C Caradu

E Lakhlifi

E C Colacchio

D Midy

X Bérard

M Poirier

Eric Ducasse
email: eric.ducasse@chu-bordeaux.fr

Systematic review and updated meta-analysis of the use of drug-coated balloon angioplasty versus plain old balloon angioplasty for femoro-popliteal arterial disease

Keywords: Peripheral artery disease, drug-coated balloon, meta-analysis, femoro-popliteal, drugeluting balloon

Objective: An endovascular-first approach is usually recommended in femoro-popliteal occlusive disease. However, despite high technical success, plain old balloon angioplasty (POBA) is burdened with high restenosis rates. To reduce this phenomenon, local delivery of drugs has been proposed by way of drug-coated balloons (DCBs). Our goal was to review the evidence for the use of DCBs in the management of femoro-popliteal disease and determine whether it is associated with improved outcomes compared with POBA.

Methods: Electronic searches of PubMed (Medline), EMBASE, the CENTRAL, ClinicalTrials.gov, and proceedings of international conferences were performed to identify Randomized controlled trials (RCTs) and observational registries evaluating the use of DCBs for femoro-popliteal arterial occlusive disease.

Results: This meta-analysis included 13 RCTs, 6 global registries and 3 global registries focusing on long lesions. They all used paclitaxel in the DCB arm. There was heterogeneity between trials, and the frequency of stent deployment and duration of dual antiplatelet therapy differed. At 2 years, there were significantly better outcomes for DCBs in terms of target lesion revascularization (TLR) (Odds Ratio (OR) 0.29, 95% confidence interval (CI): 0.20,0.40), primary patency (OR 0.38, 95%CI: 0.27,0.54), late lumen loss (LLL) (Mean diameter (MD) -0.80mm, 95%CI: -1.44,-0.16) and Rutherford category (OR 0.82, 95%CI: 0.57,1.19). There was no significant difference between DCBs and POBA in amputation or change in ankle brachial index (ABI). A subgroup analyses revealed that Male patients treated with DCBs performed significantly better than Female, and that Diabetics, heavily calcified lesions and popliteal lesions performed significantly worse than non-Diabetics, no-, mi-to moderately calcified lesions and exclusive superficial femoral artery (SFA) lesions, respectively. Secondarily stented and non-predilated lesions did not perform significantly worse but standard dose (3 µg/mm 2 ) DCBs were significantly more effective than low-dose (2 µg/mm 2 ) DCBs in reducing binary restenosis. In addition, in a low-dose DCB, the polyethylene glycol excipient performed significantly better than polysorbate and sorbitol, while binary restenosis was significantly less frequent with the urea excipient, associated with a standard dose DCB, compared to the polysorbate and sorbitol excipient, associated with a low dose DCB.

Conclusions: DCB angioplasty is an effective treatment associated with high procedural success.

In a meta-analysis of industry sponsored trials, it consistently reduced LLL, binary restenosis, and TLR when compared to POBA alone in the treatment of femoro-popliteal disease. Further independent, non-industry sponsored RCT's are necessary to better delineate the role of DCB in the treatment of infra-inguinal occlusive disease.

INTRODUCTION

Intermittent claudication (IC) is the most common form of symptomatic peripheral artery disease (PAD), with a prevalence reaching 20% in a population over 70 years old, leading to severe deterioration in the functional status in a quarter of the cases. [START_REF] Norgren | Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)[END_REF] Major amputation is rare (3% at 5 years and 10% at 15 years), [START_REF]Natural history of claudication: Long-term serial follow-up study of 1244 claudicants[END_REF] but the risk increases by 5 to 10-fold in diabetic patients. Moreover, some patients will eventually develop critical limb ischemia (CLI), with an amputation-free survival rate limited to 45% at 1 year. [START_REF] Norgren | Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)[END_REF] Femoro-popliteal arteries are most commonly affected. [START_REF] Jaff | An update on methods for revascularization and expansion of the TASC lesion classification to include belowthe-knee arteries: A supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II): The TASC steering committee[END_REF] Surgical management is indicated in the majority of cases and an endovascular-first approach is now recommended, [START_REF] Jaff | An update on methods for revascularization and expansion of the TASC lesion classification to include belowthe-knee arteries: A supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II): The TASC steering committee[END_REF][START_REF] Stroke Organisation | ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC)[END_REF] but remains challenging. [START_REF] Klein | Quantitative assessment of the conformational change in the femoropopliteal artery with leg movement[END_REF] Plain old balloon angioplasty (POBA) crushes the atheromatous plaque and increases the lumen's diameter but is burdened with high restenosis rates, ranging from 40 to 70% in long lesions at 1 year, [START_REF] Dormandy | Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC)[END_REF] secondary to immediate elastic recoil or flow-limiting dissection and late negative remodeling. [START_REF] Morimoto | Restenosis after percutaneous transluminal coronary angioplasty--a histopathological study using autopsied hearts[END_REF] Stent implantation is usually mandatory to solve these problems, [START_REF] Dick | Balloon angioplasty versus stenting with nitinol stents in intermediate length superficial femoral artery lesions[END_REF] and randomized controlled trials (RCTs) have demonstrated the superiority of primary stenting over POBA in the femoro-popliteal segment, with 1-year patency rates ranging from 63% to 81%. [START_REF] Schillinger | Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery[END_REF][START_REF] Laird | Nitinol stent implantation vs. balloon angioplasty for lesions in the superficial femoral and proximal popliteal arteries of patients with claudication: three-year follow-up from the RESILIENT randomized trial[END_REF] However, a permanent metallic implant leads to increased myo-intimal hyperplasia and the dynamic stresses exerted on the stents can negatively impact the outcomes. [START_REF] Scheinert | Prevalence and clinical impact of stent fractures after femoropopliteal stenting[END_REF] To reduce myo-intimal hyperplasia, local delivery of drugs, has been proposed by way of drug-coated balloons (DCBs) or drug-eluting stents (DESs). DESs have proven their superiority over POBA in this challenging vessel segment but still leave a permanent metallic implant. [START_REF] Stroke Organisation | ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC)[END_REF] Hence, our goal was to precisely review the evidence for the use of DCBs in the management of femoro-popliteal disease, to help guide decision-making and determine whether it is associated with improved outcomes compared with POBA, especially in specific categories of patients or lesions.

METHODS

Electronic searches of PubMed (Medline), EMBASE, the CENTRAL, ClinicalTrials.gov, and other relevant online material were performed to identify RCTs and observational registries evaluating the use of DCBs in de novo femoro-popliteal lesions. Studies focusing exclusively on in-stent restenosis were excluded. The trial selection process complied with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, as reported in Supplementary Table I and Figure 1. [START_REF] Moher | Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement[END_REF] Endpoints were defined according to international guidelines [START_REF] Sacks | Reporting Standards for Clinical Evaluation of New Peripheral Arterial Revascularization Devices[END_REF] and encompassed procedural success, mortality, target lesion revascularization (TLR), primary patency (PP), binary restenosis, Rutherford category (RC), ankle brachial index (ABI), late lumen loss (LLL), major amputations and quality of life. Two review authors independently selected trials for inclusion and assessed potential risks of bias using the Cochrane's tool, as reported in Supplementary Figure 1. [START_REF] Higgins | The Cochrane Collaboration's tool for assessing risk of bias in randomised trials[END_REF] A third review author assessed and confirmed their suitability for inclusion and acted as an adjudicator in the event of disagreement.

