Subintimal angioplasty for lower limb arterial chronic total occlusions

Abstract

Background

In recent years subintimal angioplasty (SIA) has become an established percutaneous procedure for the treatment of symptomatic lower limb arterial chronic total occlusions. However, the clinical benefits of this practice remain unclear. The aim of the review was to determine the effectiveness of SIA on clinical outcomes. This is an update of a review first published in 2013.

Objectives

To assess the effectiveness of SIA versus other treatment for people with lower limb arterial chronic total occlusions, determined by the effects on clinical improvement, technical success rate, patency rate, limb salvage rate, and morbidity rates.

Search methods

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (last searched January 2016) and Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 12). We also searched clinical trials registries.

Selection criteria

We included data from randomized controlled trials comparing the effectiveness of SIA and any other management method in the treatment of lower limb arterial chronic total occlusions. The primary intervention of interest was SIA, with or without a stent, for the restoration of vessel patency in people with occlusions of a lower limb artery. We compared SIA against alternative modalities used to restore vessel patency, including conventional percutaneous transluminal angioplasty, surgical bypass, or any other treatments. We compared different SIA devices and techniques against each other.

Data collection and analysis

Two review authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. The third review author resolved disagreements.

Main results

Two studies, involving a total of 147 participants with TransAtlantic Inter‐Society Consensus (TASC)‐II D femoropopliteal lesions, met our inclusion criteria and were included in the review. Both studies were small but otherwise of high methodological quality. However, the treatment techniques and control groups of the two studies differed, precluding the combining of study results and resulting in the evidence being less applicable. We therefore considered the quality of the evidence to be low.

In one study, participants with TASC‐II D lesions were randomized to receive either SIA with stenting of the superficial femoral artery or remote endarterectomy (RE) with stenting of the superficial femoral artery. Three‐year follow‐up results showed a Rutherford classification improvement of 64% in the SIA group compared to 80% in the RE group (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.61 to 1.03; 95 participants; P = 0.079). Postexercise ankle brachial index improvements (defined as an increased value of 0.2) were reported in 70% of participants in the SIA group compared to 82% in the RE group (RR 0.86, 95% CI 0.68 to 1.08; 95 participants; P = 0.18). The study reported the technical success rate was 93% for the SIA group and 96% for the RE group (RR 0.97, 95% CI 0.88 to 1.07; 95 participants; P = 0.91). Primary patency at 12 months was 59.1% in the SIA group compared to 78.4% in the RE group (RR 0.75, 95% CI 0.57 to 1.00; 95 participants; P = 0.05). Primary patency at 24 months was 56.8% in the SIA group compared to 76.5% in the RE group (RR 0.74, 95% CI 0.55 to 1.00; 95 participants; P = 0.05) and 47.7% in the SIA group and 62.7% in the RE group at 36 months (RR 0.76, 95% CI 0.52 to 1.11; 95 participants; P = 0.15). Assisted primary patency was 52.3% in the SIA group compared to 70.6% in the RE group (P = 0.01) at 36 months. Secondary patency was better for the RE group (P = 0.03) at 36 months. Limb salvage at three years' follow‐up was 95% in the SIA group and 98% in the RE group (RR 0.97, 95% CI 0.90 to 1.05; 95 participants; P = 0.4). There were no perioperative deaths, but complications occurred in two SIA participants (femoral pseudoaneurysm and pulmonary edema) and in three RE participants (seroma, femoral pseudoaneurysm, superficial femoral artery acute occlusion).

In the second study, the effects of the SIA OUTBACK re‐entry catheter device in people affected by TASC‐II D superficial femoral artery chronic total occlusion were compared with the SIA manual re‐entry technique. This study did not report clinical improvement and limb salvage. Technical success was achieved in all cases in both the OUTBACK device and manual groups. The primary 6‐month patency rate was 100% in the OUTBACK group (26 of 26 participants) compared to 96.2% in the manual group (25 of 26 participants) (RR 1.04, 95% CI 0.94 to 1.15). The primary 12‐month patency rate was 92.3% in the OUTBACK group (24 of 26 participants) compared to 84.6% in the manual group (22 of 26 participants) (RR 1.09, 95% CI 0.90 to 1.33). Patency rates at 24 and 36 months were not reported. The study reported that there were no complications.

Authors' conclusions

Using the GRADE approach, we classified the quality of the evidence presented by both studies in this review as low due to small study size and the small number of studies. In addition, the two included trials differed from each other in the techniques and control used, and we were therefore unable to combine the data. Consequently there is currently insufficient evidence to support SIA over other techniques. Evidence from more randomized controlled trials is needed to assess the role of SIA in people with chronic lower limb arterial total occlusions.

Plain language summary

Subintimal angioplasty for lower limb arterial chronic total obstructions

Background

The most common symptom of arterial disease of the leg is claudication, a cramping pain caused by an inadequate supply of blood to the affected muscle. Claudication often affects the calf muscle and is typically triggered by exercise and relieved by rest. More severe restriction of the blood supply may result in pain at rest, leg ulcers, or gangrene. Arterial disease, and particularly severe claudication, may require bypass surgery or angioplasty (surgical procedure to widen narrowed or obstructed arteries or veins) to improve blood flow to the leg. However, in long arterial occlusions (obstructions) with hard plaque, normal transluminal angioplasty often fails. Subintimal angioplasty for peripheral vascular disease was first described in the 1990s. The subintimal space at the start of the occlusion is entered with a wire loop that is used to cross the occlusion with the support of catheter and re‐enter the vessel lumen of the patent (not‐obstructed) distal artery to form a new blood flow channel. This technology has enabled the development of devices such as the OUTBACK re‐entry catheter.

Study characteristics and key results

We identified two randomized controlled trials involving a total of 147 participants (current until January 2016). Due to differences in the techniques and outcomes measured, we were unable to combine the data from these studies. In one study, participants were randomized to receive either subintimal angioplasty (SIA) with stenting or remote endarterectomy (RE) (a surgical procedure to unblock the artery) with stenting. This study showed significantly better vessel patency (no obstruction) with RE compared to SIA. Three‐year follow‐up results showed clinical improvement measured by a Rutherford classification improvement in 64% of participants in the SIA group compared to 80% of participants in the RE group. Postexercise ankle brachial index improvements (0.2) were reported in 70% of SIA participants compared to 82% of RE participants. The technical success rate was 93% for SIA participants and 96% for RE participants. Primary patency was 56.8% in SIA compared to 76.5% in RE at 24 months, and 47.7% in SIA and 62.7% in RE at 36 months. Assisted primary patency was 52.3% in SIA compared to 70.6% in RE at 36 months. Secondary patency favored RE at 36 months. Limb salvage at three years' follow‐up was 95% in the SIA group and 98% in the RE group. There were no deaths during or around the time of the procedure, but complications occurred in two SIA participants and three RE participants.

