Cryoplasty for peripheral arterial disease

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

Percutaneous balloon angioplasty is an endovascular technique for restoring blood flow through an artery that has become narrowed or blocked by atherosclerosis. Narrowing of the artery following angioplasty (restenosis) is the major cause of long-term failure. Cryoplasty offers a different approach to improving long-term angioplasty results. It combines the dilation force of balloon angioplasty with cooling of the vessel wall. This systematic review evaluated cryoplasty in peripheral arterial disease and provides focus for further research in the field. This is an update of a review first published in 2007.

Objectives

To assess the efficacy of, and complications associated with, cryoplasty for maintaining patency in the iliac, femoropopliteal and crural arteries in the short and medium term.

Search methods

For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 10). Trial databases were searched for ongoing or unpublished studies. We also searched the reference lists of relevant articles.

Selection criteria

All randomised controlled trials in which participants with peripheral arterial disease (PAD) of the lower limbs, or lower limb bypass graft stenoses, were randomised to cryoplasty with or without another procedure versus a procedure without cryoplasty were considered. This included trials where all participants received angioplasty and the randomisation was for cryoplasty versus no cryoplasty and trials where cryoplasty was used as an adjunct to conventional treatment (for example stenting) against a control.

Data collection and analysis

Two review authors independently reviewed, assessed and selected trials, extracted data and assessed risk of bias.

Main results

Seven trials (six primary cryoplasty and one adjunctive cryoplasty trial) with a combined total of 478 patients were included in this review. The trials reported patency and restenosis either by participant, lesion or vessel location. Follow-up ranged from 30 days to three years.

Target lesion patency measured at various time points in two primary cryoplasty trials showed no statistically significant difference between the treatment groups. The adjunctive cryoplasty study showed that cryoplasty was associated with improved patency only at six months (OR 5.37, 95% CI 1.09 to 26.49, n = 90).

Restenosis measured per patient (two primary cryoplasty trials) showed no statistically significant difference between the treatments. Restenosis measured by lesion (two primary cryoplasty trials) showed a statistically significant difference only within 24 hours of the procedure (OR 0.08, 95% CI 0.04 to 0.18, n = 192) favouring cryoplasty.

Need for re-intervention was not significantly different in primary cryoplasty trial participants (per participant: OR 0.27, 95% CI 0.05 to 1.52, n = 241, I2 = 89%; per lesion: OR 0.59, 95% CI 0.06 to 5.69, n = 307, I2 = 94%). The adjunctive cryoplasty trial did not report on need for intervention.

Immediate success of procedure (within 24 hours) was not significantly different in primary cryoplasty trial participants (per participant: OR 1.63, 95% CI 0.14 to 19.55, n = 340, I2 = 95%; per lesion: OR 1.81, 95% CI 0.19 to 17.36, n = 397, I2 = 90%). The adjunctive cryoplasty trial reported 100% success.

Limb loss, deaths from all causes and the risk of complications immediately after treatment showed no statistically significant differences between the treatments.

Authors' conclusions

The benefit of cryoplasty over conventional angioplasty cannot be established as the number of randomised controlled trials is small and their quality is not sufficiently high. The technical success and primary patency rates seen in these trials are inconsistent and do not necessarily suggest a future role for cryoplasty in the treatment of PAD, but they cannot be reliably interpreted. Currently there are insufficient data to support the routine use of cryoplasty over conventional balloon angioplasty in the treatment of PAD.

Résumé scientifique

La cryoplastie pour la maladie artérielle périphérique

Contexte

L'Angioplastie percutanée par ballonnet est une technique endovasculaire pour restaurer le flux sanguin dans une artère devenue rétrécie ou obstruée par l'athérosclérose. Un rétrécissement de l'artère après une angioplastie (resténose) est la principale cause d'échec à long terme. La cryoplastie donne une approche différente pour améliorer les résultats de l'angioplastie à long terme. Elle combine la force de dilatation lors de l'angioplastie par ballonnet avec le refroidissement de la paroi du vaisseau. Cette revue systématique a évalué la cryoplastie dans la maladie artérielle périphérique et fournit une orientation pour des recherches supplémentaires dans ce domaine. Ceci est une mise à jour d'une revue publiée pour la première fois en 2007.

Objectifs

Évaluer l'efficacité et les complications associées à la cryoplastie pour le maintien de la perméabilité dans les artères iliaque, fémoro-poplitée et de la jambe à court et moyen terme.

Stratégie de recherche documentaire

Pour cette mise à jour, le coordinateur de recherche du groupe Cochrane sur les maladies vasculaires périphériques a effectué des recherches dans dans le registre spécialisé du groupe(dernière recherche en octobre 2012) et CENTRAL (2012, numéro 10). Les bases de données des essais ont été explorées à la recherche des études en cours ou non publiées. Nous avons également consulté les références bibliographiques des articles pertinents.

Critères de sélection

Tous les essais contrôlés randomisés dans lesquels les participants atteints de maladie artérielle périphérique (MAP) des membres inférieurs, ou de sténose du greffon d'un pontage artériel des membres inférieurs, ont été randomisés pour la cryoplastie avec ou sans autre procédure par rapport à une procédure sans cryoplastie ont été pris en compte. Cela incluait les essais dans lesquels tous les participants recevaient une angioplastie et la randomisation concernait la cryoplastie versus l'absence de cryoplastie et les essais dans lesquels la cryoplastie a été utilisée en complément du traitement standard (par exemple la pose d'endoprothèse) par rapport à un groupe témoin.

Recueil et analyse des données

Deux auteurs ont examiné de manière indépendante, évalué et sélectionné les essais, extrait les données et évalué le risque de biais.

Résultats principaux

Sept essais (six concernaient la cryoplastie comme procédure principale et un la cryoplastie adjuvante) avec un total combiné de 478 patients ont été inclus dans cette revue. Les essais documentaient la perméabilité et la resténose soit par participant, soit par localisation de la lésion ou du vaisseau. Le suivi variait de 30 jours à trois ans.

La perméabilité cible mesurée à différents moments, dans deux essais de cryoplastie en procédure principale n'ont montré aucune différence statistiquement significative entre les groupes de traitement. L'étude concernant la cryoplastie adjuvantea montré que la cryoplastie était associée à une amélioration de la perméabilité uniquement à six mois (rapport des cotes 5,37, IC à 95 % 1,09 à 26.49, n =90).

La resténose mesurée par patient (dans deux essais de cryoplastie en procédure principale) n'a montré aucune différence statistiquement significative entre les traitements. La resténose mesurée par lésion (dans deux essais de cryoplastie en procédure principale)) n'ont montré une différence statistiquement significative que dans les 24 heures suivant la procédure (RC 0,08, IC à 95 % 0,04 à 0,18, n =192) en faveur de la cryoplastie.