Statistics

Statistical analyzes were performed using the Review Manager software (version 5.3.5;

Cochrane Information Management System) and GraphPad Prism v7.0 (GraphPad Inc, San Diego, Calif) and complied with the standard methods of Cochrane Vascular. Continuous outcome measures were reported using absolute numbers (%) and mean difference, while dichotomous outcome measures were reported using mean±standard deviation. When medians were reported rather than means, they were converted as per the method described in the Cochrane Handbook for Systematic Reviews of Interventions. [START_REF] Higgins | The Cochrane Collaboration's tool for assessing risk of bias in randomised trials[END_REF] Calculations were based on an intention-to-treat approach and all randomized participants were included in the analysis regardless of loss to follow-up. Between-study heterogeneity was assessed visually using a forest plot for each treatment effect. The Cochran's Q (chi-square) test and the I 2 statistic were calculated to test for evidence of statistical heterogeneity across studies. I 2 values <50% were indicative of low heterogeneity, 50% to 75% moderate, and >75% significant heterogeneity. [START_REF] Higgins | The Cochrane Collaboration's tool for assessing risk of bias in randomised trials[END_REF] A Random-effect Mantel-Haenszel model was used to calculate the pooled treatment effect data as odds ratios (OR) with 95% confidence intervals (CIs). [START_REF] Higgins | The Cochrane Collaboration's tool for assessing risk of bias in randomised trials[END_REF] Reported pooled estimates were stratified according to gender, history of diabetes, arterial segments, degree of stenosis or calcification, lesion length, use of predilation or stenting, run-off quality, paclitaxel dosage and excipients. The Grades of Recommendation Assessment, Development, and Evaluation (GRADE) methodology was used to rate our confidence in each reported outcome. [START_REF] Murad | Guideline methodology of the Society for Vascular Surgery including the experience with the GRADE framework[END_REF]

RESULTS

Studies

The meta-analysis includes 13 RCTs comparing DCBs with POBA (AcoArt I, [START_REF] Wei | 2-year results of the AcoArt I[END_REF][START_REF] Jia | Acotec Drug-Coated Balloon Catheter: Randomized, Multicenter, Controlled Clinical Study in Femoropopliteal Arteries: Evidence From the AcoArt I Trial[END_REF] BIOLUX P-I, [START_REF] Scheinert | Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial[END_REF] Clinical Trial on Peripheral Arteries Treated With SeQuent® Please Over The Wire Paclitaxel-Coated Balloon Catheter (CONSEQUENT), [START_REF] Tepe | Angiographic and Clinical Outcomes After Treatment of Femoro-Popliteal Lesions with a Novel Paclitaxel-Matrix-Coated Balloon Catheter[END_REF][START_REF] Albrecht | Two-Year Clinical Outcomes of the CONSEQUENT Trial: Can Femoropopliteal Lesions be Treated with Sustainable Clinical Results that are Economically Sound?[END_REF] Femoral Paclitaxel (FemPac), [START_REF] Werk | Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial (Fempac)[END_REF] ILLUMENATE European (EU) RCT, [START_REF] Brodmann | month results of the ILLUMENATE European randomised clinical trial[END_REF][START_REF] Brodmann | ILLUMENATE European Randomized Trial: 2-Year Results[END_REF] ILLUMENATE Pivotal and Pharmacokinetic Studies, [START_REF] Lyden | 12-month results of the ILLUMENATE pivotal trial[END_REF] IN.PACT Japan, [START_REF] Iida | Drug-Coated Balloon vs Standard Percutaneous Transluminal Angioplasty for the Treatment of Atherosclerotic Lesions in the Superficial Femoral and Proximal Popliteal Arteries: One-Year Results of the MDT-2113 SFA Japan Randomized Trial[END_REF][START_REF] Iida | 2 Year Results from the MDT-2113 SFA Japan Trial -DCB vs. standard PTA for the treatment of atherosclerotic lesions in the SFA/PPA[END_REF] IN.PACT superficial femoral artery (SFA), [START_REF] Schneider | 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[END_REF][START_REF] Laird | Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA[END_REF][START_REF] Tepe | 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[END_REF][START_REF] Laird | Long term durability of DCB treatment in the SFA: 4-year results of the IN[END_REF] Lutonix® Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis (LEVANT) 1, [START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF] LEVANT 2, 32,33 PACIFIER, [START_REF] Werk | Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial[END_REF] RANGER, [START_REF] Steiner | 12-Month Results From the First-in-Human Randomized Study of the Ranger Paclitaxel-Coated Balloon for Femoropopliteal Treatment[END_REF] Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries (THUNDER) [START_REF] Tepe | Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial[END_REF][START_REF] Tepe | Local Delivery of Paclitaxel to Inhibit Restenosis during Angioplasty of the Leg (THUNDER Trial)[END_REF] ), 6 global registries (IN.PACT Global Clinical Cohort, [START_REF] Micari | Drug-Coated Balloon Treatment of Femoropopliteal Lesions for Patients With Intermittent Claudication and Ischemic Rest Pain: 2-Year Results From the IN.PACT Global Study[END_REF] ILLUMENATE First in Human Study, [START_REF] Schroeder | Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study[END_REF] ILLUMENATE Global, [START_REF] Schroë | Stellarex drugcoated balloon for treatment of femoropopliteal arterial disease-The ILLUMENATE Global Study: 12-Month results from a prospective, multicenter, single-arm study[END_REF] Lutonix SFA Global, [START_REF] Thieme | The 24-Month Results of the Lutonix Global SFA Registry: Worldwide Experience With Lutonix Drug-Coated Balloon[END_REF] Micari et al. [START_REF] Micari | Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12month results from a multicenter Italian registry[END_REF][START_REF] Micari | 2-year results of paclitaxel-eluting balloons for femoropopliteal artery disease: evidence from a multicenter registry[END_REF] [START_REF] Laird | PACT drug-coated balloon: Consistent clinical outcomes across patient populations and challenging lesions[END_REF][START_REF] Zeller | Two-Year Results from the IN.PACT Global Study[END_REF] Lutonix Long Lesions, [START_REF] Banyai | Lutonix SFA Long Lesion Study Two Year Results : A Prospective, Multicenter, Single-Arm Trial with the Lutonix® Drug Coated Balloon for Treatment of Long Lesions in Femoropopliteal Arteries[END_REF][START_REF] Scheinert | The Lutonix EU Long Lesion study: A Prospective, Multicenter, Single-Arm Trial with the Lutonix® Drug Coated Balloon for Treatment of Long Lesions in Femoropopliteal Arteries[END_REF] Micari et al. [START_REF] Micari | 1-Year Results of Paclitaxel-Coated Balloons for Long Femoropopliteal Artery Disease: Evidence From the SFA-Long Study[END_REF][START_REF] Micari | 2-Year Results of Paclitaxel-Coated Balloons for Long Femoropopliteal Artery Disease: Evidence From the SFA-Long Study[END_REF] Long lesions' study). The primary endpoint was 6-month LLL in 8 RCTs [START_REF] Wei | 2-year results of the AcoArt I[END_REF][START_REF] Scheinert | Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial[END_REF][START_REF] Tepe | Angiographic and Clinical Outcomes After Treatment of Femoro-Popliteal Lesions with a Novel Paclitaxel-Matrix-Coated Balloon Catheter[END_REF][START_REF] Werk | Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial (Fempac)[END_REF][START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF][START_REF] Werk | Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial[END_REF][START_REF] Steiner | 12-Month Results From the First-in-Human Randomized Study of the Ranger Paclitaxel-Coated Balloon for Femoropopliteal Treatment[END_REF][START_REF] Tepe | Local Delivery of Paclitaxel to Inhibit Restenosis during Angioplasty of the Leg (THUNDER Trial)[END_REF] and 1 global registry, [START_REF] Schroeder | Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study[END_REF] 12-month PP in 5 RCTs, [START_REF] Brodmann | month results of the ILLUMENATE European randomised clinical trial[END_REF][START_REF] Lyden | 12-month results of the ILLUMENATE pivotal trial[END_REF][START_REF] Iida | Drug-Coated Balloon vs Standard Percutaneous Transluminal Angioplasty for the Treatment of Atherosclerotic Lesions in the Superficial Femoral and Proximal Popliteal Arteries: One-Year Results of the MDT-2113 SFA Japan Randomized Trial[END_REF][START_REF] Tepe | 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[END_REF][START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF] 3 global registries [START_REF] Schroë | Stellarex drugcoated balloon for treatment of femoropopliteal arterial disease-The ILLUMENATE Global Study: 12-Month results from a prospective, multicenter, single-arm study[END_REF][START_REF] Micari | Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12month results from a multicenter Italian registry[END_REF][START_REF] Schmidt | Drug-Coated Balloons for Complex Femoropopliteal Lesions: 2-Year Results of a Real-World Registry[END_REF] and 2 long lesions registries [START_REF] Laird | PACT drug-coated balloon: Consistent clinical outcomes across patient populations and challenging lesions[END_REF][START_REF] Micari | 1-Year Results of Paclitaxel-Coated Balloons for Long Femoropopliteal Artery Disease: Evidence From the SFA-Long Study[END_REF] and TLR in the IN.PACT Global Clinical Cohort, [START_REF] Micari | Drug-Coated Balloon Treatment of Femoropopliteal Lesions for Patients With Intermittent Claudication and Ischemic Rest Pain: 2-Year Results From the IN.PACT Global Study[END_REF] Lutonix SFA Global [START_REF] Thieme | The 24-Month Results of the Lutonix Global SFA Registry: Worldwide Experience With Lutonix Drug-Coated Balloon[END_REF] and Lutonix Long Lesions' [START_REF] Scheinert | The Lutonix EU Long Lesion study: A Prospective, Multicenter, Single-Arm Trial with the Lutonix® Drug Coated Balloon for Treatment of Long Lesions in Femoropopliteal Arteries[END_REF] studies.

