriate statistical methods.

The variables analyzed in this study were based on data reported in the original studies. We implemented a random-effects (RE) model using the DerSimonian-Laird method to account for variability among studies and allowing comparison.²⁰ Forest plots were utilized as a visual representation of the estimated outcomes. All statistical analyses, including the calculation of RR, were conducted using RevMan V.5.4.1 software.

Assessment of heterogeneity

To assess the heterogeneity among the included studies, Cochran’s Q-statistic was applied with a significance threshold of p < .10. Additionally, the I²-Statistic was employed to measure the extent of total variation due to heterogeneity, where values exceeding 50% indicated high levels of heterogeneity.²¹ Further exploration of heterogeneity in primary outcomes was conducted through subgroup analyses, which classified studies as multimodal based on the use of drug-coated balloon (DCB) angioplasty with either high-dose or low-dose paclitaxel coating.

Results

Study characteristics

Our analysis encompassed six studies from two countries, including one clinical trial by the COMPARE Trial, and five observational cohorts (Propensity score matching).^9,22–26 We carefully avoided duplicating the population in our outcome analysis. Of the initial 3886 patients, 2563 met our inclusion criteria. Of these, 1369 underwent LD-DCB, 1194 had HD-DCB. The PRISMA flow diagram of the study selection process can be found in Figure 1.

Figure 1.

Flow chart of literature search according to the PRISMA statement.

All included studies compared limb salvage, overall survival, and freedom from clinically driven target lesion revascularization (CD-TLR), and major amputation outcomes between HD-DCB and LD-DCB groups. Lesion volumes in the femoropopliteal arteries included both de novo and restenotic lesions. The mean age of patients was 74 years, with a gender distribution of 1551 males and 1012 females. Baseline characteristics included hypertension, smoking status, ankle-brachial index, and the presence of chronic total occlusion. The baseline characteristics of the selected studies are shown (Tables 1 and 2).

Table 1.

Main characteristics of the included studies.

#	Study ID	Country	Type of study	Total	Years of patient collecting	Group	Male	Female	Mean (SD)Age
1	Nakama, 2023	Japan	Prospective cohort (propensity score matching)	521	April 2021 to March 2022	LD-DCB	112.9 (69.2)	246	74 ± 9
1	Nakama, 2023	Japan	Prospective cohort (propensity score matching)	521	April 2021 to March 2022	HD-DCB	114.0 (69.9)	49	74 ± 9
2	Mori 2023	Japan	Retrospective cohort (propensity score matching)	320	July 2017 to June 2020	LD-DCB	105 (66)	55	74 ± 8
2	Mori 2023	Japan	Retrospective cohort (propensity score matching)	320	July 2017 to June 2020	HD-DCB	110 (69)	50	74 ± 10
3	Steiner 2022	Germany	RCT	414	2 years	LD-DCB (ranger)	132	75	68.2 ± 10
3	Steiner 2022	Germany	RCT	414	2 years	HD-DCB (in pact)	128	79	68.4 ± 9.3
4	Tomoi 2023	Japan	Retrospective cohort (propensity score match)	60	December 2018 to December 2021	LD-DCB lutonix	21 (70,0%)	9	76 ± 10
4	Tomoi 2023	Japan	Retrospective cohort (propensity score match)	60	December 2018 to December 2021	HD-DCB in pact admiral	22 (73.3%)	8	77 ± 6
5	Fujihara 2023	Japan	Prospective cohort (propensity score matching)	1.184	March 2018 to December 2019	LD-DCB	383.0 (64.7%)	209 (35.3%)	75 ± 9
5	Fujihara 2023	Japan	Prospective cohort (propensity score matching)	1.184	March 2018 to December 2019	HD-DCB	383.1 (64.7%)	209 (35.3%)	74 ± 9
6	Kodama 2024	Japan	Retrospective clinical study	64	May 2014 to March 2020	LD-DCB	15 (68.2)	7 (31.8)	73.6 ± 8.1
6	Kodama 2024	Japan	Retrospective clinical study	64	May 2014 to March 2020	HD-DCB	26 (61.9)	16 (38.1)	74.4 ± 7.9

Data presented as mean ± standard deviation or number/total (%).

Abbreviations: LD-DCB, Low dose drug-coated balloons; HD-DCB, High dose drug-coated balloons; PACSS, Peripheral Arterial Calcium Scoring System.

