Types of studies

Randomized controlled trials that compare drug‐eluting balloons (DEBs) with uncoated balloon angioplasty for in‐stent restenosis of the femoropopliteal arteries.

Types of participants

People undergoing drug‐eluting or uncoated balloon angioplasty for the treatment of in‐stent restenosis of the femoropopliteal arteries.

Types of interventions

DEBs compared with uncoated balloon angioplasty for the treatment of in‐stent restenosis of femoropopliteal arteries. The analysis will exclude hybrid studies in which DEBs are utilized simultaneously with open surgery, as well as studies that include atherectomy procedures, cutting balloon angioplasty, vascular brachytherapy, and repeat stenting with plain or drug‐eluting stents for the management of in‐stent restenosis.

Types of outcome measures

Electronic searches

The Cochrane Vascular Information Specialist (CIS) will search the following databases for relevant trials:

• The Cochrane Vascular Specialised Register;

• The Cochrane Central Register of Controlled Trials (CENTRAL) via The Cochrane Register of Studies Online.

See Appendix 1 for details of the search strategy which will be used to search CENTRAL.

The Cochrane Vascular Specialised Register is maintained by the CIS and is constructed from weekly electronic searches of MEDLINE, Embase, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used are described in the Specialised Register section of the Cochrane Vascular module in The Cochrane Library (www.cochranelibrary.com).

The CIS will search the following trials registries for details of ongoing and unpublished studies;

• ClinicalTrials.gov (www.clinicaltrials.gov)

• World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch)

• ISRCTN Register (www.isrctn.com/)

Searching other resources

We will further examine the bibliographies of studies identified in our search to identify other relevant articles.

Selection of studies

Two review authors (AK and WA) will independently select trials for inclusion in this review from the studies identified by the search. A third review author (AD) will assess these trials, and will determine their suitability and adjudicate any disagreement between the first two authors. The inclusion criteria used to determine suitability are outlined in the section Criteria for considering studies for this review.

Data extraction and management

Two review authors (AK and WA) will extract relevant data from the included studies. We will collect participant demographics (age, gender, PAD co‐morbidities, Rutherford category of PAD, and baseline ABI), interventions (type and duration of DEBs and uncoated balloon angioplasty), and outcomes (as specified in the section Criteria for considering studies for this review). A third review author (AD) will cross‐check data.

Statistical analysis will comply with the standard methods of Cochrane Vascular. We will use the computer software package Review Manager 5.3 (RevMan) (RevMan 2014) to perform all statistical analyses and generate figures.

Assessment of risk of bias in included studies

Two review authors (AK and WA) will carry out a thorough risk of bias assessment of all included studies using Cochrane's tool for assessing risk of bias (Higgins 2011). The tool assesses bias in six different domains, with each domain receiving a score of high, low, or unclear depending on each review author’s judgement. Disagreements will be adjudicated by a third review author (AD). We will contact study authors if clarification is required to better assess a risk of bias.

Measures of treatment effect

We will calculate and report continuous outcome measures, such as change in quality‐of‐life scores, using the mean difference (MD). If the included studies use different scales, however, then we will calculate a standardized mean difference (SMD) instead. We will also calculate the associated 95% confidence interval (CI) between the two treatment groups. We will calculate and report dichotomous (binary) outcome measures, such as target lesion revascularization, using the hazard ratio (HR) or risk ratio (RR) with the associated 95% CI, depending on the reported data. We will carry out analyses at different time points, as reported by the trials. We will base our calculations on an intention‐to‐treat approach.

Unit of analysis issues

The unit of analysis will be the treated limb for anatomical outcomes such as late lumen loss or binary restenosis. Conversely, the unit of analysis will be the patient for outcomes such as quality of life, or death.

Dealing with missing data

We will contact study authors to inquire about missing or incomplete data. In the event that an included study has a significant amount of missing data and attempts to contact the study authors are unsuccessful, then we will assess the risk of bias associated with including the study in the meta‐analysis and perform a sensitivity analysis.

Assessment of heterogeneity

We will assess inter‐study heterogeneity using a forest plot (Schünemann 2011). We will also calculate chi²and I² tests to measure the amount of heterogeneity (Higgins 2003). I² values less than 50% indicate low heterogeneity, I² values between 50% to 75% indicate moderate heterogeneity, and I² values greater than 75% indicate significant heterogeneity (Deeks 2011).

Assessment of reporting biases

We will construct a funnel plot to assess publication bias where 10 or more studies are available for a particular outcome (Sterne 2011).

Data synthesis

To calculate the pooled treatment effect data we will use random‐effects or fixed‐effect models, depending on the degree of inter‐study heterogeneity. If the calculated degree of inter‐study heterogeneity is significant (defined as I² greater than 75%), then we will use the random‐effects model. Otherwise, we will use the fixed‐effect model. We will calculate 95% CIs for continuous and dichotomous outcome variables, as detailed above. We will create a forest plot for each treatment effect as per Cochrane Vascular guidelines.

Subgroup analysis and investigation of heterogeneity

Depending on the available data, we will perform subgroup analyses by type of DEBs, the type and dose of pharmacological agent used in the DEB, and the clinical severity of PAD, as defined by the change in Rutherford category or WIfI stage. If possible, we also plan to perform subgroup analyses for people with diabetes and the type of antiplatelet agents that were prescribed to participants in the included trials.

Sensitivity analysis

We will exclude studies at a high risk of bias from the pooled analysis and we will perform the analysis again to assess their impact. We will then perform a sensitivity analysis by sequentially excluding studies at a high risk of bias.