Risk of bias

Most RCTs were at low risk for sequence generation and allocation concealment selection bias.

Nonetheless, the ILLUMENATE EU [START_REF] Brodmann | month results of the ILLUMENATE European randomised clinical trial[END_REF] and RANGER [START_REF] Steiner | 12-Month Results From the First-in-Human Randomized Study of the Ranger Paclitaxel-Coated Balloon for Femoropopliteal Treatment[END_REF] RCTs used "blocks of sealed envelopes" without specifying the methodology for generating those. LEVANT 2 [START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF][START_REF] Fanelli | Optimal DCB Performance LEVANT 2 and Global SFA Real-World Registry[END_REF] did not specify how participants were randomized or allocated to either study arm, and 7 studies did not specify how allocation concealment bias was addressed. [START_REF] Tepe | Angiographic and Clinical Outcomes After Treatment of Femoro-Popliteal Lesions with a Novel Paclitaxel-Matrix-Coated Balloon Catheter[END_REF][START_REF] Werk | Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial (Fempac)[END_REF][START_REF] Lyden | 12-month results of the ILLUMENATE pivotal trial[END_REF][START_REF] Iida | Drug-Coated Balloon vs Standard Percutaneous Transluminal Angioplasty for the Treatment of Atherosclerotic Lesions in the Superficial Femoral and Proximal Popliteal Arteries: One-Year Results of the MDT-2113 SFA Japan Randomized Trial[END_REF][START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF][START_REF] Tepe | Local Delivery of Paclitaxel to Inhibit Restenosis during Angioplasty of the Leg (THUNDER Trial)[END_REF] All of the included studies were at high risk for performance bias because the operators were not blinded to the procedure. Conversely, the risk of detection bias was low as outcome assessment was carried out by other blinded investigators, with the exception of THUNDER. [START_REF] Tepe | Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial[END_REF][START_REF] Tepe | Local Delivery of Paclitaxel to Inhibit Restenosis during Angioplasty of the Leg (THUNDER Trial)[END_REF] Additionally, all the RCTs and 5 out of 6 Global registries received industry sponsorship (with the exception of Schmidt et al.'s 44 registry), when a recent Cochrane database systematic review reported that sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. [START_REF] Lundh | Industry sponsorship and research outcome[END_REF] Another source of bias was the concurrent use of stenting, in conjunction with unclear stentdeployment criteria and lack of separate reporting of the outcomes of stented participants. In the DCB arm, the lowest rate was observed in the LEVANT 2 [START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF][START_REF] Fanelli | Optimal DCB Performance LEVANT 2 and Global SFA Real-World Registry[END_REF] trial (2.5%), where only patients anticipated not to require stenting after the initial angiogram were included, while the highest rate was observed in the LEVANT 1 trial (26.5%). [START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF] Moreover, BIOLUX P-I 18 reported significantly higher rates of bailout stenting after POBA (26.7%), and it was unclear whether the lesions had been previously treated or not, since more than half of the participants had a history of peripheral vascular interventions (56.7% in the DCB arm and 60% in the POBA arm).

Additionally, predilation was performed more often before DCB use (66.7% vs 30% before POBA, p=0.01), and technical success was higher (76.7% vs 46.7%, p=0.02).

Device malfunction was another potential source of bias, especially in LEVANT 1, [START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF] with a 16% rate of DCB's failing to deploy. Furthermore, follow-up compliance was low in BIOLUX P-I [START_REF] Scheinert | Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial[END_REF] and the FemPac trial [START_REF] Werk | Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial (Fempac)[END_REF] (27% lost to follow-up in the DCB arm).

Effects of interventions

Meta-analysis of RCTs

A Summary of findings is reported in Supplementary Tables II and III and Figure 2. There was no significant difference in all-cause mortality after DCB treatment or POBA at 1 year (OR 0.81, 95%CI: 0.46,1.43), 2 (OR 1.61, 95%CI: 0.95,2.75), 4 (OR 1.82, 95%CI: 0.76,4.36) and 5 years (OR 1.92, 95%CI: 0.71,5.19). However, a significantly lower mortality rate was found after POBA at 3 years (OR 5.75, 95%CI: 1.32,24.99). Nonetheless, no death was adjudicated as device-or procedure-related by the Clinical Events Committees.

There was no significant difference in the incidence of amputations after DCB treatment or POBA at 1 year (OR 1.81, 95%CI: 0.37,8.85), 2 (OR 1.32, 95%CI: 0.32, 5.42), or 5 years (OR 4.82, 95%CI: 0.52,44.70).

The DCB arm of the trials showed a significant advantage in TLR compared with POBA at 1 year (OR 0.27, 95%CI: 0.17,0.41), 2 (OR 0.29, 95%CI: 0.20,0.40), 3 (OR 0.39, 95%CI: 0.22,0.68) and 5 years (OR 0.21, 95%CI: 0.09,0.51). A funnel plot constructed to test for publication bias demonstrated asymmetry (Supplementary Figure 2), consistent with the heterogeneity observed in the 1-year analysis (Q test p=0.001).