The other study, which compared the SIA OUTBACK device with a manual re‐entry technique, reported that technical success was achieved in all cases but did not report on clinical improvement. The primary 6‐month patency rate was 100% in the OUTBACK group (26 of 26 participants) compared to 96.2% in the manual re‐entry group (25 of 26 participants). The primary 12‐month patency rate was 92.3% in the OUTBACK group (24 of 26 participants) compared to 84.6% in manual group (22 of 26 participants). Patency rates at 24 and 36 months were not reported. Limb salvage rates at 36 months were not reported. No complications were reported.

Quality of the evidence

Both studies were at an overall low risk of methodological bias, but the quality of the evidence is low due to small study size and the small number of studies. Moreover, the two included trials differed from each other in the techniques and control used, preventing the combining of trial results. Since we included only two small studies, we doubt the completeness and applicability of the evidence presented in this review. Further studies are needed to reach a definitive conclusion.

Background

Description of the condition

Lower limb arterial chronic total occlusion is a widespread problem that increases in frequency with advancing age, affecting 12% to 20% of people aged 65 years and older (Hirsch 2001). Symptoms of lower limb arterial chronic total occlusions range from calf pain on exercise (intermittent claudication (IC)) to rest pain, skin ulceration, or gangrene in people with critical limb ischemia (CLI). Management of the patient with lower limb arterial chronic total occlusions involves treating abnormal levels of risk factors plus specific interventions aimed at relieving symptoms and limb salvage. Treating risk factors such as smoking, high blood pressure, and high cholesterol levels may help to reduce disease progression in the lower limb. Conservative treatment options include the use of antiplatelet agents, exercise regimens, and therapy with vasodilators. Treatment options for more severe symptoms include endovascular interventions such as percutaneous transluminal angioplasty (PTA), stent implantation, and surgical procedures such as bypass and endarterectomy. Transluminal angioplasty, in which the area of occlusion is expanded by a balloon inserted within the artery, is an important treatment option for people with more severe symptoms, however transluminal angioplasty is hampered by the risk of chronic total occlusions. In recent years subintimal angioplasty (SIA) has become an established percutaneous procedure for the treatment of symptomatic lower limb arterial occlusions (Bolia 1994; Chen 2011; Ko 2011; Nydahl 1997; Zhu 2009).

Description of the intervention

Subintimal angioplasty is a minimally invasive percutaneous technique for the recanalization of occluded lower limb arteries (London 1993; Nydahl 1997). Subintimal angioplasty was first described in 1990 to overcome long and chronic arterial occlusions (Bolia 1990). Usually performed under local anesthesia, the aim of SIA is to create a channel between the intima and the media by means of an intentional dissection, and then to perform an angioplasty on this channel to enlarge it and maintain patency (Bolia 1994). It is now also applied to long crural artery and iliac artery occlusions (Bolia 1994; Chen 2011; Ko 2011; Nydahl 1997; Zhu 2009). Subintimal angioplasty has increased in popularity, particularly in CLI, but remains controversial in people with IC because of a perceived high complication rate and low long‐term patency (Li 2012; Met 2008).

How the intervention might work

The technique uses a catheter to enter the subintimal space proximally to the occlusion. A hydrophilic angle‐tipped guidewire is then introduced and is encouraged to form a loop by its natural tendency to do so when the tip abuts the occlusion. Once the looped guidewire advances in the subintimal space, it takes a spiral course. The loop allows the stiffer part of the guidewire to be used to continue the dissection. The guidewire will naturally tend to re‐enter the true lumen when it again encounters normal patent vessel (Bolia 1990). In recent years re‐entry devices have been introduced (Beschorner 2009; Etezadi 2010; Mixon 2009).

Why it is important to do this review

The published literature reflects polarized viewpoints, with some authors supporting the technique and others dismissing it (Aleksynas 2009; Boufi 2010; Indes 2010). The majority of these reports feature small series of patients, and there remains little long‐term follow‐up data in the literature to date. While bypass surgery and angioplasty for lower limb ischemia have been addressed in other Cochrane reviews (Fowkes 1998; Fowkes 2008), there are currently no Cochrane reviews that address SIA. We therefore set out to systematically review the effectiveness of SIA versus any other treatment for people with lower limb arterial chronic total occlusions. This is an update of a review first published in 2013.

Objectives

To assess the effectiveness of subintimal angioplasty versus other treatment for people with lower limb arterial chronic total occlusions, determined by the effects on clinical improvement, technical success rate, patency rate, limb salvage rate, and morbidity rates.

Methods

Criteria for considering studies for this review

Types of studies

We included randomized controlled trials comparing SIA with control or any other treatment. We considered trials that were published in full or in which results were presented in abstract form. We included abstracts only if there were sufficient data for analysis, or if the authors planned for a full publication or had unpublished data available on file for review and analysis. We included trials in which the minimum length of follow‐up was no less than 12 months. We included trials that were analyzed as intention to treat (that is they reviewed the effectiveness of setting out to do a subintimal angioplasty rather than setting out to do conventional angioplasty or any other intervention). There was no restriction on language. Where necessary, we planned to translate non‐English language studies for their inclusion in the analyses.

Types of participants

We included people with chronic lower limb ischemia (IC or CLI, or both) who were treated for an iliac, femoral, popliteal, or crural occlusion by subintimal angioplasty. We planned to analyze the different patient groups (IC and CLI) separately.

We selected studies including participants with:

1. symptomatic chronic lower limb arterial ischemia, IC, and CLI (rest pain, tissue loss);

2. documented occlusions of lower limb arteries (by duplex ultrasound scan, computed tomography (CT), magnetic resonance (MR), or angiogram);

3. lesions and who were allocated to treatment with SIA or any other treatments.

Types of interventions

The primary intervention of interest was SIA, with or without a stent, for the restoration of vessel patency in people with occlusions of a lower limb artery. This technique can be performed with devices such as the OUTBACK re‐entry catheter. We compared SIA against alternative modalities used to restore vessel patency including conventional percutaneous transluminal angioplasty (PTA), surgical bypass, or any other treatments. We also compared different SIA devices and techniques against each other.

Types of outcome measures

Primary outcomes

1. Clinical improvement (relief of rest pain, healing of ulcers, and improvement in walking distance).

Secondary outcomes

1. Technical success rate (good flow through the lesion immediately after intervention).

2. Vessel patency rate (i.e. restenosis or reocclusion rates, both primary and secondary, including duration to restenosis or reocclusion as defined by an imaging modality, e.g. duplex ultrasound, MR angiography, or CT angiography).

3. Limb salvage rates at 30 days, one year, and two years in participants with tissue loss.

4. Complications (including groin hematoma, vessel rupture or perforation, vessel wall dissection, distal emboli, renal failure, cerebrovascular event).