La nécessité d'une nouvelle intervention chirurgicale n'était pas significativement différente chez les participants aux essais de cryoplastie en procédure principale (par participant : OR 0,27, IC à 95 % 0,05 à 1,52, n =241, I2 Par =89%; lésion : RC 0,59, IC à 95 % 0,06 à 5,69, n =307, I2 =94%). L'essai concernant la cryoplastie adjuvante n'a pas documenté la nécessité d'une intervention.

La réussite immédiate de la procédure (dans les 24 heures) n'était pas significativement différente chez les participants aux essais de la cryoplastie comme procédure principale (par participant : RC 1,63, IC à 95 % 0,14 à 19.55, n =340, I2 Par =95%; lésion : OR 1,81, IC à 95 % 0,19 à 17.36, n =397, I2 =90 %). L'essai relatif à la cryoplastie adjuvante a rapporté un taux de réussite de 100 %.

Concernant la Perte d'un membre, le décès toutes causes confondues et le risque de complications immédiatement après le traitement il n'y avait aucune différence statistiquement significative entre les traitements.

Conclusions des auteurs

Le bénéfice de la cryoplastie par rapport à l'angioplastie classique ne peut pas être établi car les essais contrôlés randomisés sont en petit nombre et leur qualité n'est pas suffisamment élevée. Les taux de succès techniques et les taux de perméabilité primaire observés dans ces essais ne sont pas en cohérence et ne suggèrent pas nécessairement un rôle d'avenir pour la cryoplastie dans le traitement de la MAP, mais ces taux ne peuvent pas être interprétés de manière fiable. Actuellement les données sont insuffisantes pour recommander l'utilisation systématique de la cryoplastie par rapport à l'angioplastie par ballonnet conventionnelle dans le traitement de la MAP.

Plain language summary

Cryoplasty for peripheral vascular disease

Peripheral arterial disease results from narrowing or blocking of the main arteries to the legs, usually due to atherosclerosis. The resulting reduction of blood flow caused by a blocked or narrowed artery can either cause pain on walking or become so severe that loss of the leg is threatened. Endovascular surgery involves inserting a small balloon through a needle puncture into the affected artery. The balloon is then inflated to stretch the artery open (called percutaneous balloon angioplasty). Unfortunately the artery often narrows again over time, which is called restenosis. Cryoplasty cools the vessel wall at the same time as doing the balloon angioplasty and may reduce thickening of the inner muscular layer of the blood vessel to improve long-term angioplasty results and prevent restenosis. 

The benefit of cryoplasty over conventional balloon angioplasty has yet to be definitely established as there are few randomised controlled trials evaluating this method. The technical success rates and rates of unobstructed arteries (primary patency) compared with conventional angioplasty seen in seven trials (478 patients) were inconsistent. Long-term outcomes, in particular, are as yet to be assessed fully. Currently there are insufficient data to support the routine use of cryoplasty over conventional balloon angioplasty in the treatment of peripheral arterial disease.

Résumé simplifié

Traitement par cryoplastie des maladies vasculaires périphériques

Les maladies artérielles périphériques résultent du rétrécissement ou de l'obstruction des principales artères des membres inférieurs, généralement causées par l'athérosclérose. La réduction du débit sanguin due à l'obstruction ou au rétrécissement de l'artère peut entraîner de la douleur lors de la marche ou devenir tellement sévère qu'elle peut menacer l'intégrité du membre inférieur. La chirurgie endovasculaire consiste à insérer, après ponction artérielle, un petit ballon dans l'artère touchée . Le ballonnet est ensuite gonflé pour ouvrir et dilater l'artère (angioplastie percutanée par ballonnet). Malheureusement l'artère se rétrécit souvent à nouveau au fil du temps, (resténose). La cryoplastie refroidit la paroi du vaisseau en même temps qu'est pratiquée l'angioplastie par ballonnet et peut réduire l'épaississement de la couche musculaire interne du vaisseau sanguin afin d'améliorer les résultats à long terme de l'angioplastie et de prévenir la resténose.

Le bénéfice de la cryoplastie par rapport à l'angioplastie à ballonnet classique n'a pas encore été définitivement établie car il existe peu d'essais contrôlés randomisés évaluant cette méthode. Les taux de réussite technique et les taux d'artères non bouchées (perméabilité primaire) par rapport à l'angioplastie classique observée dans sept essais (478 patients) n'étaient pas en cohérence. Les résultats à long terme, en particulier, doivent encore être évalués de manière exhaustive. Actuellement les données sont insuffisantes pour recommander l'utilisation systématique de la cryoplastie par rapport à celle de l'angioplastie par ballonnet conventionnelle dans le traitement de la maladie artérielle périphérique.

Notes de traduction

Traduit par: French Cochrane Centre 1st December, 2013
Traduction financée par: Minist�re des Affaires sociales et de la Sant�

Background

Description of the condition

Symptomatic peripheral arterial disease (PAD) occurs in 5% to 7% of the population over the age of 55 years (Dewhurst 1991; Fowkes 1991) and in up to 29% of at risk people over the age of 50 years (Hirsch 2001). In 25% of the patients over the age of 55 years, the condition will deteriorate and require treatment, and 5% will go on to develop limb-threatening critical limb ischaemia (CLI) (Dormandy 1991). Most patients requiring treatment will be candidates for endovascular intervention as first-line treatment, although the evidence base for this approach is still developing (London 1995; White 2007).

Percutaneous balloon angioplasty is an endovascular technique for restoring blood flow through an artery that has become narrowed or blocked by atherosclerosis. A small balloon is inserted into the artery and inflated, thus rupturing the atheromatous plaque, stretching the smooth muscle cells within the middle of the vessel wall and widening the arterial lumen. Angioplasty is particularly effective in the iliac vessels, but the technique is also successful for treating femoropopliteal arteries. Five-year patency rates for iliac and femoropopliteal angioplasty are reported as 55% to 60% and 52% respectively (Adar 1989; Leu 1999; Long 1991; Martin 1995; Murphy 1995), while newer studies of modern stents suggest a patency rate in the iliac artery of around 80% at five years (Leville 2006; Park 2005; Park 2007).

A Cochrane review (which included only 98 patients in total) suggested that although angioplasty may be of short-term benefit, this may not be sustained in the long term (Fowkes 2001). Narrowing of the artery following angioplasty (restenosis) is the major cause of long-term failure. Restenosis is caused by three processes, immediate elastic recoil of the vessel, myointimal hyperplasia (enlargement of the inner muscular layer of vessels), and late vascular remodelling (changes in the vessel, produced in response to physical stresses on the vessel wall, which affect the shape and volume of the vessel). The addition of acute thrombosis can lead to complete occlusion (complete blockage) of a restenosed vessel.

Myointimal hyperplasia, that is the unrestricted migration and proliferation of vascular smooth muscle cells into the vessel lumen, leads to narrowing and restriction of blood flow. The stimulus for this cellular migration is unclear and therapeutic approaches are being eagerly sought to regulate this process (Clowes 1983; Dilley 1988; Mintz 1996; Sottiurai 1983).