DCBs were associated with significantly greater odds of PP at 1 year (OR 0.43, 95%CI: 0.30, 0.61), 2 (OR 0.38, 95%CI: 0.27,0.54) and 3 years (OR 2.79, 95%CI: 1.74,4.46). Importantly, PP was defined as freedom from TLR and restenosis as determined by Doppler ultrasound with a peak systolic velocity ratio (PSVR) ≤2.4, [START_REF] Wei | 2-year results of the AcoArt I[END_REF][START_REF] Iida | Drug-Coated Balloon vs Standard Percutaneous Transluminal Angioplasty for the Treatment of Atherosclerotic Lesions in the Superficial Femoral and Proximal Popliteal Arteries: One-Year Results of the MDT-2113 SFA Japan Randomized Trial[END_REF][START_REF] Laird | Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA[END_REF][START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF][START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF][START_REF] Micari | Drug-Coated Balloon Treatment of Femoropopliteal Lesions for Patients With Intermittent Claudication and Ischemic Rest Pain: 2-Year Results From the IN.PACT Global Study[END_REF][START_REF] Schroeder | Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study[END_REF][START_REF] Micari | Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12month results from a multicenter Italian registry[END_REF][START_REF] Laird | PACT drug-coated balloon: Consistent clinical outcomes across patient populations and challenging lesions[END_REF][START_REF] Micari | 1-Year Results of Paclitaxel-Coated Balloons for Long Femoropopliteal Artery Disease: Evidence From the SFA-Long Study[END_REF] a more discriminant PSVR <2.4 (RANGER, [START_REF] Steiner | 12-Month Results From the First-in-Human Randomized Study of the Ranger Paclitaxel-Coated Balloon for Femoropopliteal Treatment[END_REF] Schmidt et al. [START_REF] Schmidt | Drug-Coated Balloons for Complex Femoropopliteal Lesions: 2-Year Results of a Real-World Registry[END_REF] ), less discriminant PSVR ≤2.5 (ILLUMENATE studies [START_REF] Brodmann | month results of the ILLUMENATE European randomised clinical trial[END_REF][START_REF] Lyden | 12-month results of the ILLUMENATE pivotal trial[END_REF][START_REF] Schroë | Stellarex drugcoated balloon for treatment of femoropopliteal arterial disease-The ILLUMENATE Global Study: 12-Month results from a prospective, multicenter, single-arm study[END_REF] or not specified (BIOLUX P-I, [START_REF] Scheinert | Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial[END_REF] FemPac, [START_REF] Werk | Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial (Fempac)[END_REF] PACIFIER, [START_REF] Werk | Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial[END_REF] THUNDER, [START_REF] Tepe | Local Delivery of Paclitaxel to Inhibit Restenosis during Angioplasty of the Leg (THUNDER Trial)[END_REF] Lutonix studies [START_REF] Thieme | The 24-Month Results of the Lutonix Global SFA Registry: Worldwide Experience With Lutonix Drug-Coated Balloon[END_REF][START_REF] Scheinert | The Lutonix EU Long Lesion study: A Prospective, Multicenter, Single-Arm Trial with the Lutonix® Drug Coated Balloon for Treatment of Long Lesions in Femoropopliteal Arteries[END_REF] ).

Participants treated with DCBs had significantly lower odds of developing binary restenosis at 1 year (OR 0.36, 95%CI: 0.26,0.51) and 5 years (OR -0.12, 95%CI: 0.05,0.30) and were less likely to develop LLL at 1 year (mean diameter (MD) -0.75mm, 95%CI: -0.94,-0.56), 2 (MD -0.80mm, 95%CI: -1.44,-0.16) and 5 years (MD -0.80mm, 95%CI: -1.44,-0.16).

The number of patients presenting with a significant change in RC from baseline was significantly improved by the use of DCBs at 1 year (OR 0.60, 95%CI: 0.38,0.95), but this advantage did not persist after 2 (OR 0.82, 95%CI: 0.57,1.19) and 3 years (OR 1.27, 95%CI: 0.80,2.00). Nonetheless, walking distance was significantly improved at 2 years (MD 120.00m, 95%CI: 81.66, 158.34). Additionally, the Euro-Qol Group 5-Dimension Self-Report Questionnaire scores (EQ-5D) tended to improve at 1 (MD 0.03, 95%CI: 0.00,0.06) and 2 years (MD 0.05, 95%CI: -0.01,0.10).

Furthermore, there was no significant advantage for DCBs in ABI's improvement at 1 year (MD 0.02, 95%CI: -0.03,0.08), 2 (MD -0.03, 95%CI: -0.07,0.01) and 3 years (MD 0.00, 95%CI: -0.05,0.05).

Meta-analysis of Global registries

Overall, 3012 patients were included (3341 lesions, of a mean length of 12±9cm). They presented with more in-stent restenosis and occlusion rates compared to RCTs (23.8% vs 11.1% and 36% vs 24.7% respectively). Importantly, provisional stenting rates were more than twice as high (20.2% vs 9.7%).

All-cause mortality rates were comparable to the results obtained in the DCB arm of RCTs at 1 (2.6%) and 2 years (6.1%), as was the 1-year (0.4%) and 2-year (0.8%) major amputation rate.

Clinically-driven (CD)-TLR rates were comparable to the results obtained in the DCB arm of RCTs at 1 (6.3%) and 2 years (12.4%), as well as the 1-year PP rate (67.6%), however, it tended to decrease at 2 years (55.8% vs 69.6%). Moreover, the change in RC tended to decrease at 1 (66.9%) and 2 years (50.7% vs 58.9%).

Subgroup analysis

Data were available to conduct a subgroup analysis for TLR, LLL, binary restenosis and PP. A Summary of the main results is reported in Supplementary Table IV.

Female and Male patients treated with DCBs required significantly less TLR compared to the ones treated with POBA at 1 year (OR 0.33, 95%CI: 0.16,0.68 and OR 0.21, 95%CI: 0.07,0.60). This result only remained statistically significant for Male patients at 2 years (OR 0.05, 95%CI: 0.01,0.27). Female and Male patients were also less likely to develop LLL compared with participants treated with POBA at 1 year (MD -0.69mm, 95%CI: -0.94,-0.43 and MD -0.76mm, 95%CI: -0.99,-0.53), and showed higher PP at 1 (OR 0.34, CI%95: 0.18,0.63 and OR 0.33, 95%CI: 0.21,0.53) and 2 years (OR 0.23, 95%CI: 0.10,0.53 and OR 0.26, 95%CI: 0.14,0.48, respectively). In the meta-analysis of the DCB cohorts, Male patients treated with DCBs performed significantly better than Female patients in terms of clinically driven (CD)-TLR at 1 and 2 years. Diabetic patients receiving DCB treatment were significantly less likely to develop LLL compared to participants treated with POBA at 1 year (MD -1.1mm, 95%CI: -1.42,-0.78) and showed significantly higher PP at 1 (OR 0.33, 95%CI: 0.11,1.00) and 2 years (OR 0.27, 95%CI: 0.13,0.55). In the meta-analysis of the DCB cohorts, they showed significantly lower PP rates compared to non-diabetic patients at 2 years.

Occlusions treated with DCBs were significantly less likely to develop LLL compared to the ones treated with POBA at 1 year (MD -1.09mm, 95%CI: -1.42,-0.76), with significantly higher PP at 2 years (OR 0.17, 95%CI: 0.06,0.48). In addition, PP and TLR rates did not differ significantly between occlusions and stenosis in the meta-analysis of the DCB cohorts.

Lesions>20cm treated with DCBs were significantly less likely to develop LLL at 1 year (MD -1.12mm, 95%CI: -1.42,-0.82) and lesions>10cm showed significantly higher PP at 2 years (OR 0.22, 95%CI: 0.09,0.50) compared with POBA. Moreover, PP and TLR rates did not differ significantly between lesions>15cm and shorter lesions in the meta-analysis of the DCB cohorts.

Interestingly, a meta-analysis of the 3 global registries on long lesions (mean lesion length of 24±8mm) with a 51.3% rate of occlusions reported a three-fold increase in provisional stenting compared to RCTs (30.9% vs 9.7%). PP remained high at 1 and 2 years (78.7% and 62.4% respectively), however, the rate of CD-TLR at 2 years was almost two times higher compared to RCTs (22.4% vs 12.5%), without any major difference in terms of mortality or major amputation rates. Additionally, popliteal lesions showed significantly worse PP at 1 year and TLR rates at 1 and 2 years compared with exclusive SFA lesions.