Table 2.

Baseline demographics and treatment characteristics of study populations.

Study information			Baseline characteristics								History of revascularization
Study ID	Total Population	Doses	Population Size	Gender Male/Female	Mean (SD)Age	Hypertension	Smoking	Diabetes mellitus	Aspirin	Citostazol	None (de novo)	Drug-coated balloon
Nakama 2023	521	LD-DCB	358	112/246	74 ± 9	NR	116	116	107	51	112.8 (69.2)	18.5 (11.3)
Nakama 2023	521	HD-DCB	163	114/49	74 ± 9	NR	120	116	112	46	111.0 (68.1)	19.0 (11.7)
Mori 2023	320	LD-DCB	160	105/55	74 ± 8	137	NR	103	NR	72	127 (79)	NR
Mori 2023	320	HD-DCB	160	110/50	74 ± 10	135	NR	98	NR	68	128 (80)	NR
Steiner 2022	414	LD-DCB	207	132/75	68.2 ± 10	180	95	63	168	NR	190 (91.8)	NR
Steiner 2022	414	HD-DCB	207	128/79	68.4 ± 9.3	188	99	76	162	NR	183 (88.4)	NR
Tomoi 2023	60	LD-DCB	30	21/9	76 ± 10	27	20	19	23	4	NR	18
Tomoi 2023	60	HD-DCB	30	22/8	77 ± 6	25	21	17	23	3	NR	18
Fujihara 2023	1,184	LD-DCB	592	383/209	75 ± 9	NR	112	399	459	149	431.0 (72.8)	NR
Fujihara 2023	1,184	HD-DCB	592	383/209	74 ± 9	NR	115	396	458	148	434.1 (73.3)	NR
Kodama 2024	64	LD-DCB	22	15/7	73.6 ± 8.1	19	6	16	18	5	NR	NR
Kodama 2024	64	HD-DCB	42	26/16	74.4 ± 7.9	35	5	24	29	8	NR	NR

Study ID	Total population	Doses	Rutherford classification				Ankle-brachial index	Chronic total occlusion	% Diameter stenosis	PACSS classification
Study ID	Total population	Doses	2	3	4	5	Ankle-brachial index	Chronic total occlusion	% Diameter stenosis	Grade 0	Grade 1	Grade 2	Grade 3	Grade 4
Nakama 2023	521	LD-DCB	19.6 (12.0)	81.6 (50.1)	28.3 (17.4)	33.5 (20.6)	0.57 ± 0.37	44.5	88 ± 12	55.9 (34.3)	20.0 (12.3)	12.2 (7.5)	27.1 (16.6)	47.8 (29.4)
Nakama 2023	521	HD-DCB	17.0 (10.4)	84.0 (51.5)	30.0 (18.4)	32.0 (19.6)	0.58 ± 0.32	47	89 ± 13	61.0 (37.4)	19.0 (11.7)	10.0 (6.1)	28.0 (17.2)	45.0 (27.6)
Mori 2023	320	LD-DCB	NR	NR	NR	NR	0.63 ± 0.27	53	90 ± 11	46 (29)	27 (17)	14 (9)	28 (18)	45 (28)
Mori 2023	320	HD-DCB	NR	NR	NR	NR	0.63 ± 0.26	49	89 ± 13	49 (31)	24 (15)	15 (9)	28 (18)	44 (28)
Steiner 2022	414	LD-DCB	23(11.1)	174 (84.1)	7 (3.4)	3(1.5)	0.65 ± 0.24	84	84.2 ± 16.9	19 (9.3)	79 (38.7)	3 (1.5)	67 (32.8)	38 (17.7)
Steiner 2022	414	HD-DCB	31 (15)	163 (78.7)	10 (4.8)	3 (1.5)	0.63 ± 0.26	89	84.2 ± 17.2	25 (12.2)	58 (28.3)	5 (2.4)	82 (40)	35 (17.1)
Tomoi 2023	60	LD-DCB	NR	NR	NR	NR	0.61 ± 0.31	4	NR	8 (26,7%)	4 (13,3%)	6 (20,0%)	5 (16,7%)	7 (23,3%)
Tomoi 2023	60	HD-DCB	NR	NR	NR	NR	0.60 ± 0.35	5	NR	8 (26,7%)	4 (13,3%)	6 (20,0%)	4 (13,3%)	8 (26,7%)
Fujihara 2023	1,184	LD-DCB	137.0 (23.1%)	209.0 (35.3%)	63.0 (10.6%)	183.0 (30.9%)	0.62 ± 0.23	149	NR	NR	NR	NR	NR	111.0 (18.8%)
Fujihara 2023	1,184	HD-DCB	122.6 (20.7%)	237.4 (40.1%)	67.2 (11.4%)	164.8 (27.8%)	0.62 ± 0.24	152	NR	NR	NR	NR	NR	108.7 (18.4%)
Kodama 2024	64	LD-DCB	9	6	0	7	0.73 ± 0.16	4	37.1 ± 10.7	3	5	5	1	8
Kodama 2024	64	HD-DCB	25	17	1	2	0.70 ± 0.20	14	37.0 ± 11.8	14	13	8	3	7