Search methods for identification of studies

There was no restriction on language.

Electronic searches

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

• The Cochrane Vascular Specialised Register (13 January 2016);

• The Cochrane Central Register of Controlled Trials (CENTRAL (2015, Issue 12)) via The Cochrane Register of Studies Online.

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

The CIS searched the following trial registries for details of ongoing and unpublished studies using the terms 'subintimal' or 'sub‐intimal' (13 January 2016):

• 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

For this update we searched the reference lists of relevant trial reports and reviews identified from the electronic searches.

Data collection and analysis

Selection of studies

Two review authors (ZHC and JHZ) independently assessed all retrieved citations based on the title and abstract and independently selected trials for full review. Any disagreements were resolved by discussion with the third review author (ZYL).

Data extraction and management

Two review authors (ZHC and JHZ) independently extracted and recorded the data on forms developed by Cochrane Vascular. Disagreements were resolved by the third review author (ZYL) and, if necessary, we sought additional information from the study authors.

Assessment of risk of bias in included studies

Two review authors (ZHC and JHZ) independently assessed the included studies for risk of bias using the Cochrane 'Risk of bias' tool (Higgins 2011).

(1) Sequence generation (checking for possible selection bias)

We assessed the method used to generate the allocation sequence in the included studies to determine whether the allocation sequence method was sufficient to produce comparable groups.

We rated the method as one of:

• low risk of bias (any truly random process such as a random number table, a computerized random number generator, coin toss);

• high risk of bias (an allocation sequence using non‐random components such as odd or even date of birth, hospital or clinic record number, clinician judgement, or participant preference);

• unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We assessed each included study to determine the adequacy of the allocation concealment and whether investigators and participants could have foreseen the intervention allocations at any stage of the recruitment or intervention processes.

We rated the methods as:

• low risk of bias (e.g. central randomization or sealed, opaque envelopes);

• high risk of bias (open random allocation, e.g. unsealed or non‐opaque envelopes, alternation, case record number);

• unclear risk of bias.

(3) Blinding (checking for possible performance bias)

We assessed each included study to determine the adequacy of the methods used, if any, to blind study participants and investigators to the intervention allocations. We judged studies to be at low risk of bias if 1) they were blinded, 2) we judged that the lack of blinding could not have influenced the results, and 3) the blinding was unlikely to have been broken. We assessed blinding for different outcomes or classes of outcomes.

We assessed the methods as:

• low risk of bias, high risk of bias, or unclear risk of bias for participants;

• low risk of bias, high risk of bias, or unclear risk of bias for personnel;

• low risk of bias, high risk of bias, or unclear risk of bias for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We assessed each included study to determine the completeness of data for each outcome, including attrition and exclusions from the analysis. We planned to state whether attrition and exclusions were reported and if explanations were provided. We intended to assess the likelihood that missing outcome data biased the results, and whether the missing data and the causes for the missing data were balanced across groups. Where sufficient information was reported, or could be supplied by the trial authors, we intended to include missing data in the analyses we planned to undertake.

We assessed methods as:

• low risk of bias;

• high risk of bias;

• unclear risk of bias.

(5) Selective outcome reporting

We analyzed each included study to determine whether all of the prespecified primary and secondary outcomes had been reported, and whether outcome measures or analyses that were not prespecified had been reported.

We intended to assess the methods as:

• low risk of bias (where all of the study's prespecified outcomes and expected outcomes of interest to the review were reported);

• high risk of bias (where not all of the study's prespecified outcomes were reported; one or more of the reported primary outcomes were not prespecified; or outcomes of interest were reported incompletely);

• unclear risk of bias.

(6) Other potential threats to validity

We assessed each included study for other possible sources of bias, such as risk of bias introduced by early termination, baseline study group imbalance, fraud, or other noted contributors to bias.

We intended to classify this bias as:

• low risk of bias;

• high risk of bias;

• unclear risk of bias.

(7) Overall risk of bias

We planned to make explicit judgements about whether studies were at high risk of bias according to the criteria provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For all relevant areas of bias, we planned to assess the likely magnitude and direction of the bias and its potential impact on the outcomes. We planned to explore the magnitude of the level of bias by undertaking sensitivity analyses.

Measures of treatment effect

We intended to combine all results and perform a meta‐analysis using Review Manager 5 software provided by Cochrane (RevMan 2014).

We used risk ratios with 95% confidence intervals (CIs) for dichotomous outcomes. We planned to use mean differences with 95% CIs for continuous outcomes.

Unit of analysis issues

We intended to analyze each cluster‐randomized trial individually before deciding whether or not to include it in the review. Due to the nature of the procedures involved, we did not expect that we would include any cross‐over trials. In studies with multiple treatment groups, we planned to assess the possibility of including the subgroups with the interventions of interest. The unit of analysis was the individual participant.

Dealing with missing data

We planned not to impute missing outcome data for the primary outcome. If data were missing, or only imputed data were reported, we planned to contact the trial authors to request data on the outcomes for those participants who were assessed.

Assessment of heterogeneity

We intended to use the Chi² test to assess the heterogeneity of trials, employing Review Manager 5 (RevMan 2014), with the significance level set at P = 0.1. If we found heterogeneity to be present, we intended to explore it by subgroup analysis based on the quality of the trials. As the two included studies were clinically heterogenous, we were unable to carry out any subgroup analysis.

Assessment of reporting biases

We planned to examine funnel plots corresponding to the meta‐analysis of the primary outcome to assess the potential for small‐study effects and publication bias. Due to there being only two trials identified for inclusion, we did not do this.

Data synthesis

We intended to use Review Manager 5 (RevMan 2014) to conduct our analysis. The exact methods used would depend on the data found in the included trials. If in future updates sufficient clinically similar studies become available, we plan to pool their results in a meta‐analysis.

We used risk ratios for dichotomous outcomes. For continuous outcomes, we intended to use the mean difference between the treatment arms at the end of follow‐up if all trials measured the outcome on the same scale, otherwise we intended to use the standardized mean difference.

If in future updates any trials have multiple treatment groups, we plan to divide the 'shared' comparison group into the number of treatment groups. We intend to treat the split comparison group as independent groups for comparing with the treatment groups. In the absence of heterogeneity, we plan to use fixed‐effect models to combine data in trials of the same intervention type. Where clinical or methodological heterogeneity is present, we plan to use a random‐effects model in the meta‐analysis. Where concerns arise about small‐sample bias, we intend to analyze the data using both methods and make a determination regarding the validity of the summary statistic.

Subgroup analysis and investigation of heterogeneity

We intended to perform subgroup analyses grouping the trials by:

• SIA with or without stent in each treatment group;

• SIA with or without device (e.g. OUTBACK re‐entry catheter) in each treatment group;

• different patient groups (IC and CLI).