Description of the intervention

Cryoplasty offers a different approach to improving long-term angioplasty results. It combines the dilation force of balloon angioplasty with cooling of the vessel wall. Cryotherapy is already widely adopted in other fields of medicine as an effective modality. Previous studies have demonstrated a benign histological response in arteries in response to cold thermal energy, with no interruption in conduit function (Gage 1967).

How the intervention might work

Cryoplasty is thought to provoke apoptosis (a form of cell death necessary to make way for new cells) rather than necrosis (the death of cells in a tissue or organ caused by disease of injury) in the arterial smooth muscle cells. Thus it has the theoretical advantage of reduced myointimal hyperplasia in long-term patency (Fava 2004).

Why it is important to do this review

Many questions remain regarding the safety and efficacy of cryoplasty for PAD. This systematic review of available trial data aims to evaluate the treatment and provide focus for further research in the field.

Objectives

To assess the efficacy of, and complications associated with, cryoplasty for maintaining patency in the iliac, femoropopliteal and crural arteries in the short and medium term.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials in which patients with peripheral arterial disease (PAD) of the lower limbs or lower limb bypass graft stenoses were randomised to cryoplasty with or without another procedure versus a procedure without cryoplasty or non-interventional medical treatment. This included trials where all patients received angioplasty and the randomisation was for cryoplasty versus no cryoplasty and trials where cryoplasty was used as an adjunct to conventional treatment (for example stenting) against a control.

Types of participants

Men and women of any age, diagnosed with PAD by an expert clinician through clinical and investigative assessment (ankle-brachial pressure index, duplex, exercise testing, angiography, computerised tomography (CT), angiography or magnetic resonance (MR) angiography), and who required vascular intervention that could be appropriately managed with cryoplasty and were deemed fit to undergo such an intervention. We intended to stratify these patients on a symptomatic basis (for example rest pain, tissue loss, claudication distance) or by the Transatlantic Inter-Society Consensus (TASC) criteria.

Types of interventions

Trials including any form of therapy that involved the use of cryoplasty for the treatment of PAD were considered for inclusion. We intended to divide trials into subgroups according to the indication for intervention (critical limb ischaemia (CLI), intermittent claudication (IC)); and de novo or repeat procedures. Additional therapies, in particular the adjuvant use of antiplatelet or anticoagulant agents, were assessed.

Types of outcome measures

Primary outcomes

The following primary outcome measures were considered:

  • patency, restenosis or occlusion at various time points (e.g. 30 days, three months, six months, 12 months) using imaging studies or haemodynamics;

  • need for re-intervention;

  • limb loss.

Secondary outcomes

The following secondary outcome measures were considered:

  • immediate success of procedure (within 24 hours);

  • cardiovascular death (i.e. death from any atherogenic cause, cerebrovascular accident, myocardial infarction, aneurysm, etc., including death during surgery for these conditions);

  • death from all causes;

  • complications (e.g. late thrombosis, aneurysm formation, nerve damage, dissection of vessel);

  • ankle-brachial index (ABI);

  • walking distance;

  • maximum walking distance on treadmill;

  • grading of patency on duplex scanning or angiography;

  • time to restenosis;

  • quality of life assessments.

Search methods for identification of studies

We applied no language restriction on publications or any restrictions regarding publication status.

Electronic searches

For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched October 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 10), 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).

Ongoing studies

The following trial databases were searched by the TSC (September 2012) for details of ongoing and unpublished studies using the terms cryotherapy or cryoplasty:

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 searched the reference lists of articles and reports retrieved by electronic searches for additional citations. We also contacted the authors for further information when the data were missing or we were unsure whether to include trials in the review.

We contacted the cryoplasty device manufacturers (Boston Scientific, Natick, MA) to obtain any unpublished, missed or forthcoming trial work.

Data collection and analysis

We performed one analysis for the trials included in this review.

Selection of studies

The contact author (JM) and the co-authors (AA, GS) carried out the selection of trials for inclusion in the review. Two authors (JM, AA) independently assessed the methodological quality of each trial, with arbitration in the event of disagreement from the third co-author (GS), using the checklist recommended by the Cochrane PVD Group.

We obtained full versions of articles that potentially met the inclusion criteria based on the title or abstract and assessed these independently against the inclusion criteria. The reason for a study's exclusion is presented in the Characteristics of excluded studies table.

Data extraction and management

Data extraction was carried out by the contact author (JM) and one of the co-authors (AA) independently, including information on participants (age and sex distribution, measures of severity of disease such as ABI), interventions and outcomes (as above). Any information absent in the publications was sought directly from the authors.

Assessment of risk of bias in included studies

Two review authors (AA, JM) assessed the methodological quality of the studies using the 'Risk of bias' tool from The Cochrane Collaboration (Higgins 2011). We assessed the following domains: selection bias, performance and detection bias, attrition bias, reporting bias and other sources of bias. We allocated a judgement of high risk of bias, low risk of bias, or unclear risk of bias according to the guidelines from Higgins 2011.

Measures of treatment effect

We used Review Manager 5.2 provided by The Cochrane Collaboration to analyse the data. For dichotomous outcomes, statistical analysis was presented as odds ratio (OR) with 95% confidence interval (CI). We used mean differences (MD) with 95% CIs for continuous outcomes.

Unit of analysis issues

Participating individuals in the individually randomised trials were the unit of analysis. If data were not available in this unit of analysis, we used lesions as the unit of analysis and we have reported this.

Dealing with missing data

We contacted the principal authors of included studies, when necessary, to clarify data and to provide missing information.

Assessment of heterogeneity

We based all analyses on the intention-to-treat data from individual trials. We assessed trial heterogeneity using the I2 statistic. Where heterogeneity was identified (I2 > 50%), we investigate the reason for heterogeneity. If no apparent reason was found, we conducted a random-effects model meta-analysis. In the absence of heterogeneity, we used a fixed-effect model.

Assessment of reporting biases

We planned to use asymmetry in funnel plots to assess reporting bias. However, due to the small number of included trials, this was not performed as the power of analysis would have been too low to distinguish chance from real asymmetry.

Data synthesis

We used a random-effects model where clinical and statistical heterogeneity existed (I2 > 50%). We used a fixed-effect model in the absence of heterogeneity.

Subgroup analysis and investigation of heterogeneity

It was intended to perform subgroup analyses to include use of adjuvant therapy (including stenting), vascular territory, indication for intervention, type and length of lesion, initial presentation (TASC criteria and symptoms), and presence of diabetes. Patients with vessels requiring re-intervention (with stratification for time from intervention to re-intervention) were also intended to be analysed as a subgroup. However, due to the restricted number of small trials, this was only done in the case of adjuvant use of cryoplasty in stenting of the femoropopliteal segment.

Sensitivity analysis

We planned to perform sensitivity analyses based on the risk of bias if there were studies with high risk of bias (that is, with high risk methods of allocation concealment and random sequence generation) included in the analyses.

