Description of the condition
Chronic lower limb arterial occlusion is a widespread problem. It occurs more frequently with increasing age and affects 12% to 20% of the population aged 65 years and older (Hirsch 2001). Patients afflicted with chronic lower limb arterial occlusion have symptoms that 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 chronic lower limb arterial occlusion 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) and 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 patients with more severe symptoms; but transluminal angioplasty is hampered by the risk of chronic total occlusions. Subintimal angioplasty has become an established percutaneous procedure for the treatment of symptomatic lower limb arterial occlusions in recent years (Bolia 1994; Chen 2011; Ko 2011; Nydahl 1997; Zhu 2009).
Description of the intervention
Subintimal angioplasty (SIA) is a minimally invasive percutaneous technique for the recanalization of occluded lower limb arteries (London 1993; Nydahl 1997). SIA 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). SIA has increased in popularity, particularly in CLI, but remains controversial in patients with IC because of a perceived high complication rate and low long-term patency.
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 it 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 results in the published literature on SIA are not very clear. The published literature reflects polarized viewpoints with some authors supporting and others dismissing the technique (Aleksynas 2009; Boufi 2010; Indes 2010). The majority of these reports feature small series of patients and, to date, there remains little long-term follow-up data in the literature. 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. Therefore, we set out to systematically review the effectiveness of SIA versus any other treatment for patients with chronic lower limb arterial occlusion.
To assess the effectiveness of subintimal angioplasty versus any other treatment for patients with chronic lower limb artery occlusion. This will be determined by the effects on clinical improvement, technical success rate, patency rate, limb salvage rate, and morbidity rates.
Criteria for considering studies for this review
Types of studies
We planned to include randomized controlled trials comparing SIA with control or any other treatment. We planned to consider trials that were published in full or had results presented in abstract form. We planned to include the abstracts only if there were sufficient data for analysis, or the authors planned for a full publication or had unpublished data available on file for review and analysis. We planned to include trials in which the minimum length of follow-up was no less than 12 months. We planned to include trials which 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 planned to include patients with chronic lower limb ischemia (IC or CLI, or both) that 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.
The studies selected for review were to include:
(1) patients with symptomatic chronic lower limb arterial ischemia, IC, and CLI (rest pain, tissue loss);
(2) patients with documented occlusions of lower limb arteries (by duplex ultrasound scan, computed tomography (CT), magnetic resonance (MR), or angiogram);
(3) patients with 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, after restoration of patency in patients with occlusions of a lower limb artery. This technique can be performed with devices such as the Outback® catheter. We planned to make the comparison against alternative modalities used to restore vessel patency including conventional percutaneous transluminal angioplasty (PTA), surgical bypass, or any other treatments.
Types of outcome measures
(1) Clinical improvement (relief of rest pain, healing of ulcers, and improvement in walking distance).
(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 patients with tissue loss.
(4) Morbidity rates:
(i) stent related - stent failure or fracture, stent migration, stent infection, stent occlusion;
(ii) procedural related - groin hematoma, wound infection, wound bleeding, vessel rupture or perforation, vessel wall dissection, distal emboli;
(iii) general morbidity - development of acute myocardial infarction, acute renal failure, chronic renal failure, cerebrovascular event.
Search methods for identification of studies
There was no restriction on language.
The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12), part of The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC 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 Peripheral Vascular Diseases (PVD) Group module in The Cochrane Library (www.thecochranelibrary.com).
The following trials databases were searched by the TSC for details of ongoing and unpublished studies using the terms subintimal or sub-intimal:
- World Health Organization International Clinical Trials Registry (http://apps.who.int/trialsearch/);
- ClinicalTrials.gov (http://clinicaltrials.gov/);
- Current Controlled Trials (http://www.controlled-trials.com/).
Searching other resources
We handsearched the following journals:
- Journal of Endovascular Therapy (2000, Volume 7; 2001, Volume 8, Issues 1 to 4 and 6; 2005, Volume 12; 2006, Volume 13; 2007, Volume 14; 2008, Volume 15; 2009, Volume 16, Issue 1);
- European Journal of Vascular and Endovascular Surgery (1997 to 2004).
We also contacted the major catheter device manufacturers to obtain information on unpublished data and any ongoing trials:
- Johnson & Johnson Cordis;
- WL Gore & Associates;
- Boston Scientific;
- Edwards Life Sciences;
- Cook Incorporated;
- Abbott Laboratories.