Interestingly, patients who received additional stenting did not show any statistical advantage after DCB treatment over patients treated with POBA at 1 year, while patients who did not require stenting were significantly less likely to develop LLL (MD -0.74mm, 95%CI: -1.36,-0.12). Nonetheless, PP and TLR rates were not significantly different between stented and unstented lesions in the meta-analysis of the DCB cohorts. Heavily calcified lesions showed significantly worse PP rates at 2 years compared to no-, mid-to moderately calcified lesions, without a significant increase in TLR. Additionally, un-predilated lesions did not perform significantly worse than predilated lesions.

More importantly, standard dose (3µg/mm 2 ) DCBs showed significantly lower binary restenosis rates compared with low-dose (2µg/mm 2 ) DCBs, without any significant difference in TLR or PP rates. In addition, in a low-dose DCB, the polyethylene glycol excipient performed significantly better than polysorbate and sorbitol in terms of TLR rates (p=0.03). Moreover, there were significantly fewer TLRs with the urea excipient, associated with a standard dose DCB, compared to the polysorbate and sorbitol excipient, associated with a low dose DCB (p=0.03), and significantly fewer binary restenosis as reported in Figure 3.

DISCUSSION

In the past few years, several meta-analyses have compared DCBs with POBA for femoropopliteal lesions but none have compiled all of the available data to date. This systematic review and updated meta-analysis confirmed that DCB angioplasty was associated with high procedural success (>95%), comparable to that of femoro-popliteal bypass surgery in the literature. [START_REF] Adam | Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial[END_REF] It resulted in improved PP up to 3 years, reduced LLL, binary restenosis and TLR up to 5 years compared to POBA. Moreover, DCBs not only reduce the frequency of restenosis of treated lesions, but also decrease their severity, facilitating their subsequent treatment, with significantly shorter restenosis lengths compared to the initial ones (14 vs 24cm; p<0.0005). [START_REF] Micari | 2-year results of paclitaxel-eluting balloons for femoropopliteal artery disease: evidence from a multicenter registry[END_REF] The analysis of global registries showed that, in "real world" patients, the same results could be anticipated.

Even though endovascular procedures do not carry the same risk as open bypass surgery, it is still burdened with complications and reducing the patient's likelihood of going back to surgery alone is quality-of-life improvement.

The enthusiasm for DCBs has been responsible for a considerable increase in the supply from the industry and all currently available DCBs use dry state paclitaxel, but differences in drug concentration (2-3µg/mm 2 with an incremental anti-restenotic effect), [START_REF] Iida | Influence of stent fracture on the long-term patency in the femoro-popliteal artery: experience of 4 years[END_REF] excipient and elution kinetics may influence the outcome. [START_REF] Fanelli | Optimal DCB Performance LEVANT 2 and Global SFA Real-World Registry[END_REF] The crystalline form of paclitaxel offers better retention of the molecule within the arterial wall by the formation of "reservoirs", [START_REF] Gongora | Impact of Paclitaxel Dose on Tissue Pharmacokinetics and Vascular Healing: A Comparative Drug-Coated Balloon Study in the Familial Hypercholesterolemic Swine Model of Superficial Femoral In-Stent Restenosis[END_REF] but induces a greater risk of distal embolization, resulting in more paclitaxel-associated fibrinoid necrosis in downstream tissues. On the contrary, the "amorphous" form offers more uniform balloon coverage and lower downstream toxicity. [START_REF] Pósa | Optimization of drug-eluting balloon use for safety and efficacy: evaluation of the 2nd generation paclitaxel-eluting DIOR-balloon in porcine coronary arteries[END_REF] Indeed, in vitro studies identified a drug wash off of 21-39%, a drug load deposit of 40% in the vessel wall during inflation, a drug transfer of 22-44% and a residual drug load on the balloon of 17-54% with a coating loss of 100±106 to 790±191 particles ≥10µm and 16±12 to 53±11 particles ≥25µm, depending on the DCB. [START_REF] Kaule | Correlating Coating Characteristics with the Performance of Drug-Coated Balloons -A Comparative In Vitro Investigation of Own Established Hydrogel-and Ionic Liquid-Based Coating Matrices[END_REF] Reassuringly, our meta-analysis did not show a significant increase in major amputation rates after DCB angioplasty, however, most patients suffered from IC. Importantly, our meta-analysis reported that the dose of paclitaxel was related to the magnitude of treatment effect; standard dose (3µg/mm 2 ) DCBs were significantly more effective compared with low-dose (2µg/mm 2 ) DCBs in reducing binary restenosis, consistent with the results of another meta-analysis (risk ratio (RR) 2.1, 95%CI: 1.2,3.4; p<0.001 and RR 2.5, 95%CI: 1.9,3.8; p<0.001, respectively). [START_REF] Katsanos | Systematic Review and Meta-analysis of Randomized Controlled Trials of Paclitaxel-Coated Balloon Angioplasty in the Femoropopliteal Arteries: Role of Paclitaxel Dose and Bioavailability[END_REF] In addition, the difference in restenosis is largely dependent on the excipient, which plays a crucial role in drug transfer and absorption, and this meta-analysis demonstrated that in low-dose DCBs, polyethylene glycol performed significantly better than polysorbate and sorbitol. As of today, the best formulation remains unknown, as no head-to-head comparisons between different DCBs were made in clinical or preclinical studies.

Another important point is the quality of vessel preparation, as demonstrated by lower dissection and reintervention rates in the POBA arm of all RCTs compared to historical data. [START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF] At first no predilatation was performed, then, it became optional and now it is considered an integral part of the procedure to avoid drug loss during crossing and ensure an equal distribution of the drug across the vessel surface. Thus, predilatation rates reached 92.1% in the DCB arm of RCTs and 87.8% in global registries. Nonetheless, predilatation rates were significantly lower in the POBA group vs the DCB group of the Acot-Art, [START_REF] Wei | 2-year results of the AcoArt I[END_REF] BIOLUX-PI [START_REF] Jia | Acotec Drug-Coated Balloon Catheter: Randomized, Multicenter, Controlled Clinical Study in Femoropopliteal Arteries: Evidence From the AcoArt I Trial[END_REF] and IN.PACT SFA [START_REF] Iida | 2 Year Results from the MDT-2113 SFA Japan Trial -DCB vs. standard PTA for the treatment of atherosclerotic lesions in the SFA/PPA[END_REF][START_REF] Schneider | 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[END_REF][START_REF] Laird | Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA[END_REF][START_REF] Tepe | 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[END_REF] RCTs. Hence, improved preparation of the vessel could be responsible for the accentuation of a difference in efficiency in favor of the DCB. Moreover, the technical characteristics of predilatation, such as duration, inflation pressure or the diameter of the balloon were rarely specified. A cautious approach with a balloon 1mm in diameter smaller than the size of the target artery was generally recommended to minimize parietal trauma, and only the registries of Micari et al. [START_REF] Thieme | The 24-Month Results of the Lutonix Global SFA Registry: Worldwide Experience With Lutonix Drug-Coated Balloon[END_REF][START_REF] Scheinert | The Lutonix EU Long Lesion study: A Prospective, Multicenter, Single-Arm Trial with the Lutonix® Drug Coated Balloon for Treatment of Long Lesions in Femoropopliteal Arteries[END_REF] demanded a predilatation time ≥120sec. Notably, skipping pre-dilatation did not influence outcomes in the subgroup analysis, in accordance with the 2-year results of the IN.PACT Global Clinical Cohort. [START_REF] Tepe | Local Delivery of Paclitaxel to Inhibit Restenosis during Angioplasty of the Leg (THUNDER Trial)[END_REF] This will require further investigation, since losing an additional balloon could increase cost-effectiveness.