Data presented as mean ± standard deviation or number/total (%).

Abbreviations: LD-DCB, Low dose drug-coated balloons; HD-DCB, High dose drug-coated balloons; PACSS, Peripheral Arterial Calcium Scoring System.

We analyzed the outcomes of limb salvage, overall survival, freedom from clinically driven target lesion revascularization, perioperative complications, and major amputation between HD-DCB and LD-DCB groups.

Limb salvage

At 6 months, the HD-DCB group showed a statistically significant improvement in limb salvage compared to the LD-DCB group (RR = 0.38, 95% CI = 0.18–0.78, p = .009), with no observed heterogeneity (I² = 0%). At 12 months, there was no significant difference in limb salvage between the HD-DCB and LD-DCB groups (RR = 3.08, 95% CI = 0.14–67.13, p = .47), with substantial heterogeneity among the studies (I² = 94%). Overall, HD-DCB was not associated with a significant effect on limb salvage (RR = 0.97, 95% CI = 0.24–3.97, p = .96), and the studies displayed high heterogeneity (I² = 85%). Figure 2.

Figure 2.

Limb Salvage: HD-DCB versus LD-DCB at 6 and 12 months.

Overall survival

At 6 months, the HD-DCB group did not show a statistically significant difference in overall survival compared to the LD-DCB group (RR = 1.53, 95% CI = 0.25–9.57, p = .65). The studies displayed high heterogeneity (I² = 97%). At 12 months, the HD-DCB group similarly showed no significant improvement in overall survival (RR = 1.21, 95% CI = 0.17–8.84, p = .85), with substantial heterogeneity (I² = 98%). Overall, HD-DCB was not associated with a statistically significant increase in survival (RR = 1.35, 95% CI = 0.43–4.28, p = .61), and the studies demonstrated high heterogeneity (I² = 97%). Figure 3.

Figure 3.

Overall Survival: HD-DCB versus LD-DCB at 6 and 12 months.

Freedom from clinically driven target lesion revascularization

At 6 months, there was no statistically significant difference in freedom from clinically driven target lesion revascularization between the HD-DCB and LD-DCB groups (RR = 1.33, 95% CI = 0.72–2.45, p = .36), with low heterogeneity (I² = 24%). At 12 months, the HD-DCB group also showed no significant difference compared to the LD-DCB group (RR = 0.71, 95% CI = 0.37–1.38, p = .32), with moderate heterogeneity (I² = 78%). At 24 months, there was similarly no significant difference between the two groups (RR = 1.03, 95% CI = 0.81–1.32, p = .80), and no heterogeneity was observed (I² = 0%). Overall, HD-DCB was not associated with a statistically significant improvement in freedom from clinically driven target lesion revascularization (RR = 0.97, 95% CI = 0.71–1.32, p = .83), with moderate heterogeneity across the studies (I² = 58%). Figure 4.

Figure 4.

Freedom from Target Lesion Revascularization: HD-DCB versus LD-DCB at 6, 12, and 24 months.

Major amputation

HD-DCB group showed no statistically significant difference in the risk of major amputation compared to the LD-DCB group (RR = 4.73, 95% CI = 0.54–41.52, p = .16). The studies showed no heterogeneity (I² = 0%). Figure 5(a).

Figure 5.

(A) Major Amputation: HD-DCB versus LD-DCB. (B) Perioperative Complications: HD-DCB versus LD-DCB.