If in future updates data are available, we plan to consider factors such as age, basic clinical diseases (diabetes, hypertension, cerebral infarction), location of occlusion segment, length of follow‐up, adjusted or unadjusted analysis in the interpretation of heterogeneity.

Sensitivity analysis

To test the robustness of the results, we intended to perform sensitivity analysis using both fixed‐effect and random‐effects models where possible. Furthermore, we intended to perform the analysis with and without the inclusion of studies with lower methodologic quality and studies at high risk of bias. We planned to evaluate the effect of trial size, large and small trials, on the total estimated effect size. As we included only two clinically different trials, this was not possible.

Summary of findings

Given that the two included studies described different comparisons, we created two 'Summary of findings' tables to summarise the results. We developed the tables in accordance with the GRADE approach using GRADEpro GDT.

Table 1 describes the comparison subintimal angioplasty versus remote endarterectomy. Table 2 describes the comparison of the SIA device OUTBACK re‐entry catheter versus SIA manual re‐entry technique for chronic total occlusions in the superficial femoral artery. Study populations consisted of people with TransAtlantic Inter‐Society Consensus (TASC)‐II D femoropopliteal lesions and chronic total occlusions in the superficial femoral artery, respectively. We selected the most important and clinically relevant outcomes thought to be essential for decision‐making for the 'Summary of findings' tables. These were clinical improvement, technical success, patency, and limb salvage, as described in the Types of outcome measures section. We graded the quality of the evidence as high, moderate, low, or very low, based on within‐study risk of bias, directness of evidence, heterogeneity, precision of effects estimates, and risk of population bias (GRADE 2004).

Summary of findings for the main comparison. Subintimal angioplasty with stenting versus remote endarterectomy for TASC‐II D femoropopliteal lesions.

Subintimal angioplasty with stenting versus remote endarterectomy for TASC‐II D femoropopliteal lesions
Patient or population: 95 people with Rutherford 3 to 5 TASC‐II D lesions Settings: hospital, Italy (October 2004 to December 2008) Intervention: subintimal angioplasty with stenting Comparison: remote endarterectomy
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Remote endarterectomy	Subintimal angioplasty with stenting
Clinical improvement: Rutherford classification improvement Rutherford classification Follow‐up: mean 51.2 months	804 per 1000	638 per 1000 (411 to 816)	RR 0.79 (0.61 to 1.03)1	95 (1 study)	⊕⊕⊝⊝ low2
Clinical improvement: ABI improvement Significant postexercise ABI improvement Follow‐up: mean 51.2 months	824 per 1000	708 per 1000 (560 to 889)	RR 0.86 (0.68 to 1.08)1	95 (1 study)	⊕⊕⊝⊝ low2
Technical success rate Follow‐up: mean 51.2 months	96 per 1000	932 per 1000 (845 to 1000)	RR 0.97 (0.88 to 1.07)1	95 (1 study)	⊕⊕⊝⊝ low2
12 months' patency rate Follow‐up: mean 51.2 months	784 per 1000	588 per 1000 (447 to 784)	RR 0.75 (0.57 to 1.00)1	95 (1 study)	⊕⊕⊝⊝ low2
24 months' patency rate Follow‐up: mean 51.2 months	765 per 1000	566 per 1000 (421 to 765)	RR 0.74 (0.55 to 1.00)1	95 (1 study)	⊕⊕⊝⊝ low2
36 months' patency rate Follow‐up: mean 51.2 months	627 per 1000	477 per 1000 (326 to 696)	RR 0.76 (0.52 to 1.11)1	95 (1 study)	⊕⊕⊝⊝ low2
36 months' limb salvage rate Follow‐up: mean 51.2 months	980 per 1000	951 per 1000 (882 to 1000)	RR 0.97 (0.9 to 1.05)1	95 (1 study)	⊕⊕⊝⊝ low2
Complications Follow‐up: mean 51.2 months	59 per 1000	45 per 1000 (8 to 260)	RR 0.77 (0.14 to 4.42)1	95 (1 study)	⊕⊕⊝⊝ low2	There were no perioperative deaths in Gabrielli 2012, but complications occurred in 2 SIA participants (femoral pseudoaneurysm and pulmonary edema) and in 3 RE participants (seroma, femoral pseudoaneurysm, superficial femoral artery acute occlusion)
*The basis for the assumed risk was the average risk in the RE group (i.e. the number of participants with events divided by total number of participants of the RE group included in the meta‐analysis). The corresponding risk (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). ABI: ankle brachial index; CI: confidence interval; RR: risk ratio; SIA: subintimal angioplasty
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹Assumed and corresponding risks calculated by GRADEpro GDT software, risk ratio calculated by Review Manager 5 (RevMan 2014) using figures provided by study.
 ²Downgraded to low due to indirectness, inconsistency, and imprecision resulting from the limited number of studies (1) and small study size.

Summary of findings 2. OUTBACK re‐entry catheter versus manual re‐entry for chronic total occlusions in the superficial femoral artery.

OUTBACK re‐entry catheter versus manual re‐entry for chronic total occlusions in the superficial femoral artery
Patient or population: 52 people with TASC‐II D superficial femoral artery chronic total occlusions Settings: University Hospital Tor Vergata, Italy (October 2006 to March 2007) Intervention: subintimal angioplasty by OUTBACK re‐entry catheter Comparison: subintimal angioplasty by manual re‐entry
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Manual re‐entry technique	OUTBACK re‐entry catheter
Clinical improvement	See comment	See comment	See comment	52 (1 study)	‐	Gandini 2013 did not report on clinical improvement.
Technical success rate Follow‐up: > 36 months	1000 per 1000	0 per 1000 (930 to 1000)	RR 1.00 (0.93 to 1.08)1	52 (1 study)	⊕⊕⊝⊝ low2
6 months' patency rate Follow‐up: > 36 months	962 per 1000	1000 per 1000 (904 to 1000)	RR 1.04 (0.94 to 1.15)1	52 (1 study)	⊕⊕⊝⊝ low2
12 months' patency rate Follow‐up: > 36 months	846 per 1000	922 per 1000 (762 to 1000)	RR 1.09 (0.9 to 1.33)1	52 (1 study)	⊕⊕⊝⊝ low2
24 months' primary patency rate	See comment	See comment	See comment	52 (1 study)	‐	Gandini 2013 did not report patency at this time point.
36 months' primary patency rate	See comment	See comment	See comment	52 (1 study)	‐	Gandini 2013 did not report patency at this time point.
Limb salvage	See comment	See comment	See comment	52 (1 study)	‐	Gandini 2013 did not report on limb salvage.
Complications	See comment	See comment	Not estimable	52 (1 study)	⊕⊕⊝⊝ low2	Gandini 2013 reported that no major complications occurred.
*The basis for the assumed risk was the average risk in the manual re‐entry technique group (i.e. the number of participants with events divided by total number of participants of the manual re‐entry technique group included in the meta‐analysis). The corresponding risk (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: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹Assumed and corresponding risks calculated by GRADEpro GDT software, risk ratio calculated by Review Manager 5 (RevMan 2014) using figures provided by study.
 ²Downgraded to low due to inconsistency, imprecision, and indirectness resulting from the limited number of studies (1) and small study size.