Interestingly, a post-hoc analysis of the LEVANT 2 study suggests that full DCB apposition to the arterial wall (balloon/artery ratio=1.04) provides better 1-year PP (79.9% with DCBs vs 48.2% with POBA, 65% improvement) [START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF] compared to an inflated balloon's diameter lower than that of the arterial lumen (ratio=0.9, 73.5% vs 56.8%, 29% improvement). This same analysis suggests that 1-year PP could be positively influenced by transit time (<30sec), inflation pressure (≥7atm), inflation time (≥120sec) and a final residual stenosis <20%. Consistently, in a porcine model, higher concentrations were found for transit times of 30sec (vs 3min), inflation durations of 3min (vs 30sec) and an inflation pressure of 12atm (vs 6 and 18atm). [START_REF] Schorn | The L utonix ® drug-coated balloon: A novel drug delivery technology for the treatment of vascular disease[END_REF] Hence, the inflation time recommended for optimal drug release is between 30 and 60sec, [START_REF] Diehm | Drug eluting balloons[END_REF] and it was mostly >100sec in the RCTs and global registries, with the exception of the PACIFIER trial. [START_REF] Fanelli | Optimal DCB Performance LEVANT 2 and Global SFA Real-World Registry[END_REF] Importantly, it was significantly higher in the POBA arm of the LEVANT 2 study (151.2sec in the DCB group vs 173.6sec, p=0.004), [START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF][START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF] which could have led to better early outcomes after POBA, and especially lower rates of severe dissection [START_REF] Horie | Impact of Prolonged Inflation Times During Plain Balloon Angioplasty on Angiographic Dissection in Femoropopliteal Lesions[END_REF][START_REF] Zorger | Peripheral arterial balloon angioplasty: effect of short versus long balloon inflation times on the morphologic results[END_REF] leading to a smaller advantage of DCB's over POBA in this study. Few data are available regarding transit time, and only the LEVANT 1 30 and 2 [START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF][START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF] studies recommended a transit time <180sec, while the average pressures were above 8atm in the RCTs and around 10atm in global registries. It is important to emphasize that in the LEVANT 2 study, the inflation pressure for POBA (8.4 ± 2.6atm) was significantly higher compared to DCB angioplasty (7.8±2.0atm, p=0.002). It was also higher in the global registry (9.5atm), [START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF] which resulted in fewer residual stenosis (14.6% in the global registry vs 23.4% in the DCB group of the RCT). But above all, it surprisingly resulted in fewer dissections (18.4% vs 63.4% in the DCB group of the RCT) despite lower predilatation rates (64.9% vs 100%).

The operators' experience probably plays an important role in these differences, as illustrated by a comparison of the German subpopulation of the LEVANT 2 study to the rest of the cohort. [START_REF] Scheinert | German Center Subanalysis of the LEVANT 2 Global Randomized Study of the Lutonix Drug-Coated Balloon in the Treatment of Femoropopliteal Occlusive Disease[END_REF] Indeed, DCBs have been prevalent in Germany for longer than other regions of the world and this study reported significantly shorter transit time (21.8sec in the German subgroup vs 39.5sec, p<0.001) and higher maximum DCB inflation pressures (9atm vs 7.7atm, p<0.001), resulting in fewer residual stenosis (19% vs 22%, p=0.04) despite greater preoperative stenosis, higher PP (80% vs 58%, p=0.015) and higher freedom from CD-TLR (96 % vs 82%, p=0.012) at 1 year.

Importantly, the absence of at least one patent tibial artery to the foot, was an exclusion criterion in all RCTs and treatment of leg arteries was only allowed in Micari et al.'s registries. [START_REF] Micari | Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12month results from a multicenter Italian registry[END_REF][START_REF] Micari | 1-Year Results of Paclitaxel-Coated Balloons for Long Femoropopliteal Artery Disease: Evidence From the SFA-Long Study[END_REF] Overall, 70-80% of the patients had 2 to 3 patent tibial arteries. It is important to note that in the IN.PACT SFA study, [START_REF] Iida | 2 Year Results from the MDT-2113 SFA Japan Trial -DCB vs. standard PTA for the treatment of atherosclerotic lesions in the SFA/PPA[END_REF][START_REF] Schneider | 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[END_REF][START_REF] Laird | Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA[END_REF][START_REF] Tepe | 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[END_REF] this level was significantly higher in the DCB group (83% vs 68.7% in the POBA group, p=0.04), which could have led to an overestimation of PP in this group, given the importance of downstream bed quality on long-term patency. [START_REF] Ihnat | Contemporary outcomes after superficial femoral artery angioplasty and stenting: the influence of TASC classification and runoff score[END_REF] Anyway, our subgroup analysis did not show any significant difference between patients requiring or not run-off angioplasty.

Studied lesions could be located partly or exclusively on the popliteal artery, inclusion criteria diverged from P1 in the IN.PACT [START_REF] Laird | Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA[END_REF][START_REF] Schmidt | Drug-Coated Balloons for Complex Femoropopliteal Lesions: 2-Year Results of a Real-World Registry[END_REF] and ILLUMENATE EU RCTs, [START_REF] Werk | Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial (Fempac)[END_REF][START_REF] Brodmann | month results of the ILLUMENATE European randomised clinical trial[END_REF] to P3 in the LEVANT 1 [START_REF] Laird | Long term durability of DCB treatment in the SFA: 4-year results of the IN[END_REF] and 2 [START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF][START_REF] Rosenfield | Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease[END_REF] studies, to not clearly defined in other RCTs. One argument for DCB use is that they do not leave any permanent scaffold behind and could therefore be more suitable for the femoro-popliteal arteries, submitted to a considerable amount of flexion and torsion. However, RCTs had low rates of popliteal involvement (1.5-31.3% in the DCB arms, mean 11.1%), even the more complex lesions of the AcoArt I, [START_REF] Murad | Guideline methodology of the Society for Vascular Surgery including the experience with the GRADE framework[END_REF][START_REF] Wei | 2-year results of the AcoArt I[END_REF] and THUNDER trials [START_REF] Tepe | Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial[END_REF] did not exceed 26 and 31.3%, respectively. In global registries, the rate was higher (3.8-49.4%, mean 23.1%).