Perioperative complications

HD-DCB was associated with a significantly higher risk of perioperative complications compared to LD-DCB (RR = 1.90, 95% CI = 1.14–3.17, p = .01). Moderate heterogeneity was observed among the studies (I² = 58%). Figure 5(b).

Risk of bias assessment

This study included few articles, because our article selection was based on strict inclusion and exclusion criteria for achieving homogenous studies. Our evaluation of the six included studies revealed varied risk of bias levels. Utilizing the ROB2 tool, one randomized controlled trial (Steiner, 2022) adhering to an intention-to-treat protocol was considered to have a “Low risk of bias.”²⁵ This assessment was attributed to the appropriate randomization process, implementation of multivariable analysis adjusting for confounders, and the absence of missing data.

Similarly, the observational cohort studies evaluated with the Newcastle–Ottawa Scale were also assessed for bias. Three studies (Mori, 2023; Tomoi, 2023; Kodama, 2024) were deemed to have a “Low risk of bias.”^23,24,26 This categorization was attributed to their control of treatment confounders, subgroup analysis based on exposure of interest, and lack of missing data.

Conversely, the observational cohort studies by Nakama, 2023 and Fujihara, 2023 were assessed as having a “High risk of bias” and “Some concerns,” respectively.^9,22 Supplemental Material 1, 2.

Discussion

Our meta-analysis included six studies from two countries, encompassing 2563 patients treated with HD-DCB and LD-DCB for isolated femoropopliteal disease. The results indicated that HD-DCB showed a significant improvement in limb salvage at 6 months, though this benefit was not observed at 12 months. Overall survival and freedom from clinically driven target lesion revascularization (CD-TLR) did not differ significantly between the two groups. While there was a trend toward a higher risk of major amputation with HD-DCB, this result did not reach statistical significance, and HD-DCB was associated with a significant increase in perioperative complications.

Our findings on limb salvage with HD-DCB align with the theoretical advantage of higher paclitaxel doses for short-term limb preservation. This contrasts with Tepe et al. (2015), who reported no significant differences in limb salvage rates between HD-DCB and LD-DCB, suggesting that patient selection or advancements in device technology may influence outcomes.⁷ In addition, our lack of a long-term survival advantage with HD-DCB aligns with Katsanos et al. (2018), indicating that the benefits of higher paclitaxel doses may be limited to early procedural success without extending to long-term survival.²⁷

Regarding freedom from CD-TLR, our findings are consistent with those of Laird et al. (2015), who also reported no significant differences between HD-DCB and LD-DCB groups.²⁸ However, we found a higher risk of perioperative complications in the HD-DCB group, which is consistent with the results reported by Schneider et al. (2018).²⁹

The recent meta-analysis by Jin et al. (2024) further contextualizes our findings. The authors reported and concluded that HD-DCB improved arterial patency, reduced restenosis, and decreased CD-TLR events compared to LD-DCB, which aligns with our findings on procedural efficacy.³⁰ However, unlike our results showing significant limb salvage improvement at 6 months, Jin et al. found no difference in limb salvage rates. This discrepancy may be due to variations in study selection, patient populations, or follow-up periods, as well as potential differences in clinical practice across regions. Another divergence is our finding of a significantly higher risk of perioperative complications with HD-DCB, a result that Jin et al. did not emphasize. This could be due to differences in study designs or definitions, suggesting that perioperative risks should be carefully considered, particularly for patients at high surgical risk. Our findings indicate that HD-DCB may provide advantages in terms of short-term limb salvage when compared to LD-DCB. This benefit could be especially valuable for patients with severe symptoms or higher risk of limb loss, where preserving the limb is a primary goal. However, this potential benefit comes with an increased likelihood of perioperative complications. Thus, while HD-DCB may be a viable approach for certain patients, it is essential for clinicians to weigh these risks carefully when determining the most suitable treatment. A multidisciplinary approach is key, enabling teams to thoroughly communicate the potential benefits and risks with patients, allowing for informed, individualized decisions.

The observed trend towards a higher risk of major amputations in patients treated with HD-DCB highlights the need for vigilant postoperative monitoring and the implementation of preventive strategies to reduce complications. These findings underscore the importance of tailoring treatment to each patient’s specific health profile and risk factors, aiming to optimize outcomes and minimize adverse events.