Results

Description of studies

For a detailed description of studies see: Characteristics of included studies, Characteristics of excluded studies and Characteristics of ongoing studies.

Results of the search

For this update seven randomised controlled trials pertaining to cryoplasty in the treatment of PAD were identified following screening of the CENTRAL and PVD Specialised Register search results. A further 11 studies were excluded and two ongoing studies were identified. Case series examining the short- and medium-term results of cryoplasty were excluded (see table Characteristics of excluded studies).

Included studies

See the table Characteristics of included studies.

In total seven trials were included in this review (Banerjee 2012; Diaz 2011; Fossaceca 2011; Jahnke 2010; Shammas 2012; Spiliopoulos 2010; Wang 2011).

The breakdown of trials according to the countries in which they were performed was as follows:

A total of 478 patients were recruited into the trials. The number of participants in each trial ranged from 25 (Wang 2011) to 155 (Diaz 2011). These trials considered cryoplasty versus angioplasty for iliac and infra-inguinal arterial disease (Wang 2011), femoropopliteal arterial disease (Diaz 2011; Fossaceca 2011; Shammas 2012; Spiliopoulos 2010) and popliteal arterial disease (Jahnke 2010). One trial examined the use of cryoplasty in the treatment of in-stent restenosis after superficial femoral artery stenting with nitinol self-expanding stents (Banerjee 2012). Three of the trials (Banerjee 2012; Fossaceca 2011; Spiliopoulos 2010) included only patients with diabetes, three studies included diabetic and non-diabetic patients (Diaz 2011; Jahnke 2010; Shammas 2012) and one study did not specify if the patients had any pre-existing conditions (Wang 2011).

The seven trials included were:

Primary cryoplasty trials are defined as trials comparing cryoplasty only with a procedure without cryoplasty. Adjunctive cryoplasty trials are defined as trials comparing cryoplasty used as an adjunct to conventional treatment (for example stenting) with a procedure without cryoplasty.

Mixed units of analysis were used by the seven included trials and a list of these units is included as follows:

Two trials also used as additional units of analysis: limbs (Spiliopoulos 2010) and vessels (Shammas 2012).

The investigated blood vessels were as follows:

Power calculations were not reported in any of the trials. Intention-to-treat analysis was performed in all seven trials (Banerjee 2012; Diaz 2011; Fossaceca 2011; Jahnke 2010; Shammas 2012; Spiliopoulos 2010; Wang 2011).

The length of the follow-up varied between trials:

In terms of primary outcome events, five trials (Banerjee 2012; Diaz 2011; Fossaceca 2011; Jahnke 2010; Shammas 2012) reported patency, restenosis or occlusion at various time points. Need for re-intervention was reported in four trials (Diaz 2011; Jahnke 2010; Shammas 2012; Spiliopoulos 2010), while limb loss was reported in three trials (Banerjee 2012; Shammas 2012; Spiliopoulos 2010).

In terms of secondary outcome events, the following information was reported:

Sources of funding were declared in two trials (Banerjee 2012; Shammas 2012).

Excluded studies

There were 16 studies excluded. For this update 11 studies (Bakken 2008; Banerjee 2009; Basco 2012; Bosiers 2010; FIX-IT Retro; Gisbertz 2009; Gonzalo 2010; Korteweg 2009; Schmieder 2010; Shin 2010; Silva 2011) were excluded in addition to those excluded in the previous version (Das 2009; Fava 2004; Karthik 2007; Laird 2006; Samson 2008). Studies were excluded for the following reasons:

Risk of bias in included studies

See also the 'Risk of bias' tables for the included studies and Figure 1 and Figure 2.

Figure 1.

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

Figure 2.

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

Allocation

In four trials (Jahnke 2010; Shammas 2012; Spiliopoulos 2010; Wang 2011) the method of treatment allocation was described as 'random', using generated random number or sealed envelopes containing the treatment, with a low perceived risk of bias. In one trial (Fossaceca 2011) the allocation was not described. In two trials the patients were randomised according to the operator's preference (Diaz 2011) or during the procedure (Banerjee 2012) with a high perceived risk of bias.

Blinding

Only in one trial (Jahnke 2010) was the blinding assured, with a low risk of bias. The blinding of trial personnel to treatment allocation was not clear in three trials (Fossaceca 2011; Shammas 2012; Wang 2011). In two trials (Banerjee 2012; Diaz 2011) personnel were not blinded and in one trial (Spiliopoulos 2010) the envelopes were opened only after lesions were successfully crossed, with high risk of bias.

In one trial (Fossaceca 2011) the detection bias was low as the outcomes were assessed independently. The other six studies (Banerjee 2012; Diaz 2011; Jahnke 2010; Shammas 2012; Spiliopoulos 2010; Wang 2011) did not provide information and were perceived as having an unclear risk of bias.

Incomplete outcome data

All trials conducted intention-to-treat analyses, and continued follow-up reporting of most of the patients. The risk of bias was high for two trials (Diaz 2011; Jahnke 2010) as not all patients reached the expected follow-up and partial data were reported.

The risk of bias was low for five trials (Banerjee 2012; Fossaceca 2011; Shammas 2012; Spiliopoulos 2010; Wang 2011) as all the outcome data were accounted for.

Selective reporting

Five trials (Banerjee 2012; Fossaceca 2011; Jahnke 2010; Shammas 2012; Wang 2011) were free of reporting bias. However, the risk of bias was high for the other two trials (Diaz 2011; Spiliopoulos 2010) because not all outcomes were reported.

Other potential sources of bias

Five trials had a low risk of bias (Fossaceca 2011; Jahnke 2010; Shammas 2012; Spiliopoulos 2010; Wang 2011), while two trials were at high risk of other sources of bias because the patients were randomised after stenting (Banerjee 2012) or by operator preference (Diaz 2011).

Effects of interventions

Seven trials that fulfilled the inclusion criteria were included in the review. The data were reported as per patient or per lesion in six trials (Banerjee 2012; Diaz 2011; Jahnke 2010; Shammas 2012; Spiliopoulos 2010; Wang 2011) and as per site in one trial (Fossaceca 2011).

Out of the 478 patients included in the seven trials, 295 were diabetics. Three trials (Banerjee 2012; Fossaceca 2011; Spiliopoulos 2010) included only diabetics, while three other trials (Diaz 2011; Jahnke 2010; Shammas 2012) included both diabetics and non-diabetics but did not analyse the outcomes based on patient groups. One trial did not specify whether any of the included patients were diabetic (Wang 2011).

The data were presented separately for six primary cryoplasty trials (Diaz 2011; Fossaceca 2011; Jahnke 2010; Shammas 2012; Spiliopoulos 2010; Wang 2011) and for one adjunctive cryoplasty trial (Banerjee 2012).