In addition, we searched proceedings and abstracts presented at key vascular surgery or medical meetings in order to find relevant studies. These meetings included:
- Society for Vascular Surgery (SVS) Vascular Annual Meeting (2011 to 2012);
- Society of Vascular Surgeons of Great Britain and Ireland meeting (2000 to 2012);
- Radiological Society of North America (RSNA) (2000 to 2011);
- European Congress of Radiology (ECR) (2000 to 2012);
- Cardiovascular and Interventional Radiological Society of Europe (CIRSE) (2000 to 2012).
We searched the reference lists of relevant trial reports and reviews identified from the electronic searches.
Data collection and analysis
Selection of studies
The two review authors independently assessed all retrieved citations on the basis of the title and abstract and independently selected the trials for full review. We resolved disagreements by consensus.
Data extraction and management
For all eligible studies, we planned for both authors to extract data onto the Cochrane PVD Group data extraction table. We planned to resolve any disagreement on data extraction between review authors by consensus. We also planned to contact primary investigators of studies for additional information or clarification as required.
Assessment of risk of bias in included studies
We planned for both authors to independently assess included studies for risk of bias using the 'Risk of bias' tool developed by The Cochrane Collaboration (Higgins 2011).
(1) Sequence generation (checking for possible selection bias)
We planned to assess the method used to generate the allocation sequence in included studies to determine whether the allocation sequence method was sufficient to produce comparable groups.
We intended to rate the method as:
• 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 planned to assess each included study for the adequacy of the concealment of the allocation and whether investigators and participants could have foreseen their allocation at any stage of the recruitment or intervention processes.
We intended to rate 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 planned to assess each included study for the adequacy of the methods used, if any, to blind study participants and investigators to the intervention allocations. We intended to judge studies to have low risk of bias if they: were blinded, if we judged that the lack of blinding could not have influenced the results, and if the blinding was unlikely to have been broken. We intended to assess blinding for different outcomes or classes of outcomes.
We intended to assess 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 planned to assess each included study for 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 were balanced across groups. Where sufficient information was reported, or could be supplied by the trial authors, we intended to reinclude missing data in the analyses, which we planned to undertake.
We intended to assess methods as:
• low risk of bias;
• high risk of bias;
• unclear risk of bias.
(5) Selective outcome reporting
We planned to analyze each included study to determine whether all of the pre-specified primary and secondary outcomes had been reported, and whether outcome measures or analyses that were not pre-specified had been reported.
We intended to assess the methods as:
• low risk of bias (where all of the study's pre-specified outcomes and expected outcomes of interest to the review were reported);
• high risk of bias (where not all the study's pre-specified outcomes were reported, one or more of the reported primary outcomes were not pre-specified, or outcomes of interest were reported incompletely);
• unclear risk of bias.
(6) Other potential threats to validity
We planned to assess 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 given in the Cochrane Handbook for Systematic Reviews of Interventions. 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 through undertaking sensitivity analyses.
Measures of treatment effect
We intended to combine all results and perform a meta-analysis using Review Manager 5.1 software provided by The Cochrane Collaboration.
We planned to use the following measures of the effect of treatment.
1. For dichotomous outcomes, we planned to use the risk ratio (RR).
2. For continuous outcomes, we planned to use the mean difference (MD) between treatment groups.
Unit of analysis issues
We intended to analyze each cluster-randomized trial individually before deciding whether or not to include it in the review. Because of the nature of the procedures involved, it was not expected that there would be any cross-over trials. In studies with multiple treatment groups, we intended to assess the possibility of including the subgroups with the interventions of interest. We intended to analyze the different patient groups (IC and CLI) separately.
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 Chi
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.
We intended to use Review Manager 5.1 to conduct our analysis. The exact methods used would depend on the data found in the included trials.
If sufficient clinically similar studies become available, we plan to pool their results in a meta-analysis.
1. For dichotomous outcomes, we intend to use the RR.
2. For continuous outcomes, we intend to use the MD between the treatment arms at the end of follow up if all trials measured the outcome on the same scale, otherwise we intend to use the standardized mean difference.
If 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 the comparisons 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:
1. SIA with or without stent in each treatment group;
2. SIA with or without device (e.g. Outback® catheter) in each treatment group.
We planned 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 any heterogeneity.
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 inclusion of studies with lower methodologic quality and studies with high risk of bias. We planned to evaluate the effect of trial size, large and small trials, on the total estimated effect size.
Description of studies
We did not find any randomized controlled trials (RCTs). Most of the studies identified through the searches were retrospective or prospective patient series.