Results

Description of studies

Results of the search

See Figure 1.

1.

Study flow diagram.

Included studies

See Characteristics of included studies. We included two trials involving a total of 147 participants in this review update (Gabrielli 2012; Gandini 2013).

In Gabrielli 2012, participants with TASC‐II D lesions were randomized to receive either SIA with stenting or remote endarterectomy (RE) of the superficial femoral artery. Gandini 2013 compared SIA using the OUTBACK re‐entry device with SIA using a control (manual re‐entry) technique in people with TASC‐II D superficial femoral artery chronic total occlusion.

Excluded studies

See Characteristics of excluded studies. We excluded six new studies in this update, resulting in a total of six excluded studies. We excluded four studies because they were not randomized (Antusevas 2008; Fialova 2014; Schmidt 2014; Sultan 2009), and two studies because selection of subintimal or transluminal angioplasty was not randomized (Bradbury 2010; Liistro 2013).

Ongoing studies

See Characteristics of ongoing studies. We identified one ongoing study (NCT02544555), which compares intraluminal versus subintimal angioplasty for the treatment of atherosclerotic chronic occlusive femoropopliteal arterial disease.

Risk of bias in included studies

We assigned both included studies a grade of low risk of bias for methodological quality as we assessed most domains as being at low risk of bias (Gabrielli 2012; Gandini 2013). See also Characteristics of included studies and Figure 2 and Figure 3.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

While in both Gabrielli 2012 and Gandini 2013 the method of treatment allocation was described as "random," no clear description was given in Gabrielli 2012 as to which methods were used to generate the random sequence. In Gandini 2013, participants were randomly assigned in pairs using computerized random numbers and were divided into two groups. The allocation concealment is not mentioned in Gabrielli 2012.

Blinding

Neither Gabrielli 2012 nor Gandini 2013 mentioned the blinding of all trial personnel (participants, clinicians, and outcome assessors) to treatment allocation. Due to the differences between the two treatments, blinding could not be applied in Gabrielli 2012. However, in Gandini 2013, the difference between the two methods related only to the application of the OUTBACK re‐entry catheter, so some form of blinding may have been possible.

Incomplete outcome data

Both Gabrielli 2012 and Gandini 2013 included all randomized participants in the analysis of outcome data and did not lose any participants during follow‐up.

Selective reporting

We did not identify any reporting bias. For both Gabrielli 2012 and Gandini 2013, all outcomes specified in the protocols of the studies were described in the results.

Other potential sources of bias

We did not identify any other potential sources of bias in the included studies.

Effects of interventions

See: Table 1; Table 2

We did not perform a meta‐analysis in the present review because the two included studies differed significantly from one another. Gandini 2013 compared two SIA techniques (OUTBACK catheter versus manual re‐entry technique), and Gabrielli 2012 compared SIA plus stenting with RE. The two studies also used different outcome assessment points. We have therefore presented and discussed the data separately for Gabrielli 2012 and Gandini 2013. In future updates of this review, as new studies emerge, it may be possible to perform a meta‐analysis.

Subintimal angioplasty with stenting versus remote endarterectomy

This comparison was assessed in Gabrielli 2012.

Clinical improvement

Rutherford grade and postexercise ankle brachial index improvement were used to evaluate clinical improvement in Gabrielli 2012. Three‐year follow‐up results showed Rutherford classification improvement in 64% of SIA participants compared to 80% of RE participants (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.61 to 1.03; P = 0.079; Analysis 1.1). An ankle brachial index improvement (postexercise value increased by more than 0.2) was reported in 70% of SIA participants and 82% of RE participants (RR 0.86, 95% CI 0.68 to 1.08; P = 0.18; Analysis 1.2).

1.1. Analysis.

Comparison 1 Subintimal angioplasty with stenting versus remote endarterectomy, Outcome 1 Clinical improvement: Rutherford.

1.2. Analysis.

Comparison 1 Subintimal angioplasty with stenting versus remote endarterectomy, Outcome 2 Clinical improvement: ABI.

Technical success rate

Gabrielli 2012 reported that technical success was achieved in 93% of SIA participants and 96% of RE participants (RR 0.97, 95% CI 0.88 to 1.07; P = 0.91; Analysis 1.3).

1.3. Analysis.

Comparison 1 Subintimal angioplasty with stenting versus remote endarterectomy, Outcome 3 Technical success rate.

Vessel patency rate

In Gabrielli 2012, the 12‐month primary patency rate was 59.1% (26 of 44 participants) in the SIA group compared to 78.4% (40 of 51 participants) in the RE group (RR 0.75, 95% CI 0.57 to 1.00; P = 0.05; Analysis 1.4). The 24‐month primary patency rate was 56.8% (25 of 44 participants) in the SIA group versus 76.5% (39 of 51 participants) in the RE group (RR 0.74, 95% CI 0.55 to 1.00; P = 0.05; Analysis 1.5). The 36‐month primary patency rate was 47.7% (21 of 44 participants) in the SIA group versus 62.7% (32 of 51 participants) in the RE group (RR 0.76, 95% CI 0.52 to 1.11; P = 0.15; Analysis 1.6).

1.4. Analysis.

Comparison 1 Subintimal angioplasty with stenting versus remote endarterectomy, Outcome 4 12 months' patency rate.

1.5. Analysis.

Comparison 1 Subintimal angioplasty with stenting versus remote endarterectomy, Outcome 5 24 months' patency rate.

1.6. Analysis.

Comparison 1 Subintimal angioplasty with stenting versus remote endarterectomy, Outcome 6 36 months' patency rate.

Gabrielli 2012 reported an assisted primary patency rate of 52.3% (23 of 44 participants) in the SIA group and 70.6% (36 of 51 participants) in the RE group (P = 0.01).

Gabrielli 2012 reported no difference in secondary patency at 12 and 24 months. However, at 36 months the secondary patency of the RE group was better than that of the SIA group (P = 0.03).

Limb salvage rates

In Gabrielli 2012, limb salvage at three years' follow‐up was 95% in the SIA group and 98% in the RE group (RR 0.97, 95% CI 0.90 to 1.05; P = 0.4; Analysis 1.7).

1.7. Analysis.

Comparison 1 Subintimal angioplasty with stenting versus remote endarterectomy, Outcome 7 36 months' limb salvage rate.