Primary outcomes

Patency, restenosis, occlusion at various time points

One primary cryoplasty trial provided per site (vessels location superficial femoral artery (SFA) and popliteal artery (PA)) data (Fossaceca 2011) with 29 sites in the cryoplasty group and 31 sites in the conventional angioplasty group. At six months, the cryoplasty group had 10 stenoses and 18 patent sites, while the conventional angioplasty group had three stenosis and 28 patent sites, with a statistically significant reduction in restenosis rate (P = 0.02) in the conventional angioplasty group. At 12 months the study authors reported four occlusions, 15 stenoses and eight patent sites in the cryoplasty group, while in the conventional angioplasty group they reported one occlusion, 14 stenoses and 15 patent sites, with no significant difference in the degree of restenosis (P = 0.122).

Binary restenosis was reported by one primary cryoplasty trial (Spiliopoulos 2010) and one adjunctive cryoplasty trial (Banerjee 2012). At 12 months, binary restenosis occurred in 55.8% of the conventional balloon dilation group and 29.3% of the cryoplasty group (OR 0.36, 95% CI 0.15 to 0.89, n = 74) (Banerjee 2012). In-lesion binary restenosis was significantly higher in the cryoplasty group at 12, 24 and 36 months (OR 1.3, 95% CI 0.6 to 2.6, n = 50) (Spiliopoulos 2010).

Per patient data

Two primary cryoplasty trials provided per patient data for target lesion patency (Diaz 2011; Jahnke 2010). There was no statistically significant difference in patency after six months between patients treated with cryoplasty versus conventional angioplasty for PA occlusive disease (OR 0.62, 95% CI 0.36 to 1.07, n = 241, I2 = 0%). These trials also reported patency per patient at three and nine months (Jahnke 2010) and 12, 24 and 36 months (Diaz 2011), but none of the results showed a statistically significant difference in patency (Analysis 1.1).

Restenosis was reported by two primary cryoplasty trials either within 24 hours of the procedure (Jahnke 2010) or at six months follow-up (Shammas 2012), but there was no statistically significant difference between the treatments (Analysis 1.3).

Per lesion data

Patency data per lesion were extracted from one study which examined cryoplasty after SFA stenting (Banerjee 2012) at two monthly intervals up to one year. Only at six months, cryoplasty was associated with improved patency at a statistically significant level (OR 5.37, 95% CI 1.09 to 26.49, n = 90). The trend was similar for the other intervals, but they were not statistically significant. However, these limited significant results should be interpreted in the context of randomisation occurring during the procedure, and the resulting high risk of bias of this method (Analysis 1.2).

Restenosis was reported by two primary cryoplasty trials (Diaz 2011; Shammas 2012). Within 24 hours of the procedure, a statistically significant result (OR 0.08, 95% CI 0.04 to 0.18, n = 192) favoured cryoplasty (Diaz 2011), although at six months the results were not statistically significant (Shammas 2012). Again, this result was subject to the bias of operator randomisation during the procedure in the trial by Diaz 2011, which could have a significant effect on the immediate patency shown (Analysis 1.4).

Need for re-intervention

Per patient data were provided by two primary cryoplasty trials (Diaz 2011; Jahnke 2010). There was no statistically significant difference in the need for re-intervention between patients treated with cryoplasty versus conventional angioplasty for PA occlusive disease (OR 0.27, 95% CI 0.05 to 1.52, n = 241, I2 = 89%), with a trend for patients treated by cryoplasty to be at lower risk for re-intervention (Analysis 1.5).

Per lesion data were provided by three primary cryoplasty trials (Diaz 2011; Shammas 2012; Spiliopoulos 2010). There was no statistically significant difference in the need for re-intervention between patients treated with cryoplasty versus angioplasty for treatment of atherosclerotic lesions in the SFA and PA (OR 0.59, 95% CI 0.06 to 5.69, n = 307, I2 = 94%), with patients treated by cryoplasty at lower risk of re-intervention (Analysis 1.6).

The adjunctive cryoplasty trial (Banerjee 2012) did not report on need for intervention.

Limb loss

There was no statistically significant effect of cryoplasty on limb loss compared with conventional balloon angioplasty in the three trials (adjunctive cryoplasty: Banerjee 2012; primary cryoplasty: Shammas 2012; Spiliopoulos 2010) that reported this outcome in patients treated for stenosis or occlusion of the SFA and PA at six, 12 and 24 months, or three years. There was no limb loss at six months (Shammas 2012) or 12 months (Spiliopoulos 2010) in primary cryoplasty trials (Analysis 1.7) or at 12 months in the adjunctive cryoplasty trial (Banerjee 2012) (Analysis 1.8).

Secondary outcomes

Immediate success of procedures

Per patient data were provided by four trials (Banerjee 2012; Diaz 2011; Jahnke 2010; Wang 2011). The combination of data from the three primary cryoplasty trials indicated no statistically significant difference in the immediate success of cryoplasty compared with conventional angioplasty (OR 1.63, 95% CI 0.14 to 19.55, n = 266, I2 = 95%) (Analysis 1.9), while the adjunctive cryoplasty trial reported 100% success (Banerjee 2012) (Analysis 1.10).

Per lesion data were provided by four trials (Banerjee 2012; Diaz 2011; Shammas 2012; Spiliopoulos 2010). The combination of data from the three primary cryoplasty trials indicated no statistically significant difference between procedures (OR 1.81, 95% CI 0.19 to 17.36, n = 307, I2 = 90%) (Analysis 1.11), while the adjunctive cryoplasty trial reported 100% success (Banerjee 2012) (Analysis 1.12).

One study reported success rate by site (vessels location: SFA and PA), with technical success achieved in 25/29 sites in the cryoplasty group and 28/31 sites in the angioplasty group (Fossaceca 2011).

Cardiovascular death

The adjunctive cryoplasty trial (Banerjee 2012) reported three cases of sudden cardiac death but the trialists did not specify in which treatment group these deaths occurred. The primary cryoplasty studies did not report on cardiovascular deaths.

Death from all causes

Death from all causes was reported at different intervals by five trials (Banerjee 2012; Diaz 2011; Fossaceca 2011; Shammas 2012; Spiliopoulos 2010). No deaths occurred by 30 days or three months follow-up (Spiliopoulos 2010). Deaths were reported by four primary cryoplasty trials at six (three trials, n = 245), 12 (three trials, n = 327) and 24 (two trials, n = 205) months, and at three years (two trials, n = 205), and showed no significant difference between cryoplasty and angioplasty (Analysis 1.13). Similar results were obtained for the adjunctive cryoplasty trial (Analysis 1.14).

Complications

Complications that occurred immediately after treatment were reported by five trials (Banerjee 2012; Diaz 2011; Jahnke 2010; Shammas 2012; Wang 2011). Combining data from the primary cryoplasty trials indicated no statistically significant difference in complication rates for cryoplasty versus conventional angioplasty (OR 2.26, 95% CI 0.70 to 7.37, n = 306, I2 = 0%) (Analysis 1.15). Similar results were obtained for the adjunctive cryoplasty trial (Analysis 1.16).