Results of the search
See Figure 1.
|Figure 1. Study flow diagram.|
We did not find any relevant RCTs, therefore no studies were included in the review.
There were no excluded studies.
Risk of bias in included studies
There were no included studies, therefore we were unable to assess risk of bias.
Effects of interventions
Results based on RCTs were not available as no RCTs were identified. Information regarding whether SIA is more effective than any other treatment for chronic lower limb arterial occlusion is currently based on non-RCTs only.
Summary of main results
There are no RCTs in which SIA is compared with any other treatment, so there is currently no evidence based on RCTs that supports the benefit of SIA over any other treatment.
Overall completeness and applicability of evidence
RCT evidence for the effectiveness of SIA is lacking.
Quality of the evidence
There is a need for more high-quality evidence about the optimal management of chronic lower limb arterial occlusion. A well-designed multi-center RCT of SIA versus any other treatment in patients with chronic lower limb arterial occlusion would be of great benefit. Such a trial should include patient-reported outcomes such as relief of rest pain, healing of ulcers, and improvement in walking distance. Subgroup analyses could explore factors affecting patency and which groups of patients derive most benefit. The role of stents and re-entry devices should also be evaluated in randomized trials.
Potential biases in the review process
There are no included or excluded studies therefore we were unable to assess the potential bias of the review process. After extensive searches, we found that the only evidence regarding whether SIA is more effective than any other treatment is from non-randomized studies such as cohort studies. This type of study presents biases inherent in non-randomized studies.
Agreements and disagreements with other studies or reviews
This review set out to identify all available RCTs on this topic. However, after extensive searching there were no RCTs available and the only available evidence on this topic comes from studies that are not RCTs, such as case note reviews and cohort studies. Despite the absence of RCTs, we found three systematic reviews about SIA that reviewed non-RCT evidence (Bown 2009; Li 2012; Met 2008).
Bown et al have 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% confidence interval (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). From the available data the authors concluded that the outcomes for subintimal angioplasty are good, and this method should be considered as an alternative to surgical bypass (Bown 2009).
A recent meta-analysis by Li et al included 13 retrospective studies and one prospective study (2350 patients). In this review, 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 pre-operative anti-platelet medication compared to without preoperative anti-platelet 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 concluded that the selective use of re-entry devices and pre-operative anti-platelet medication results in a statistically significant improved technical success rate (P < 0.01) and primary patency rate (P < 0.01) (Li 2012).
Met et al analyzed the outcomes of 23 cohort studies including 1549 patients. The technical success rates varied between 80% and 90%, with lower rates for crural lesions compared with femoral lesions. After one year, the clinical success was between 50% and 70%, primary patency was around 50%, and limb salvage varied from 80% to 90%. Because methodological quality and reporting quality were moderate, and clinical heterogeneity was significant, the authors did not conduct a meta-analysis but the authors concluded that SIA can play an important role in the treatment of critical limb ischemia (Met 2008).
Although the three reviews reviewing non-RCT evidence indicate that SIA can play a role in the treatment of critical limb ischemia, the types of studies included in these reviews were not consistent, methodological and reporting quality were moderate, and clinical heterogeneity was significant. Because to date this is the best evidence available, we believe that a systematic review based on RCTs is needed.
Implications for practice
There is insufficient evidence from randomized controlled trials comparing SIA with any other treatment to draw any conclusions for practice. Randomized controlled trials are needed to compare SIA with any other treatment for chronic lower limb arterial occlusion.
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. Randomised 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 (for example, site of the lesion, symptoms, and risk factor status) can be determined in the analysis. These features should, therefore, be balanced across treatment groups by randomization to prevent bias. 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, and improvement in walking distance, is also important in this group of patients. Furthermore, randomized controlled trials are required to compare the effects of simple SIA to SIA plus stenting, and the results with and without re-entry devices.
We are very grateful to Dr Marlene Stewart and the Cochrane PVD Group editorial base for their help with the review preparation.
Data and analyses
This review has no analyses.
Appendix 1. CENTRAL search strategy
Contributions of authors
Zhihui Chang: designed the protocol, selected trials, extracted data, interpreted data, and wrote the review.
Zhaoyu Liu: designed the protocol and reviewed the review.
Declarations of interest
Sources of support
- No sources of support supplied
- Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.The PVD Group editorial base is supported by the Chief Scientist Office.
Medical Subject Headings (MeSH)
MeSH check words