Complications

There were no perioperative deaths in Gabrielli 2012, but complications occurred in two SIA participants (femoral pseudoaneurysm and pulmonary edema) and three RE participants (seroma, femoral pseudoaneurysm, superficial femoral artery acute occlusion) (RR 0.77, 95% CI 0.14 to 4.42; Analysis 1.8).

1.8. Analysis.

Comparison 1 Subintimal angioplasty with stenting versus remote endarterectomy, Outcome 8 Complications.

OUTBACK catheter versus manual re‐entry technique

Gandini 2013 compared SIA using the OUTBACK re‐entry catheter with SIA using a manual re‐entry technique.

Clinical improvement

This outcome was not reported in Gandini 2013.

Technical success rate

In Gandini 2013, technical success was achieved in all cases, both treatment and control (RR 1.00, 95% CI 0.93 to 1.08; Analysis 2.1).

2.1. Analysis.

Comparison 2 OUTBACK re‐entry versus manual re‐entry, Outcome 1 Technical success.

Vessel patency rate

In Gandini 2013, the six‐month primary patency rate was 100% in the OUTBACK group (26 of 26 participants) versus 96.2% in manual group (25 of 26 participants) (RR 1.04, 95% CI 0.94 to 1.15; Analysis 2.2). The 12‐month primary patency rate was 92.3% in the OUTBACK group (24 of 26 participants) versus 84.6% in manual group (22 of 26 participants) (RR 1.09, 95% CI 0.90 to 1.33; Analysis 2.3). Patency rates at 24 and 36 months were not reported.

2.2. Analysis.

Comparison 2 OUTBACK re‐entry versus manual re‐entry, Outcome 2 6 months' patency rate.

2.3. Analysis.

Comparison 2 OUTBACK re‐entry versus manual re‐entry, Outcome 3 12 months' patency rate.

Limb salvage rates

Limb salvage was not reported in Gandini 2013.

Complications

No major peri‐ (within 24 hours) or postprocedural complications were reported in Gandini 2013.

Discussion

Summary of main results

In recent years subintimal angioplasty has become an established percutaneous procedure for the treatment of lower limb arterial occlusion. However, the clinical benefits of this practice remain unclear. Two trials were available in this update to address the current uncertainties regarding the clinical application of SIA in the treatment of lower limb arterial occlusion.

We included two studies involving a total of 147 participants with TASC‐II D femoropopliteal lesions in the review. The two included studies differed significantly from one another and we were unable to pool the data from these studies. One compared two SIA techniques (OUTBACK catheter versus manual re‐entry technique), and one compared SIA plus stenting with RE.

Gandini 2013 compared the effects of SIA using the OUTBACK device with SIA using a manual re‐entry technique in people with TASC‐II D superficial femoral artery chronic total occlusion. Technical success was achieved in all cases but did no report on clinical improvement. The primary 6‐month patency rate was 100% in the OUTBACK group (26 of 26 participants) compared to 96.2% in the manual re‐entry group (25 of 26 participants). The primary 12‐month patency rate was 92.3% in the OUTBACK group (24 of 26 participants) compared to 84.6% in manual group (22 of 26 participants). Patency rates at 24 and 36 months were not reported. Limb salvage rates at 36 months were not reported. No major peri‐ (within 24 hours) or postprocedural complications were reported (Gandini 2013).

In Gabrielli 2012, participants with TASC‐II D lesions were randomized to receive either SIA with stenting or RE with endpoint stenting of the superficial femoral artery. Three‐year follow‐up results showed clinical improvement measured by Rutherford classification improvement in 64% of participants in the SIA group compared to 80% of participants in the RE group. Postexercise ankle brachial index improvements (0.2) were reported in 70% of SIA participants compared to 82% of RE participants. The technical success rate was 93% for SIA participants and 96% for RE participants. Primary patency was 56.8% in SIA compared to 76.5% in RE at 24 months, and 47.7% in SIA and 62.7% in RE at 36 months. Assisted primary patency was 52.3% in SIA compared to 70.6% in RE at 36 months. Secondary patency favored RE at 36 months. Limb salvage at 36 months follow‐up was 95% in the SIA group and 98% in the RE group. There were peri‐operative deaths, but complications occurred in two SIA participants and three RE participants (Gabrielli 2012).

Overall completeness and applicability of evidence

The two included trials differed from each other in a variety of aspects, precluding the combining of the trial results. In addition, these two studies only addressed occlusion of the femoral‐popliteal arteries. As only two studies were eligible for inclusion, we have concerns about the applicability of the evidence presented in this review. We did not identify any studies comparing SIA against transluminal angioplasty, surgical bypass, or any other treatments other than endarterectomy or studies using SIA in iliac or crural vessels. Further studies are needed to reach a definitive conclusion.

Quality of the evidence

Both of the included studies were at overall low risk of methodological bias. We considered the overall quality of the evidence in the present studies to be low according to the GRADE approach. We downgraded the evidence due to indirectness, inconsistency, and imprecision as a result of the limited number of studies and the small size of each study.

See Table 1; Table 2.

Potential biases in the review process

In order to minimise the possibility of introducing bias, two review authors independently performed selection of studies and extraction of data according to Higgins 2011.

Agreements and disagreements with other studies or reviews

Met 2008 analyzed the outcomes of 23 cohort studies including 1549 participants. The technical success rates varied between 80% and 90%, with lower rates for crural lesions than for femoral lesions. After one year, clinical success was between 50% and 70%, primary patency was around 50%, and limb salvage ranged from 80% to 90%. As methodological quality and reporting quality were moderate and clinical heterogeneity was significant, the authors did not conduct a meta‐analysis, but concluded that SIA can play an important role in the treatment of critical limb ischemia.

Bown 2009 reviewed the results of SIA in 2810 limbs from 37 mainly retrospective case note reviews, prospective cohort studies, and registry reviews. The overall technical success rate for SIA was 85.7% (95% CI 83.3% to 87.7%; 2810 limbs). The primary patency at 12 months was 55.8% (95% CI 47.9% to 63.4%; 1342 limbs) and limb salvage at 12 months was 89.3% (95% CI 85.5% to 92.2%; 2810 limbs). The authors concluded from the available data that the outcomes for SIA are good, and that this method should be considered as an alternative to surgical bypass.

Markose 2010 performed a systematic review of 13 reports including systematic review of cohort studies, reviews, and prospective and retrospective case series. Initial technical success of SIA ranged from 99.5% to 83%, with primary patencies ranging from 70% to 50% at one year and 61% to 53% at two years. The authors concluded that SIA is extremely valuable in the management of critical limb ischemia and that it is likely to have an increasing role in the management of intermittent claudication.

In the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial (Bradbury 2010), the 224 participants randomized to receive balloon angioplasty received transluminal, subintimal, or a mixture of transluminal and subintimal balloon angioplasty. As the type of balloon angioplasty was not randomly allocated, this study was not eligible for inclusion in this review. The amputation‐free survival and overall survival were approximately equal for patients undergoing transluminal angioplasty and those undergoing subintimal angioplasty.