Ankle-brachial index (ABI)

ABI was reported by five trials (Diaz 2011; Banerjee 2012; Jahnke 2010; Shammas 2012; Wang 2011). In one of these (Diaz 2011) ABI was measured immediately after treatment only. Two trials (Diaz 2011; Jahnke 2010) reported ABI within 24 hours of the procedures with no statistically significant difference in ABI rates for cryoplasty versus conventional angioplasty (MD -0.05, 95% CI -0.12 to 0.03, n = 241, I2 = 0%). In the other three primary cryoplasty trials, there was a statistically significant difference in ABI between the cryoplasty and angioplasty groups only at three months (MD 0.13, 95% CI 0.02 to 0.24, n = 86) favouring angioplasty (Analysis 1.17). The adjunctive cryoplasty trial at 12 months also favoured angioplasty (MD 0.12, 95% CI 0.00 to 0.24, n = 90) (Analysis 1.8).

Other secondary outcomes

None of the included trials reported any of the other secondary outcomes of this review, including walking distance, maximum walking distance on a treadmill, grading of patency on duplex scanning or angiography, time to restenosis or quality of life assessment.

Banerjee 2012 reported baseline and follow-up Rutherford stages and walking impairment questionnaires. Mean walking impairment scores were similar after 12 months follow-up (P = 0.53) but were higher compared to baseline in both the cryoplasty (P = 0.005) and the conventional balloon (P = 0.002) groups. Similarly, there were no significant differences between the Rutherford stages at baseline, six months and 12 months follow-up (no P values provided) but the mean Rutherford stage decreased significantly (P < 0.0001) for each treatment arm between baseline and six months and between baseline and 12 months follow-up.

Discussion

Summary of main results

Two primary cryoplasty trials provided data for target lesion patency at various time points showing no statistically significant difference in patency. The adjunctive cryoplasty study showed that only at six months cryoplasty was associated with improved patency at a statistically significant level (OR 5.37, 95% CI 1.09 to 26.49, n = 90). The trend was similar for the other intervals but these were not statistically significant. Per patient restenosis (two primary cryoplasty trials), either within 24 hours of the procedure or at six-month follow-up, showed no statistically significant difference between the treatments. Per lesion restenosis (two primary cryoplasty trials) showed a statistically significant difference within 24 hours of the procedure (OR 0.08, 95% CI 0.04 to 0.18, n = 192) favouring cryoplasty; at six months the results were not statistically significant.

The need for re-intervention was not significantly different in primary cryoplasty trial participants (per patient: OR 0.27, 95% CI 0.05 to 1.52, n = 241, I2 = 89%; per lesion: OR 0.59, 95% CI 0.06 to 5.69, n = 307, I2 = 94%). The adjunctive cryoplasty trial did not report on need for intervention.

Limb loss was reported at four intervals by three different trials but showed no statistically significant difference at any interval. Immediate success of the procedure (within 24 hours) was not significantly different in patients treated by cryoplasty (OR 1.63, 95% CI 0.14 to 19.55, n = 340, I2 = 95%), with similar results for success of the procedures in lesions (OR 1.81, 95% CI 0.19 to 17.36, n = 397, I2 = 90%). The adjunctive cryoplasty trial reported 100% success.

Deaths from all causes were reported by four primary cryoplasty trials and showed no statistically significant difference between cryoplasty and angioplasty. Similar results were obtained for the adjunctive cryoplasty trial. The risk of complications immediately after treatment was reported by four primary cryoplasty trials and showed no statistically significant difference (OR 2.26, 95% CI 0.70 to 7.37, n = 306, I2 = 0%). Similar results were obtained for the adjunctive cryoplasty trial.

Four primary cryoplasty trials reported no difference in ABI except for one trial at the three-month interval showing a statistically significant difference in ABI (MD 0.13, 95% CI 0.02 to 0.24, n = 86) favouring angioplasty. The adjunctive cryoplasty trial at 12 months also favoured angioplasty (MD 0.12, 95% CI 0.00 to 0.24, n = 90).

The seven studies included in this review were grouped by units of analysis (per patient or per lesion) and were further grouped by primary or adjunctive cryoplasty trials. The grouping meant that many subgroup analyses included only one trial with either unit of analysis at any time point. Therefore, there is little evidence to support that the outcomes differ between primary or adjunctive cryoplasty trials.

Overall completeness and applicability of evidence

Overall, the data are not sufficient to make robust practice recommendations for cryoplasty. As three studies included only diabetic patients and as over 60% (295/478) of the included patients were diabetics, and because of the variety of outcome measures, the data potentially do not represent a complete picture for using cryoplasty in the treatment of peripheral arterial disease (PAD).

Quality of the evidence

The review included only direct comparisons of the two procedures. The effect estimates for some of the primary outcome patency, restenosis, occlusion at various time points, and limb loss produced narrow 95% confidence intervals; together with the absence of heterogeneity between trials these suggest that the findings are robust. However, for the outcomes 'need for re-intervention' and 'immediate success of procedures', where the heterogeneity was more than 50%, the findings should be interpreted with caution.

Only four studies specified the method of sequence generation, two studies did not specify the method of sequence generation, and one study did not provide sufficient information and therefore was classed as at unclear risk of selection bias. Allocation concealment was appropriately presented in four studies, in two studies the concealment was not considered, and one study did not include sufficient information. The risk of performance bias was low for one study, unclear for three studies because of insufficient information, and high risk for three studies because the study personnel were not blinded or the patients were randomised only after lesions were successfully crossed. Only one of the studies was at low risk of detection bias and the remaining six studies did not include sufficient information and were assessed to be at unclear risk of bias. Five studies presented all expected outcomes and were at low risk of attrition bias and two studies were at high risk because not all expected outcomes were reported. Five studies were deemed to be at low risk of other bias while two studies were at high risk of other bias because the operators allocated the treatments.

Potential biases in the review process

The methods used to conduct the review are described in detail in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Particular strengths are the independent application of the review eligibility criteria, independent data extraction and assessment of the risk of bias. The search strategies were designed and run by the Cochrane PVD group Trials Search Co-ordinator. Two authors (AA, JM) independently selected the included studies and extracted the data. All relevant studies were identified and included in this review. Further data and information were obtained in order to be included in specific outcomes of this review. Studies used patient, lesion, or both, as the unit of analysis. The results were separated by patient or lesion as the unit of analysis and the interpretation of the results may be affected as some patients had more than one lesion and subsequently received more than one treatment.

Agreements and disagreements with other studies or reviews

No other published systematic reviews of randomised controlled trials (RCTs) in which patients with PAD of the lower limbs or lower limb bypass graft stenoses were randomised to cryoplasty with or without another procedure versus a procedure without cryoplasty or non-interventional medical treatment were identified. Other non-RCT evidence has been reported in the form of registries, case series and retrospective cohorts and reviews. 

