Abstract: Three trials that randomized a combined total of 263 participants met the review inclusion criteria. All three trials examined the treatment of symptomatic in-stent restenosis within the femoropopliteal arteries. These trials were carried out in Germany and Austria and used paclitaxel as the agent in the drug-eluting balloons. Two of the three trials were industry sponsored. Two companies manufactured the drug-eluting balloons (Eurocor, Bonn, Germany; Medtronic, Fridley, Minnesota, USA). The trials examined both anatomical and clinical endpoints. We noted heterogeneity in the frequency of bailout stenting deployment between studies as well as in the dosage of paclitaxel applied by the DEBs. Using GRADE assessment criteria, we determined that the certainty of evidence presented was very low for the outcomes of amputation, target lesion revascularization, binary restenosis, death, and improvement of one or more Rutherford categories. Most participants were followed up to 12 months, but one trial followed participants for up to 24 months. Trial results show no difference in the incidence of amputation between DEBs and uncoated balloon angioplasty. DEBs showed better outcomes for up to 24 months for target lesion revascularization (odds ratio (OR) 0.05, 95% confidence Interval (CI) 0.00 to 0.92 at six months; OR 0.24, 95% CI 0.08 to 0.70 at 24 months) and at six and 12 months for binary restenosis (OR 0.28, 95% CI 0.14 to 0.56 at six months; OR 0.34, 95% CI 0.15 to 0.76 at 12 months). Participants treated with DEBs also showed improvement of one or more Rutherford categories at six and 12 months (OR 1.81, 95% CI 1.02 to 3.21 at six months; OR 2.08, 95% CI 1.13 to 3.83 at 12 months). Data show no clear differences in death between DEBs and uncoated balloon angioplasty. Data were insufficient for subgroup or sensitivity analyses to be conducted. Based on a meta-analysis of three trials with 263 participants, evidence suggests an advantage for DEBs compared with uncoated balloon angioplasty for anatomical endpoints such as target lesion revascularization (TLR) and binary restenosis, and for one clinical endpoint - improvement in Rutherford category post intervention for up to 24 months. However, the certainty of evidence for all these outcomes is very low due to the small number of included studies and participants and the high risk of bias in study design. Adequately powered and carefully constructed randomized controlled trials are needed to adequately investigate the role of drug-eluting technologies in the management of in-stent restenosis.

Plain-language summary: Our review included three clinical trials that randomized 263 participants (most recent search - November 28, 2017). Trials included leg arteries at and above the knee and were carried out in Europe; all used DEBs that contained the chemical known as "paclitaxel." Two companies manufactured the DEBs: Eurocor and Medtronic. Most study participants were followed for six or more months; this is called "follow-up." Results showed that DEBs were not better for participants than uncoated balloon angioplasty with regard to the need for amputation. At 24 months of follow-up, DEBs were associated with fewer target lesion revascularizations, which refers to the need to perform a procedure on a stent that had already been treated with a DEB or an uncoated balloon angioplasty for in-stent restenosis. DEBs were also found to have better binary restenosis rates, which refers to the percentage of treated stents that develop new stenosis after they have been treated with a DEB or an uncoated balloon angioplasty. Finally, more people who were treated with DEBs described improvement in their leg symptoms, as measured by a change in their Rutherford category. DEBs were not found to be better for participants than uncoated balloon angioplasty with regard to patient death. The certainty of the evidence presented was very low because we identified only three studies with small numbers of participants, and because many participants in those studies were lost to follow-up. Furthermore, risk of performance and attrition bias was significant, as was risk of other biases, due to lack of accounting for the type of stent treated and the need for bailout stenting.