A recent meta‐analysis by Li 2012 included 13 retrospective studies and one prospective study (2350 participants). The overall technical success rate was 88.1%, and the overall primary patency rate was 82.9% and 69.9% at six months and 12 months, respectively. The average complication rate was 8.25%, but the majority of complications did not require special treatment. The technical success rate was higher using re‐entry catheters (96.4% versus 87%), and the primary patency rate was higher with the use of preoperative antiplatelet medication compared to without preoperative antiplatelet medication (91.0% versus 68.5%). As well as concluding that SIA is safe and effective in treating chronic arterial occlusive disease, the authors also determined that the selective use of re‐entry devices and preoperative antiplatelet medication results in a statistically significant improved technical success rate (P < 0.01) and primary patency rate (P < 0.01) (Li 2012).

In Klimach 2014, the authors performed a search to find the best evidence to answer the question of how SIA compares to transluminal angioplasty (TA) for the treatment of femoral occlusive disease. Only five studies represented the best evidence to answer the clinical question. There were no randomized controlled trials comparing SIA to TA for pathologically equivalent lesions. The authors concluded that the evidence on this subject is limited, although SIA offers a safe and effective alternative when TA is not an option. However, the question of whether SIA or TA is superior remains unanswered (Klimach 2014). In Bosiers 2012, the authors found that both TA and SIA have a place as an endovascular treatment for below‐the‐knee lesions. Bosiers and colleagues suggest that until the release of definitive data directly comparing the TA and SIA techniques, proving that one technique is advantageous over the other, interventionalists should continue to perform procedures using the treatment modality they feel most comfortable with based on their personal experience. Chun 2010 advocates SIA as a first‐line therapy in people with limb‐threatening ischemia, especially as it does not compromise later successful surgical revascularization.

All of the above reviews indicate that SIA can play a role in the treatment of lower limb arterial chronic total occlusions, but the types of studies included in these reviews were not consistent, the methodological and reporting quality were moderate, and clinical heterogeneity was significant.

Authors' conclusions

Implications for practice.

The data from the published trials suggest that there is insufficient evidence to support SIA over other techniques. These results were based on only two trials. Both studies were at overall low risk of methodological bias, but the small number of studies, small sample sizes, and the differences in treatment techniques and control groups between the studies resulted in the evidence being less applicable. Evidence from more randomized controlled trials is therefore needed to assess the role of subintimal angioplasty (SIA) in people with lower limb arterial chronic total occlusions.

Implications for research.

One of the challenges for the vascular surgeon or interventional radiology specialist is to identify which treatment is most appropriate for which patient. Randomized controlled trials are needed to assess the effectiveness of SIA compared with other treatments. Trials should be large enough to ensure that any impact on outcome of potentially important features (e.g. site of the lesion, symptoms, and risk factor status) can be determined in the analysis. To prevent bias, these features should be balanced across treatment groups by randomization. Trials should also have sufficiently long follow‐up periods to determine the patency rate and limb salvage rate. Assessment of clinical improvements, such as relief of rest pain, healing of ulcers, improvement in walking distance, and quality of life, is also important. Furthermore, randomized controlled trials are required to compare the effects of simple SIA to SIA plus stenting, SIA to surgical treatment, and the results of SIA with or without re‐entry devices. Subgroup analyses could explore factors affecting patency and which groups of patients derive the most benefit.

What's new

Date	Event	Description
13 January 2016	New citation required and conclusions have changed	Searches rerun; two new studies included in this previously empty review, six new studies excluded, and one new ongoing study identified. Text amended to reflect current Cochrane standards. 'Summary of findings' tables added. Conclusions changed.
13 January 2016	New search has been performed	Searches rerun; two new studies included, six new studies excluded, and one new ongoing study identified.

Appendices

Appendix 1. CENTRAL search strategy

Search run on Wed Jan 13 2016
#1	MESH DESCRIPTOR Arteriosclerosis	867
#2	MESH DESCRIPTOR Arteriolosclerosis EXPLODE ALL TREES	0
#3	MESH DESCRIPTOR Arteriosclerosis Obliterans	70
#4	MESH DESCRIPTOR Atherosclerosis	579
#5	MESH DESCRIPTOR Arterial Occlusive Diseases	713
#6	MESH DESCRIPTOR Intermittent Claudication	697
#7	MESH DESCRIPTOR Ischemia	771
#8	MESH DESCRIPTOR Peripheral Vascular Diseases EXPLODE ALL TREES	2165
#9	(atherosclero* or arteriosclero* or PVD or PAOD or PAD ):TI,AB,KY	8392
#10	((arter* or vascular or vein* or veno* or peripher*) near3 (occlus* or reocclus* or re‐occlus* or steno* or restenos* or obstruct* or lesio* or block* or harden* or stiffen* or obliter*) ):TI,AB,KY	7090
#11	(peripheral near3 dis*):TI,AB,KY	3057
#12	(claudic* or IC):TI,AB,KY	2778
#13	(isch* or CLI):TI,AB,KY	21338
#14	arteriopathic:TI,AB,KY	7
#15	dysvascular*:TI,AB,KY	10
#16	(leg near3 (occlus* or reocclus* or re‐occlus* or steno* or restenos* or obstruct* or lesio* or block* or harden* or stiffen* or obliter*) ):TI,AB,KY	84
#17	(limb near3 (occlus* or reocclus* or re‐occlus* or steno* or restenos* or obstruct* or lesio* or block* or harden* or stiffen* or obliter*) ):TI,AB,KY	124
#18	((lower near3 extrem*) near3 (occlus* or reocclus* or re‐occlus* or steno* or restenos* or obstruct* or lesio* or block* or harden* or stiffen* or obliter*) ):TI,AB,KY	73
#19	((iliac or femoral or popliteal or femoro* or fempop* or crural) near3(occlus* or reocclus* or re‐occlus* or steno* or restenos* or obstruct* or lesio* or block* or harden* or stiffen* or obliter*) ):TI,AB,KY	853
#20	MESH DESCRIPTOR Leg EXPLODE ALL TREES WITH QUALIFIERS BS	1096
#21	MESH DESCRIPTOR Iliac Artery	141
#22	MESH DESCRIPTOR Popliteal Artery	266
#23	MESH DESCRIPTOR Femoral Artery	790
#24	MESH DESCRIPTOR Tibial Arteries	32
#25	(((femor* or iliac or popliteal or fempop* or crural or poplite* or infrapopliteal or inguinal or femdist* or inguinal or infrainquinal or tibial) near3 (occlus* or reocclus* or re‐occlus* or steno* or restenos* or obstruct* or lesio* or block* or harden* or stiffen* or obliter*) )):TI,AB,KY	989
#26	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25	39870
#27	MESH DESCRIPTOR Angioplasty EXPLODE ALL TREES	4101
#28	(angioplas* or percutan* or PTA or venoplasty):TI,AB,KY	12137
#29	(recanali* or revascular*):TI,AB,KY	6549
#30	dilat*:TI,AB,KY	6912
#31	(balloon or baloon):TI,AB,KY	6481
#32	MESH DESCRIPTOR Endovascular Procedures	168
#33	endovascular:TI,AB,KY	1171
#34	MESH DESCRIPTOR Blood Vessel Prosthesis EXPLODE ALL TREES	406
#35	MESH DESCRIPTOR Blood Vessel Prosthesis Implantation EXPLODE ALL TREES	389
#36	MESH DESCRIPTOR Stents EXPLODE ALL TREES	3123
#37	(stent* or graft* or endograft* or endoprosthe*):TI,AB,KY	22086
#38	#27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37	40298
#39	subintim* :TI,AB,KY	23
#40	#26 AND #38 AND #39	17