The effects of freeze injury on arterial smooth muscle has been studied in animal (Gage 1967) and human models (Grassl 2005). The first in vivo human experience was reported by Fava et al in 2004 (Fava 2004). Cryoplasty has received mixed support in the last five years. A number of reports (Das 2009; Fava 2004; Laird 2006) supported the use of cryoplasty, several reports (Fossaceca 2011; Karthik 2007; Korteweg 2009; Samson 2008; Shin 2010) did not support the use of cryoplasty, while one retrospective study (Schmieder 2010) found cryoplasty an expensive tool with marginal clinical benefit.

One limitation of cryoplasty relates to the cost effectiveness, especially if cryoplasty adds procedural costs without improved clinical outcomes. The cost of cryoplasty was higher than stenting and up to three times more expensive than conventional balloon angioplasty according to the included study by Diaz 2011. It is considered to be close to USD 2000 (Samson 2008; Schmieder 2010).

A comment on the COBRA trial (Prasad 2012) highlighted the need for performing RCTs by comparing 16 trials, out of which four RCTs (Diaz 2011; Fossaceca 2011; Jahnke 2010; Spiliopoulos 2010) were included in this review. Even though the COBRA study showed that cryoplasty is a good alternative for angioplasty, its findings were limited by the small number of patients and by co-morbidities as all included patients were diabetics. 

Cryoplasty reviews underlined that the use of cryoplasty is hardly justified in the management of PVD as it brings no gain for patency (Karthik 2007a) and the advantages of cryoplasty over balloon angioplasty are considered minimal (Kessel 2008; Wildgruber 2008). While cryoplasty can be used for treating SFA, PA and infra-popliteal lesions, the long-term outcomes are unknown. There is limited evidence to suggest that cryoplasty may not yield the same results in patients with restenosis. Larger RCTs with clearly defined outcomes and time points are required to compare this treatment against other more established practice before it can be widely recommended.

Authors' conclusions

Implications for practice

  • The benefit of cryoplasty over conventional angioplasty cannot be established as the number of randomised controlled trials is small and their quality is not sufficiently high. The technical success and primary patency rates seen in these trials are inconsistent and do not necessarily suggest a future role for cryoplasty in the treatment of PAD, but cannot be reliably interpreted. Currently there are insufficient data to support the routine use of cryoplasty over conventional balloon angioplasty in the treatment of PAD.

Implications for research

  • Clarification of the role of cryoplasty requires further well designed randomised controlled trials. These trials would need to be adequately powered across a variety of potentially important patient subgroups, such as diabetic and non-diabetic (including with and without stenting), and arterial territories to allow proper evaluation of this method.

Acknowledgements

The authors would like to thank the personnel from the Cochrane Peripheral Vascular Disease Review (PVD) Group, especially Marlene Stewart and Karen Welch for their invaluable support and advice.

Data and analyses

Download statistical data

Comparison 1. Cryoplasty versus angioplasty
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Patency per patient (primary cryoplasty trials)2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 3 months186Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.30, 2.37]
1.2 6 months2241Odds Ratio (M-H, Fixed, 95% CI)0.62 [0.36, 1.07]
1.3 9 months186Odds Ratio (M-H, Fixed, 95% CI)1.35 [0.58, 3.17]
1.4 12 months1155Odds Ratio (M-H, Fixed, 95% CI)0.72 [0.38, 1.36]
1.5 24 months1155Odds Ratio (M-H, Fixed, 95% CI)0.74 [0.39, 1.40]
1.6 36 months1155Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.41, 1.47]
2 Patency per lesion (adjunctive cryoplasty trials)1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 2 months190Odds Ratio (M-H, Fixed, 95% CI)3.07 [0.12, 77.32]
2.2 4 months190Odds Ratio (M-H, Fixed, 95% CI)3.14 [0.31, 31.42]
2.3 6 months190Odds Ratio (M-H, Fixed, 95% CI)5.37 [1.09, 26.49]
2.4 8 months190Odds Ratio (M-H, Fixed, 95% CI)2.64 [0.90, 7.73]
2.5 10 months190Odds Ratio (M-H, Fixed, 95% CI)1.71 [0.68, 4.25]
2.6 12 months190Odds Ratio (M-H, Fixed, 95% CI)1.91 [0.82, 4.48]
3 Restenosis per patient (primary cryoplasty trials)2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Within 24 hours (immediate)186Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.35, 2.98]
3.2 6 months140Odds Ratio (M-H, Fixed, 95% CI)1.59 [0.24, 10.70]
4 Restenosis per lesion (primary cryoplasty trials)2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Within 24 hours (immediate)1192Odds Ratio (M-H, Fixed, 95% CI)0.08 [0.04, 0.18]
4.2 6 months150Odds Ratio (M-H, Fixed, 95% CI)1.27 [0.25, 6.38]
5 Need for re-intervention per patient - no time interval (primary cryoplasty trials)2241Odds Ratio (M-H, Random, 95% CI)0.27 [0.05, 1.52]
6 Need for re-intervention per lesion - no time interval (primary cryoplasty trials)3307Odds Ratio (M-H, Random, 95% CI)0.59 [0.06, 5.69]
7 Limb loss (primary cryoplasty trials)2 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 6 months140Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 12 months150Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
7.3 24 months150Odds Ratio (M-H, Fixed, 95% CI)1.09 [0.14, 8.42]
7.4 3 years150Odds Ratio (M-H, Fixed, 95% CI)1.09 [0.14, 8.42]
8 Limb loss (adjunctive cryoplasty trials)1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
8.1 12 months1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9 Immediate success of procedure per patient - within 24 hours (primary cryoplasty trials))3266Odds Ratio (M-H, Random, 95% CI)1.63 [0.14, 19.55]
10 Immediate success of procedure per patient - within 24 hours (adjunctive cryoplasty trials)1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
11 Immediate success of procedure per lesion - within 24 hours (primary cryoplasty trials)3307Odds Ratio (M-H, Random, 95% CI)1.81 [0.19, 17.36]
12 Immediate success of procedure per lesion - within 24 hours (adjunctive cryoplasty trials)1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
13 Death from all causes (primary cryoplasty trials)4 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
13.1 30 days150Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13.2 3 months150Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
13.3 6 months3245Odds Ratio (M-H, Fixed, 95% CI)3.32 [0.36, 30.38]
13.4 12 months3253Odds Ratio (M-H, Fixed, 95% CI)2.34 [0.60, 9.13]
13.5 24 months2205Odds Ratio (M-H, Fixed, 95% CI)1.52 [0.57, 4.01]
13.6 3 years2205Odds Ratio (M-H, Fixed, 95% CI)1.11 [0.48, 2.59]
14 Deaths from all causes (adjunctive cryoplasty trials)1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
14.1 12 months1 Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
15 Complications - Immediate post treatment (primary cryoplasty trials)4306Odds Ratio (M-H, Fixed, 95% CI)2.26 [0.70, 7.37]
16 Complications - immediate post treatment (adjunctive cryoplasty trials)1 Odds Ratio (M-H, Fixed, 95% CI)Totals not selected
17 Ankle brachial index (primary cryoplasty trials)4 Mean Difference (IV, Fixed, 95% CI)Subtotals only
17.1 Within 24 hours2241Mean Difference (IV, Fixed, 95% CI)-0.05 [-0.12, 0.03]
17.2 2 days125Mean Difference (IV, Fixed, 95% CI)0.02 [-0.11, 0.15]
17.3 30 days125Mean Difference (IV, Fixed, 95% CI)0.0 [-0.13, 0.13]
17.4 3 months186Mean Difference (IV, Fixed, 95% CI)0.13 [0.02, 0.24]
17.5 6 months140Mean Difference (IV, Fixed, 95% CI)0.03 [-0.11, 0.17]
17.6 9 months186Mean Difference (IV, Fixed, 95% CI)0.02 [-0.06, 0.10]
18 Ankle brachial index (adjunctive cryoplasty trials)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
18.1 12 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Cryoplasty versus angioplasty, Outcome 1 Patency per patient (primary cryoplasty trials).