Interestingly, the subgroup analysis of the German retrospective cohort showed that lesions located exclusively on the SFA had significantly higher PP compared to lesions encompassing the popliteal artery (84% and 57% for SFA lesions vs 69% and 47% at 1 and 2 years, respectively, p=0.015), [START_REF] Micari | 2-year results of paclitaxel-eluting balloons for femoropopliteal artery disease: evidence from a multicenter registry[END_REF] which was confirmed in our subgroup analysis. Indeed, fatigue resistance of Nitinol stents is a critical issue, especially in segments subjected to large cyclic daily activity. [START_REF] Klein | Quantitative assessment of the conformational change in the femoropopliteal artery with leg movement[END_REF] Fracture rates go up to 24.5%, [START_REF] Iida | Influence of stent fracture on the long-term patency in the femoro-popliteal artery: experience of 4 years[END_REF] and are often associated with in-stent restenosis and late device failure. These rates are going down with the new generation of stents, nonetheless, stent's struts may still obstruct important side branches and become an obstacle to future treatment, with an alteration of the distal target in 30% of early-failure patients. [START_REF] Joels | Surgical implications of early failed endovascular intervention of the superficial femoral artery[END_REF] This meta-analysis confirms that stenting will not be abolished completely, even though bailout stenting was significantly less frequent in the DCB group of the BIOLUX-PI, 17 LEVANT 1 [START_REF] Laird | Long term durability of DCB treatment in the SFA: 4-year results of the IN[END_REF] and 2 [START_REF] Tepe | Angiographic and Clinical Outcomes After Treatment of Femoro-Popliteal Lesions with a Novel Paclitaxel-Matrix-Coated Balloon Catheter[END_REF][START_REF] Tepe | Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial[END_REF] and THUNDER trial [START_REF] Schroeder | Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study[END_REF] . Since the operators were not blinded, it is difficult to know if it was their bias not to stent after DCB use or if it was related to more satisfying results. Noticeably, lower rates of post-procedural dissection have been reported after DCB vs POBA, [START_REF] Tepe | Local Delivery of Paclitaxel to Inhibit Restenosis during Angioplasty of the Leg (THUNDER Trial)[END_REF] possibly related to increased confidence in DCBs. [START_REF] Laird | Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA[END_REF] Indeed, a secondary analysis of the THUNDER study showed that, even in high grade dissections, DCBs made it possible to obtain significantly better results in terms of LLL (0.4 vs 2.4mm, p=0.05) and restenosis (20 vs 55%, p=0.02), due to positive remodeling. [START_REF] Tepe | High-grade, non-flow-limiting dissections do not negatively impact long-term outcome after paclitaxelcoated balloon angioplasty: an additional analysis from the THUNDER study[END_REF] In our subgroup analysis, there was no significant difference in PP or TLR between stented and unstented patients in the DCB cohorts, but in the RCTs, patients who received additional stenting did not show any statistical advantage after DCB treatment over patients treated with POBA, while patients who did not were significantly of lesions with severe calcifications (and again, the definitions of "severe calcification" are variable), while others do not report any data. Nevertheless, the retrospective study of Schmidt et al. reported that severe calcifications were responsible of significantly lower PPs (60% and 36% in severely calcified lesions vs 82% and 56% in non/moderately calcified lesions at 1 and 2 years, respectively, p=0.023), and were an independent risk factor for restenosis (OR: 2.15, 95%CI: 1.018,4.54; p=0.045). [START_REF] Laird | PACT drug-coated balloon: Consistent clinical outcomes across patient populations and challenging lesions[END_REF] Fanelli et al. made the same observation, [START_REF] Fanelli | Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease[END_REF] and also showed that the circumferential distribution of calcifications is more pejorative than their length, and that in case of involvement of only one quadrant of the parietal circumference, the efficacy of paclitaxel seems to be preserved. Consistently, our subgroup analysis reported significantly worse PP in heavily calcified lesions compared to no, mid-to moderately calcified lesions at 2 years.

On the other hand, our meta-analysis showed a significant decrease in PP in diabetic vs nondiabetic patients, in agreement with the results observed in coronary interventions. [START_REF] Wang | New predictors of instent restenosis in patients with diabetes mellitus undergoing percutaneous coronary intervention with drug-eluting stent[END_REF] Nonetheless, the subgroup analysis of diabetic patients in the AcoArt study showed significantly lower 6-month LLL in the DCB group vs POBA, [START_REF] Schneider | 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[END_REF] suggesting an efficacy of DCBs even in diabetic patients, which was confirmed at 1 and 2 years in our subgroup analysis.

RCTs included short or intermediate lesions, when the lesion length of femoro-popliteal disease exceeds 10cm in two-thirds of the cases. [START_REF] Dearing | Primary stenting of the superficial femoral and popliteal artery[END_REF] However, DCB angioplasty also appears to be significantly superior to POBA in long lesions (>15cm). Indeed, the SFA-Long study found no significant difference in PP between the lesion subgroups <25cm and >25cm (75% vs 66% at 2 years respectively, p=0.25), [START_REF] Micari | 1-Year Results of Paclitaxel-Coated Balloons for Long Femoropopliteal Artery Disease: Evidence From the SFA-Long Study[END_REF] just like the IN.PACT SFA [START_REF] Fanelli | Optimal DCB Performance LEVANT 2 and Global SFA Real-World Registry[END_REF][START_REF] Werk | Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial[END_REF][START_REF] Steiner | 12-Month Results From the First-in-Human Randomized Study of the Ranger Paclitaxel-Coated Balloon for Femoropopliteal Treatment[END_REF][START_REF] Jia | Acotec Drug-Coated Balloon Catheter: Randomized, Multicenter, Controlled Clinical Study in Femoropopliteal Arteries: Evidence From the AcoArt I Trial[END_REF] study between the subgroups <5cm, 5-10cm and 10-18cm (89% vs 79.1% vs 72.6% at 2 years respectively, p=0.57), even though a progressive decrease in PP was observed with the increase in lesion length. Similarly, our meta-analysis showed no significant difference between short and long lesions in terms of PP at 1 and 2 years. Interestingly, TLR and PP rates did not differ significantly between occlusions and stenosis, with occlusion rates ranging from 16 to 57% in RCTs, 12 to 65% in global registries and 42 to 60% in long lesions' studies.

Finally, at a time when health systems are severely indebted, any new treatment must show an economic advantage. The cost-difference between DCB and POBA for femoral-popliteal lesions is difficult to assess, as there is variability between countries in terms of costs and reimbursement. However, the initially higher cost of these devices appears to be compensated by a significant reduction in CD-TLR. [START_REF] Diehm | Cost-effectiveness analysis of paclitaxel-coated balloons for endovascular therapy of femoropopliteal arterial obstructions[END_REF][START_REF] Pietzsch | Economic analysis of endovascular interventions for femoropopliteal arterial disease: a systematic review and budget impact model for the United States and Germany[END_REF][START_REF] Salisbury | Cost-Effectiveness of Endovascular Femoropopliteal Intervention Using Drug-Coated Balloons Versus Standard Percutaneous Transluminal Angioplasty: Results From the IN.PACT SFA II Trial[END_REF] Nonetheless, despite significant efforts to correct the misalignment between the financial interest of patients, health care providers and payers, the operational margins for hospitals remain the lowest with the use of DCBs. Additionally, to avoid geographic miss, the balloon length should always exceed the lesion length, and at current reimbursement, the use of more than two DCBs per procedure would no longer be cost-effective compared with drug eluting stents (DESs). [START_REF] Sridharan | Cost-effectiveness analysis of drug-coated therapies in the superficial femoral artery[END_REF]

Limitations

Importantly, the only significant clinical improvement was seen in RC and walking distance capacity. However, treadmill tests were not always reported, thus, it is possible that walking capacity was not always objectively verified [START_REF] Rutherford | Recommended standards for reports dealing with lower extremity ischemia: revised version[END_REF] and that lack of blinding could have influenced the results. Nonetheless, there is a consistency between the significant improvement in walking distance objectified by a 6-min walking test and the significant improvement in RC.

Interestingly, the absence of correlation between walking capacity and ABI, [START_REF] Long | Correlation between ankle-brachial index, symptoms, and health-related quality of life in patients with peripheral vascular disease[END_REF] is largely due to the limitations of the ABI, [START_REF] Manfredini | Ankle brachial pressure index: faulty or overused?[END_REF] which is more sensitive for detecting PAD than for identifying IC, such that only 10-30% of patients identified with PAD (ABI<0.90) exhibit the classic symptoms of IC. [START_REF] Potier | Use and Utility of Ankle Brachial Index in Patients with Diabetes[END_REF] This lack of significant advantage for DCBs in most of the clinical endpoints seems contradictory with the highly significant decrease in TLR and highlights the fact that TLR may not be as objective as other endpoints. Using GRADE assessment criteria, the quality of the evidence was low for the outcome of RC; moderate for death, amputation, TLR, LLL and PP and high for binary restenosis, as reported in Supplementary Table V. Indeed, performance bias was high and the criteria used to determine the need for CD-TLR were never directly defined.