Data and analyses

Comparison 1. Subintimal angioplasty with stenting versus remote endarterectomy.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical improvement: Rutherford	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Clinical improvement: ABI	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Technical success rate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 12 months' patency rate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 24 months' patency rate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6 36 months' patency rate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7 36 months' limb salvage rate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8 Complications	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. OUTBACK re‐entry versus manual re‐entry.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Technical success	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 6 months' patency rate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 12 months' patency rate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Gabrielli 2012.

Methods	Study design: stated as randomized Method of randomization: not stated
Participants	Country: Italy Participants: 95 randomized Mean age: age > 65 years (RE: 34/51; SIA: 31/44) Sex: M/F (RE: 33/18; SIA: 29/15) Inclusion criteria: severe lifestyle‐limiting claudication (Rutherford category 3) in 41 participants (20 RE and 21 SIA), CLI (Rutherford category 4) in 41 participants (23 RE and 18 SIA), or gangrene (Rutherford category 5) in 13 participants (8 RE and 5 SIA) Exclusion criteria: previous treatment (endovascular intervention or bypass), chronic renal insufficiency (serum creatinine 1.5 mg/dL), and occlusion of iliac, common femoral, and popliteal arteries (P2‐3 segments)
Interventions	Treatment group: received RE of the SFA with endpoint stenting Control group: SIA with stenting
Outcomes	Primary outcomes: clinical improvement technical success rate primary patency secondary patency Secondary outcomes: limb salvage rate Outcome assessment points: baseline and months 6, 12, 18, 24, 30, and 36
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Article states: "Patients with TASC‐II D lesions were enrolled in a prospective randomized (1:1) trial"; further details not provided
Allocation concealment (selection bias)	Unclear risk	Not mentioned
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not mentioned
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants were accounted for.
Selective reporting (reporting bias)	Low risk	We did not identify any reporting bias.
Other bias	Low risk	We did not identify any other potential sources of bias.

Gandini 2013.

Methods	Study design: stated as randomized Method of randomization: stated
Participants	Country: Italy Participants: 52 randomized Mean age: treatment group (65.3 ± 6.2); control group (68.1 ± 5) Sex: M/F (treatment group: 12/14; control group: 14/12) Inclusion criteria: people with TASC‐II D superficial femoral artery CTO. Clinical indications for endovascular recanalization were claudication, tissue loss, and at‐rest leg pain with CLI.
Interventions	Treatment group: OUTBACK re‐entry catheter was used. Control group: Manual re‐entry technique was used.
Outcomes	Primary outcomes: technical success rate success rate (defined as planned in‐target re‐entry within 5 cm) mean procedural time and mean fluoroscopy time Secondary outcomes: patency rate Outcome assessment points: baseline and months 6, 9, and 12
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned in pairs using computerized random numbers and divided into 2 groups.
Allocation concealment (selection bias)	Low risk	Participants were randomly assigned in pairs using computerized random numbers and divided into 2 groups.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not mentioned
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants were accounted for.
Selective reporting (reporting bias)	Low risk	We did not identify any reporting bias.
Other bias	Low risk	We did not identify any other potential sources of bias.

CLI: critical limb ischemia
 CTO: chronic total occlusion
 F: female
 M: male
 RE: remote endarterectomy
 SFA: superficial femoral artery
 SIA: subintimal angioplasty
 TASC: TransAtlantic Inter‐Society Consensus

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Antusevas 2008	Not randomized
Bradbury 2010	Selection of subintimal or transluminal not randomized: the participants randomized to receive balloon angioplasty received transluminal, subintimal, or a mixture of transluminal and subintimal balloon angioplasty. The type of balloon angioplasty was not randomly allocated.
Fialova 2014	Not randomized
Liistro 2013	Selection of subintimal or transluminal angioplasty not randomized
Schmidt 2014	Not randomized
Sultan 2009	Not randomized

Characteristics of ongoing studies [ordered by study ID]

NCT02544555.

Trial name or title	Efficacy of subintimal versus intraluminal approach for atherosclerotic chronic occlusive femoropopliteal arterial disease
Methods	Randomized parallel assignment
Participants	Peripheral arterial disease atherosclerosis
Interventions	Intentional intraluminal and intentional subintimal approach
Outcomes	The rate of binary restenosis, limb salvage rate free of above‐the‐ankle amputation, sustained clinical improvement rate
Starting date	May 2014
Contact information	Seung‐Woon Rha, MD, PhD 82‐2‐818‐6387; email: swrha617@yahoo.co.kr
Notes	clinicaltrials.gov/ct2/show/NCT02544555 (accessed January 2016)

Differences between protocol and review

Subintimal angioplasty (SIA) is used mainly for the treatment of arterial chronic total occlusions. Chronic total occlusions is a professional term used by doctors. Due to this and to make the review more easily retrieved, we have changed the title from "Subintimal angioplasty for chronic lower limb arterial occlusion" to "Subintimal angioplasty for lower limb arterial chronic total occlusions"

We clarified that in addition to comparing SIA against other techniques to restore vessel patency, we also planned to compare different SIA devices or techniques to each other.

We added a third review author (Jia He Zheng) to resolve disagreements.

As 'morbidity rates' is not a reasonable outcome measure, we modified this to 'complications' in Types of outcome measures.

Contributions of authors

ZhiHui Chang: designed the protocol, selected trials, extracted data, interpreted data, and wrote the review
 JiaHe Zheng: selected trials and extracted data
 ZhaoYu Liu: designed the protocol and reviewed the review

Sources of support

Internal sources

• No sources of support supplied

External sources

• Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

  The Cochrane Vascular editorial base is supported by the Chief Scientist Office.

Declarations of interest

ZhiHui Chang: none known
 JiaHe Zheng: none known
 ZhaoYu Liu: none known

New search for studies and content updated (conclusions changed)