Limitations

While this study provides valuable insights, several limitations should be considered. First, most of the included studies were observational, which may introduce bias compared to randomized controlled trials.³¹ Second, notable heterogeneity was present among studies, particularly in terms of design and patient characteristics, potentially affecting the reliability of our findings.³² Additionally, the limited sample size across studies may reduce the statistical power needed to detect differences in certain outcomes.³³

Another important limitation is the lack of standardized definitions for lesion characteristics and restenotic lesion management, which likely contributed to variability in our results. Standardized classifications in future studies could improve comparability and lead to a more accurate assessment of treatment efficacy.³⁴ Furthermore, the absence of quality-of-life data restricts our understanding of the broader impact of HD-DCB and LD-DCB on patient-centered outcomes.

Finally, the high heterogeneity observed in several analyses, particularly in limb salvage outcomes, was significantly reduced to 0% when excluding Fujihara (2023). This suggests that this particular study contributed substantially to the observed variability. The reduction in heterogeneity reinforces the consistency of the results when excluding studies with high variability. However, this highlights the need for future well-designed studies with better standardization of criteria and methods to improve comparability and applicability of results in clinical practice and should also include quality of life measures to provide a more comprehensive assessment of the benefits and risks of HD-DCB and LD-DCB treatments.

Conclusion

This meta-analysis demonstrates that HD-DCB provide a significant short-term advantage in limb salvage over LD-DCB, though this benefit is accompanied by an increased risk of perioperative complications. These findings underscore the potential role of HD-DCB in enhancing treatment options for femoropopliteal disease. Future research should aim to address these complication risks and refine patient selection criteria to further improve clinical outcomes.

Supplemental Material

Supplemental Material - “Comparison of safety and efficacy of femoropopliteal arterial disease using different dose drug-coated balloons: Systematic review and meta-analysis”

Supplemental Material for “Comparison of safety and efficacy of femoropopliteal arterial disease using different dose drug-coated balloons: Systematic review and meta-analysis” by Carlos A. Núñez Castellanos, María F. Esquinca-Morales, Meritxell C. Beristain-Bolaños, Daniela I. De León Avecilla, Jorge S. Aguirre Ocaña, Osiris Y. Diaz-De-La-Cruz, Javier E. Anaya-Ayala, and Carlos A. Hinojosa in Vascular

Footnotes

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) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Carlos A Núñez-Castellanos

Meritxell C Beristain-Bolaños

Jorge S Aguirre-Ocaña

Carlos A Hinojosa

Supplemental Material

Supplemental material for this article is available online.

References

Criqui

Aboyans

. Epidemiology of peripheral artery disease. Circ Res 2015; 116(9): 1509–1526.

Krawisz

Raja

Secemsky

. Femoral-popliteal peripheral artery disease: from symptom presentation to management and treatment controversies. Prog Cardiovasc Dis 2021; 65: 15–22.

Zhang

Song

Zheng

, et al. Long-term clinical efficacy of drug-coated balloon angioplasty for TASCII C/D femoropopliteal lesions in older patients with chronic limb-threatening ischemia: a retrospective study. Medicine (Baltim) 2024; 103(33): e39331.

Anantha-Narayanan

Love

Nagpal

, et al. Safety and efficacy of paclitaxel drug-coated balloon in femoropopliteal in-stent restenosis. Expet Rev Med Dev 2020; 17(6): 533–539.

Ang

Koppara

Cassese

, et al. Drug-coated balloons: technical and clinical progress. Vasc Med 2020; 25(6): 577–587.

Böhme

Noory

Beschorner

, et al. Evaluation of mortality following paclitaxel drug-coated balloon angioplasty of femoropopliteal lesions in the real world. JACC Cardiovasc Interv 2020; 13(17): 2052–2061.

Tepe

Laird

Schneider

, et al. IN.PACT SFA Trial Investigators. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015; 131(5): 495–502.

Mehrotra

Paramasivam

Mishra

. Paclitaxel-coated balloon for femoropopliteal artery disease. Curr Cardiol Rep 2017; 19(2): 10.

Nakama

Takahara

Iwata

, et al. Low-dose vs high-dose drug-coated balloon for symptomatic femoropopliteal artery disease: the PROSPECT MONSTER study outcomes. JACC Cardiovasc Interv 2023; 16(21): 2655–2665.

