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Drug‐eluting balloon angioplasty versus uncoated balloon angioplasty for the treatment of in‐stent restenosis of the femoropopliteal arteries

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy of drug‐eluting balloons (DEBs) compared with conventional uncoated balloon angioplasty in people with in‐stent restenosis of the femoropopliteal arteries. We define in‐stent restenosis as a 50% or greater narrowing of a previously stented vessel by duplex ultrasound or angiography.

Background

Description of the condition

Peripheral arterial disease (PAD) of the lower extremities is closely associated with atherosclerosis, a progressive and chronic disease process that leads to hardened vessels and decreased blood flow (Stary 1994). While many people with PAD of the lower extremities are asymptomatic, others present with a variety of symptoms, including pain with walking (intermittent claudication), pain at rest, and tissue loss in the affected limbs (McDermott 2001).

Numerous treatment modalities have been used for the management of PAD of the lower extremities. Medical therapies aim to arrest the progression of atherosclerotic disease and improve clinical outcomes by modifying patient risk factors (Ali 2012). Open surgical and endovascular interventions are used in conjunction with medical therapies to improve blood delivery to ischemic tissues by bypassing or otherwise opening arterial blockages with wires, catheters, and other specialized devices (Conte 2015).

Of the growing number of interventions available for treating lower‐extremity PAD, the deployment of stents across a stenotic or occluded arterial segment has become a routine practice in certain circumstances, such as long lesions and those that do not respond well to balloon angioplasty alone (OHTAC 2010). Stenting provides mechanical support required to maintain the patency of arterial lesions, but its effectiveness is limited by the occurrence of neointimal proliferation and overgrowth of the inner lining of the artery within the stent. This process, known as in‐stent restenosis, limits the amount of blood flow through the stent and results in the recurrence of the ischemic symptoms (Alfonso 2014).

Description of the intervention

Numerous endovascular interventions have been described for the treatment of in‐stent restenosis, including repeat balloon angioplasty, also known as plain old balloon angioplasty (POBA) alone, cutting balloon angioplasty, angioplasty with drug‐eluting balloons (DEBs), repeat stenting, and atherectomy (Singh 2014).

In all of the above interventions, a wire is first used to cross the stenotic or occlusive lesion within the stent before the treatment can be administered. The use of DEBs requires pre‐dilation of the stenotic lesion with a plain balloon. A second balloon is then used to coat the inside of the stent with a cytotoxic chemical to hopefully reduce neointimal proliferation.

How the intervention might work

POBA has been widely and successfully used for the treatment of lower‐extremity PAD and in‐stent restenosis, but is limited by recurrence of the neointimal hyperplastic process. DEBs address this limitation by applying a chemical to the stent that exerts an antiproliferative effect and arrests the re‐stenotic process (Waksman 2009).

The most commonly used DEB cytotoxic agent is the taxane paclitaxel, a chemotherapeutic medication that exerts its cytotoxic effect by stabilizing microtubules (Marupudi 2007). Paclitaxel is a safe and effective DEB agent for the treatment of PAD and has been used successfully to decrease the incidence of binary restenosis in femoropopliteal vessels (Canaud 2014).

Why it is important to do this review

There have been numerous prospective studies comparing DEB with POBA for the treatment of in‐stent restenosis. DEBs have shown promising results in the treatment of coronary in‐stent restenosis (Indermuehle 2013). However, the evidence for their use in femoropopliteal vessels is still unclear. Furthermore, DEB technologies are more expensive and less widely‐available than uncoated balloon angioplasty. Our review will help assess the efficacy of this intervention and determine whether it is associated with improved clinical outcomes.

Objectives

To assess the efficacy of drug‐eluting balloons (DEBs) compared with conventional uncoated balloon angioplasty in people with in‐stent restenosis of the femoropopliteal arteries. We define in‐stent restenosis as a 50% or greater narrowing of a previously stented vessel by duplex ultrasound or angiography.

Methods

Criteria for considering studies for this review

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

Primary outcomes

  • Amputation‐free survival, defined as the probability of being alive without loss of the affected lower extremity

  • Vessel patency, both primary and secondary, measured by late lumen loss, target lesion revascularization, and binary restenosis rate, defined as a 50% or greater narrowing of the vessel by duplex ultrasound or angiography.

  • Death

Secondary outcomes

  • Change in Rutherford category of PAD

  • Change in the Society for Vascular Surgery Wound, Ischemia, and Foot Infection (WIfI) stage (Mills 2014).

  • Change in ankle‐brachial index (ABI)

  • Change in quality of life (QoL) scores, measured by validated instruments such as the Short Form 36 (SF‐36)

  • Change in functional walking ability, measured by change in walking distance (using a treadmill or other walking test) or a walking impairment questionnaire

Search methods for identification of studies

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;

Searching other resources

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

Data collection and analysis

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.

Summary of findings

We will prepare a 'Summary of findings' table (Table 1) using the GRADEpro Guideline Development Tool (www.gradepro.org) to present the main findings of the review for the time point at which the most relevant data are available from the included studies (Atkins 2004). The population will consist of people with PAD and we will compare DEBs with uncoated balloon angioplasty for the treatment of in‐stent restenosis of femoropopliteal arteries. We will include the main outcomes listed in the Types of outcome measures that we consider essential for decision‐making in our 'Summary of findings' table. We will evaluate the quality of the evidence using the GRADE approach (Schünemann 2011b). We will assign one of four levels of quality: high, moderate, low, or very low, based on overall risk of bias, directness of the evidence, inconsistency of results, precision of the estimates, and risk of publication bias as previously described (Higgins 2011).

Open in table viewer
Table 1. Example summary of findings for the main comparison

Drug‐eluting balloon compared with uncoated balloon angioplasty

Patient or population: people with in‐stent restenosis of the femoropopliteal vessels
Setting: hospital
Intervention: drug‐eluting balloon angioplasty
Comparison: uncoated balloon angioplasty

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with uncoated balloon angioplasty

Risk with drug‐eluting balloon angioplasty

Amputation

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Primary vessel patency

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Target lesion revascularization

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Binary restenosis

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Death

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Change in Rutherford category

The mean change in Rutherford category was 0

The mean change in Rutherford category in the intervention group was 0 undefined (0 to 0 )

( studies)

Change in ankle brachial index

The mean change in ankle brachial index was 0

The mean change in ankle brachial index in the intervention group was 0 undefined (0 to 0 )

( studies)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Table 1. Example summary of findings for the main comparison

Drug‐eluting balloon compared with uncoated balloon angioplasty

Patient or population: people with in‐stent restenosis of the femoropopliteal vessels
Setting: hospital
Intervention: drug‐eluting balloon angioplasty
Comparison: uncoated balloon angioplasty

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with uncoated balloon angioplasty

Risk with drug‐eluting balloon angioplasty

Amputation

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Primary vessel patency

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Target lesion revascularization

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Binary restenosis

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Death

Study population

not estimable

( studies)

0 per 1000

0 per 1000
(0 to 0)

Change in Rutherford category

The mean change in Rutherford category was 0

The mean change in Rutherford category in the intervention group was 0 undefined (0 to 0 )

( studies)

Change in ankle brachial index

The mean change in ankle brachial index was 0

The mean change in ankle brachial index in the intervention group was 0 undefined (0 to 0 )

( studies)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Figuras y tablas -
Table 1. Example summary of findings for the main comparison