Hence, in the LEVANT 2 [START_REF] Tepe | Angiographic and Clinical Outcomes After Treatment of Femoro-Popliteal Lesions with a Novel Paclitaxel-Matrix-Coated Balloon Catheter[END_REF][START_REF] Tepe | Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial[END_REF] trial, in which the clinical evaluation was made by a blinded physician, there was a 0.5% difference in TLR rates between DCB and POBA at 1 year, while in the IN.PACT trial, [START_REF] Werk | Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial[END_REF] in which it was performed by the non-blinded treating physician, there was a 59.8% difference. This lack of blinding might have resulted in more reinterventions after POBA in the IN.PACT trial, in which the bias of the non-blinded physician could have been responsible for delayed reinterventions in the DCB arm, in comparison to patients showing the same imaging and clinical presentations but treated with POBA, since similar binary restenosis rates were observed in both trials (10.9% in the LEVANT 2 [START_REF] Tepe | Angiographic and Clinical Outcomes After Treatment of Femoro-Popliteal Lesions with a Novel Paclitaxel-Matrix-Coated Balloon Catheter[END_REF][START_REF] Tepe | Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial[END_REF] trial vs 12.0%). Consequently, the particularly low rate of reinterventions resulted in a lack of statistical power on this criterion.

Likewise, most studies were powered to detect anatomic endpoints. Indeed, primary endpoints included LLL, PP or TLR. As such, most clinical endpoints were secondary endpoints, which are usually not taken into consideration from a power of randomization standpoint when designing a trial. Hence, they may not be statistically sound and should be interpreted with caution. In addition, the evaluation of functional improvement is not yet well standardized and several criteria have been used, which makes their interpretation difficult. Nonetheless, it is interesting to note that to achieve equivalent clinical improvement, a significantly lower number of reinterventions were needed after DCB angioplasty.

More importantly, patient randomization always occurred after crossing the lesion and in the event of successful predilatation. This led to an "over-selection" and patients most likely to require secondary stenting were excluded from the outset, which partly explains the low rates of stenting in the RCTs compared to global registries. Additionally, 91.7% and 88.6% of the patients included in the RCTs and global registries suffered from IC. Only the BIOLUX-PI [START_REF] Laird | Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA[END_REF] and AcoArt I [START_REF] Schneider | 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[END_REF][START_REF] Scheinert | Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial[END_REF] studies distinguished themselves by including patients with more advanced stages of PAD (13-20% and 40-44% of CLI patients respectively), which seems to be more representative of populations treated in current practice.

Their results regarding the primary efficacy endpoint (LLL) are at least equivalent to those of other RCTs. However, concerns were raised about the safety of DCBs in the calf arteries of CLI patients, [START_REF] Hammad | Analysis of IN.PACT DEEP trial on the association between changes in perfusion from pre-to postrevascularization and clinical outcomes in critical limb ischemia[END_REF] nonetheless, these may not translate to patients with femoro-popliteal disease, as DCBs differ between the two arterial segments and the amount of paclitaxel reaching the foot may be smaller after being filtered by the calf muscles. To further respond to the question of safety and efficacy of DCBs in CLI patients in this vascular bed, a study with the IN.PACT DCB (NCT02758847) is actually enrolling 50 patients.

The size of study groups was limited to support in depth subgroup analyses and meta-regression of a larger number of covariates and long-term follow-up is missing. Moreover, the width of the confidence interval after 2 years increases in the meta-analysis, in relation to the small number of studies and the small sample size available at later time points. Furthermore, some trials have not been published in peer-reviewed journals (in whole or their long-term follow-up) and data extraction was based on or supplemented by presentations and online archived material from international meetings or regulatory authorities. However, we have chosen to include those to counteract any risk of publication bias, thus, this meta-analysis is the first to compile the data from 8 different DCBs.

At last, all the studies recommended dual antiplatelet therapy but the duration was widely variable (range 1-6 months) and could be increased in case of "bail-out" stenting.

CONCLUSION

DCB angioplasty is an effective treatment associated with high procedural success. In a metaanalysis of industry sponsored trials, it consistently reduced LLL, binary restenosis, and TLR when compared to POBA alone in the treatment of femoro-popliteal disease. Further independent, non-industry sponsored RCT's are necessary to better delineate the role of DCB in the treatment of infra-inguinal occlusive disease.

Figure 1 .Figure 2 .Figure 3 .Figure 1 .

 1231 Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

  and Schmidt et al.'s 44 studies) and 3 global registries focusing on long lesions (IN.PACT Global Long Lesions,

support for the research, authorship, and/

less likely to develop LLL. Nonetheless, a cohort of 33 patients was followed in the margin of the randomized population of the ILLUMENATE EU RCT following predilatation failure, [START_REF] Scheinert | The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty[END_REF] all treated with stents and DCBs. Their lesions were longer (8.8 vs 7.1cm in the ILLUMINATE EU RCT), more severely calcified (15.6 vs 12% respectively) and showed more occlusions (54.5 vs 19% respectively). The PP and CD-TLR rates were therefore slightly lower than those of the DCB group of the ILLUMINATE EU RCT study (78.8 vs 83.9% and 12 vs 5.9% respectively) but remained better than those of the POBA group (60.6% and 16.8% respectively). In addition, DCBs helped reduce stent coverage, in correlation with a subgroup analysis of the IN.PACT Global study showing a 24.4% rate of spot stenting, 37.8% of partial lesion coverage and 37.8% of whole lesion coverage. [START_REF] Ansel | Stented versus Non-Stented Outcomes at 2 Years: A Sub-analysis of the IN[END_REF] However, the question, whether DCBs can still provide positive remodeling in the presence of primary or secondary stenting is still open. Hopefully the BIOLUX-4EVER (DCB use followed by secondary stenting) and DEBAS studies (primary stenting followed by DCB use) will provide some answers. [START_REF] Deloose | BIOLUX 4EVER : Combining Passeo-18 Lux DCB and Pulsar-18 BMS : 12 month results of full cohort[END_REF] Post-dilatation was generally recommended before considering "bail-out stenting," however it remained necessary in 9.7% of DCB procedures in RCTs, one in four procedures in the metaanalysis of the DCB cohorts (20.2%) and 30.9% in the long lesions subanalysis. Interestingly, nearly 40% of patients required stenting in the LUTONIX Long Lesion registry, [START_REF] Banyai | Lutonix SFA Long Lesion Study Two Year Results : A Prospective, Multicenter, Single-Arm Trial with the Lutonix® Drug Coated Balloon for Treatment of Long Lesions in Femoropopliteal Arteries[END_REF] contrasting with the 10.5% of the SFA-Long study, [START_REF] Micari | 1-Year Results of Paclitaxel-Coated Balloons for Long Femoropopliteal Artery Disease: Evidence From the SFA-Long Study[END_REF] despite equivalent lesion lengths (21.3cm vs 25.1cm for the SFA-Long study) and similar occlusion levels (52.1% vs 49.5% respectively), only the calcification rate was higher in the LUTONIX Long Lesion registry (88.1% vs 50.4% respectively). Yet, it is difficult to compare the degrees of calcification between studies, some authors give the percentage of calcified lesions, regardless of their stage, others describe the rate

Screening

2-year results

B. Primary Patency 1-year results

2-year results

C. Binary Restenosis 1-year results

D. Rutherford Category Improvement from Baseline By number of patients 1-year results

2-year results

Mortality