10.

Ouriel

Adelman

Rosenfield

, et al. Safety of paclitaxel-coated balloon angioplasty for femoropopliteal peripheral artery disease. JACC Cardiovasc Interv 2019; 12(24): 2515–2524.

11.

Cassese

Ndrepepa

Fusaro

, et al. Paclitaxel density and clinical efficacy of drug-coated balloon angioplasty for femoropopliteal artery disease: meta-analysis and adjusted indirect comparison of 20 randomised trials. EuroIntervention 2019; 15(6): e560–e562.

12.

Haddaway

Page

Pritchard

, et al. PRISMA2020: an R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Syst Rev 2022; 18(2): e1230.

13.

Higgins

JPT

Thomas

Chandler

, et al. Cochrane Handbook for systematic reviews of interventions version 6.3. Cochrane. Published 2022.

14.

Cumpston

Page

, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev 2019; 10(10): ED000142.

15.

Ouzzani

Hammady

Fedorowicz

, et al. Rayyan—a web and mobile app for systematic reviews. Syst Rev 2016; 5: 210.

16.

Gierisch

Beadles

Shapiro

, et al. Health disparities in quality indicators of healthcare among adults with mental illness [Internet]. Washington (DC): Department of Veterans Affairs (US); 2014. PMID: 26065051.

17.

Sterne

JAC

Savović

Page

, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.

18.

Kadam

. Limb salvage surgery. Indian J Plast Surg 2013; 46(2): 265–274.

19.

Brodmann

Keirse

Scheinert

, et al. Drug-coated balloon treatment for femoropopliteal artery disease: the IN.PACT global study de novo in-stent restenosis imaging cohort. JACC Cardiovasc Interv 2017; 10(20): 2113–2123.

20.

DerSimonian

Laird

. Meta-analysis in clinical trials. Control Clin Trials 1986; 7(3): 177–188.

21.

Higgins

JPT

Thompson

Deeks

, et al. Measuring inconsistency in meta- analyses. BMJ 2003; 327(7414): 557–560.

22.

Fujihara

Takahara

Soga

, et al. Application of first-generation high- and low-dose drug-coated balloons to the femoropopliteal artery disease: a sub-analysis of the POPCORN registry. CVIR Endovasc 2023; 6(1): 41.

23.

Kodama

Soga

Tomoi

, et al. Difference in one-year late lumen loss between high- and low-dose paclitaxel-coated balloons for femoropopliteal disease. Heart Ves 2024; 39(7): 582–588.

24.

Mori

Yamauchi

Doijiri

, et al. Comparison between clinical outcomes of low- and high-dose paclitaxel drug-coated balloon in endovascular therapy for femoropopliteal lesion. Cardiovasc Intervent Radiol 2023; 46(5): 590–597.

25.

Steiner

Schmidt

Zeller

, et al. Low-dose vs high-dose paclitaxel-coated balloons for femoropopliteal lesions: 2-year results from the COMPARE trial. JACC Cardiovasc Interv 2022; 15(20): 2093–2102.

26.

Tomoi

Takahara

Soga

, et al. Effect of high-dose drug-coated balloon repetition after drug-coated balloon failure. J Endovasc Ther 2023: 15266028231214167.

27.

Katsanos

Spiliopoulos

Kitrou

, et al. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2018; 7(24): e011245.

28.

Laird

Schneider

Tepe

, et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol 2015; 66(21): 2329–2338.

29.

Schneider

Laird

Tepe

, et al. Treatment effect of drug-coated balloons is durable to 3 Years in the femoropopliteal arteries: long-term results of the IN.PACT SFA randomized trial. Circ Cardiovasc Interv 2018; 11(1): e005891.

30.

Jin

Sun

Liu

, et al. High- versus low-dose paclitaxel-coated balloons for femoropopliteal disease: a systematic review and meta-analysis. Cardiol Rev 2024.

31.

von Elm

Altman

Egger

, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61(4): 344–349.

32.

Higgins

Thompson

. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11): 1539–1558.

33.

Borenstein

Hedges

Higgins

JPT

, et al. Introduction to meta-analysis. Wiley, 2009.

34.

Cutlip

Windecker

Mehran

, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115(17): 2344–2351.

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