title: Systematic Review and Meta-analysis of Randomized Controlled Trials of Paclitaxel-Coated Balloon Angioplasty in the Femoropopliteal Arteries: Role of Paclitaxel Dose and Bioavailability.
abstract: OBJECTIVE
  To provide a qualitative analysis and quantitative synthesis of randomized controlled trials (RCTs) investigating paclitaxel-coated balloons (PCBs) in the femoropopliteal artery.
  
  
  METHODS
  PubMed, EMBASE, AMED, Scopus, CENTRAL, online content, and abstracts from international meetings were last screened in April 2015 for eligible RCTs using the PRISMA selection process. Risk of bias was assessed using the Cochrane Collaboration's tool, and quality of evidence was evaluated with the GRADE system. Outcome measures included late lumen loss (LLL) at 6 months and event rates of major limb amputations, binary lesion restenosis, and target lesion revascularization (TLR). Pooled treatment effects were analyzed in a random effects model to account for clinical heterogeneity; the outcomes are presented as the rate ratios (RRs) and their 95% confidence intervals (CIs). Extensive meta-regression was performed to analyze potential confounders. The review was registered in the PROSPERO database (CRD42015023938; www.crd.york.ac.uk/PROSPERO).
  
  
  RESULTS
  Eleven RCTs with 1609 subjects (1403 claudicants and 206 patients with critical limb ischemia) with medium-length femoropopliteal lesions (mean range 5.1-11.9 cm) were included. There was consistently high-quality evidence supporting the clear superiority of PCBs in terms of reduced LLL (mean difference -0.89 mm, 95% CI -1.14 to -0.64, p<0.001), less binary restenosis (RR 0.47, 95% CI 0.37 to 0.61, p<0.001), and fewer TLR events (RR 0.33, 95% CI 0.22 to 0.49, p<0.001). Major amputations were rare in both active and control arms (pooled event rate: 0.7%, 95% CI 0.3% to 1.2%). Results were stable across all potential risk modifiers and in the presence of stents as well. There was high-quality evidence that the dose of paclitaxel was related to the magnitude of the treatment effect; standard dose (3.0-μg and 3.5-μg) PCBs were significantly more effective compared with low-dose 2-μg PCB in reducing both restenosis (RR 2.1, 95% CI 1.2 to 3.4, p<0.001) and TLR (RR 2.5, 95% CI 1.9 to 3.8, p<0.001).
  
  
  CONCLUSIONS
  PCBs reduce by more than half the rates of restenosis and TLR in the femoropopliteal artery regardless of stent placement. Biologic effect size may vary according to paclitaxel bioavailability.
authors.affiliation: Department of Interventional Radiology, Guy's and St. Thomas' Hospitals, NHS Foundation Trust, King's Health Partners, London, UK Department of Interventional Radiology, Patras University Hospital, School of Medicine, Patras, Rion, Greece katsanos@med.upatras.gr.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Katsanos
authors.affiliation: Department of Interventional Radiology, Patras University Hospital, School of Medicine, Patras, Rion, Greece.
authors.forename: Stavros
authors.initials: S
authors.lastname: Spiliopoulos
authors.affiliation: Department of Interventional Radiology, Guy's and St. Thomas' Hospitals, NHS Foundation Trust, King's Health Partners, London, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Paraskevopoulos
authors.affiliation: Department of Interventional Radiology, Guy's and St. Thomas' Hospitals, NHS Foundation Trust, King's Health Partners, London, UK.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Diamantopoulos
authors.affiliation: Department of Interventional Radiology, Patras University Hospital, School of Medicine, Patras, Rion, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Karnabatidis
mesh_terms: D000671:Amputation, Surgical; D000800:Angioplasty, Balloon / Q000009:adverse effects / Q000295:instrumentation*; D001682:Biological Availability; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016009:Chi-Square Distribution; D020099:Coated Materials, Biocompatible; D003251:Constriction, Pathologic; D004867:Equipment Design; D005263:Femoral Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D023821:Limb Salvage; D016017:Odds Ratio; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058729:Peripheral Arterial Disease / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D011150:Popliteal Artery / Q000000981:diagnostic imaging / Q000503:physiopathology*; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D062666:Vascular Access Devices; D014654:Vascular Patency
chemical_list: D002317:Cardiovascular Agents; D020099:Coated Materials, Biocompatible; C495179:Pacliex; D017239:Paclitaxel
keywords: amputation; balloon angioplasty; bioavailability; dose; femoropopliteal segment; meta-analysis; meta-regression; paclitaxel; restenosis; stent; target lesion revascularization