Analysis 1.2.

Comparison 1 Cryoplasty versus angioplasty, Outcome 2 Patency per lesion (adjunctive cryoplasty trials).

Analysis 1.3.

Comparison 1 Cryoplasty versus angioplasty, Outcome 3 Restenosis per patient (primary cryoplasty trials).

Analysis 1.4.

Comparison 1 Cryoplasty versus angioplasty, Outcome 4 Restenosis per lesion (primary cryoplasty trials).

Analysis 1.5.

Comparison 1 Cryoplasty versus angioplasty, Outcome 5 Need for re-intervention per patient - no time interval (primary cryoplasty trials).

Analysis 1.6.

Comparison 1 Cryoplasty versus angioplasty, Outcome 6 Need for re-intervention per lesion - no time interval (primary cryoplasty trials).

Analysis 1.7.

Comparison 1 Cryoplasty versus angioplasty, Outcome 7 Limb loss (primary cryoplasty trials).

Analysis 1.8.

Comparison 1 Cryoplasty versus angioplasty, Outcome 8 Limb loss (adjunctive cryoplasty trials).

Analysis 1.9.

Comparison 1 Cryoplasty versus angioplasty, Outcome 9 Immediate success of procedure per patient - within 24 hours (primary cryoplasty trials)).

Analysis 1.10.

Comparison 1 Cryoplasty versus angioplasty, Outcome 10 Immediate success of procedure per patient - within 24 hours (adjunctive cryoplasty trials).

Analysis 1.11.

Comparison 1 Cryoplasty versus angioplasty, Outcome 11 Immediate success of procedure per lesion - within 24 hours (primary cryoplasty trials).

Analysis 1.12.

Comparison 1 Cryoplasty versus angioplasty, Outcome 12 Immediate success of procedure per lesion - within 24 hours (adjunctive cryoplasty trials).

Analysis 1.13.

Comparison 1 Cryoplasty versus angioplasty, Outcome 13 Death from all causes (primary cryoplasty trials).

Analysis 1.14.

Comparison 1 Cryoplasty versus angioplasty, Outcome 14 Deaths from all causes (adjunctive cryoplasty trials).

Analysis 1.15.

Comparison 1 Cryoplasty versus angioplasty, Outcome 15 Complications - Immediate post treatment (primary cryoplasty trials).

Analysis 1.16.

Comparison 1 Cryoplasty versus angioplasty, Outcome 16 Complications - immediate post treatment (adjunctive cryoplasty trials).

Analysis 1.17.

Comparison 1 Cryoplasty versus angioplasty, Outcome 17 Ankle brachial index (primary cryoplasty trials).

Analysis 1.18.

Comparison 1 Cryoplasty versus angioplasty, Outcome 18 Ankle brachial index (adjunctive cryoplasty trials).

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Arteriosclerosis] this term only 893

#2 MeSH descriptor: [Arteriolosclerosis] this term only 0

#3 MeSH descriptor: [Arteriosclerosis Obliterans] this term only 71

#4 MeSH descriptor: [Atherosclerosis] this term only 379

#5 MeSH descriptor: [Arterial Occlusive Diseases] this term only 753

#6 MeSH descriptor: [Intermittent Claudication] this term only 708

#7 MeSH descriptor: [Ischemia] this term only 747

#8 MeSH descriptor: [Peripheral Vascular Diseases] explode all trees 2140

#9 atherosclero* or arteriosclero* or PVD or PAOD or PAD 16742

#10 (arter* or vascular or vein* or veno* or peripher*) near (occlus* or reocclus* or re-occlus* or steno* or obstruct* or lesio* or block* or harden* or stiffen*) 7851

#11 peripheral near/3 dis* 3181

#12 claudic* or IC 3325

#13 isch* or CLI 16610

#14 re-vasculari* or revasculari* 4571

#15 MeSH descriptor: [Popliteal Artery] explode all trees 248

#16 MeSH descriptor: [Femoral Artery] explode all trees 715

#17 infrainguinal or inguinal 1686

#18 femoro* or femora* 5299

#19 infrapopliteal or poplite* 702

#20 MeSH descriptor: [Iliac Artery] explode all trees 151

#21 iliac 981

#22 ileo* 581

#23 (#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) 48958

#24 MeSH descriptor: [Cryotherapy] explode all trees 1030

#25 cryo* 2074

#26 Polarcath* 2

#27 MeSH descriptor: [Cold Temperature] explode all trees 1096

#28 cold 5131

#29 cool* 1726

#30 #24 or #25 or #26 or #27 or #28 or #29 8544

#31 #23 and #30 877 in Trials

What's new

DateEventDescription
11 July 2013New search has been performedSearch has been re-run, seven new studies have been included, 11 additional studies excluded and two ongoing studies identified.
11 July 2013New citation required and conclusions have changedNew author has joined the review team, search has been re-run, seven new studies included, 11 additional studies excluded and two ongoing studies identified. Conclusions changed from previous version of the review which contained no included studies.

History

Protocol first published: Issue 4, 2005
Review first published: Issue 4, 2007

DateEventDescription
22 July 2009New search has been performedNew search has been performed. No new studies identified.
12 August 2008AmendedConverted to new review format.

Contributions of authors

  • Conceiving the review: GS

  • Designing the review: GS, JM

  • Co-ordinating the review: AA

  • Designing electronic search strategy: Cochrane PVD Group editorial base

  • Screening search results: AA, JM

  • Obtaining copies of trials: AA, JM

  • Appraising quality of papers: AA, JM

  • Abstracting data from papers: AA, JM

  • Data management for the review: AA

  • Entering data into RevMan: AA

  • Analysis of data: AA

  • Interpretation of data: all authors

  • Writing the review: AA, JM, GS

  • Draft the final review: all authors

  • Guarantor for the review: GS

Declarations of interest

JM reports: I received travel, course fees, accommodation and meals from Medtronic as part of the Medtronic University program. This is an educational program, and includes registration and attendance at the European Vascular Course 2012. No financial remuneration was received by myself, other than costs of travel, accommodation, course fees and meals. I received sponsorship from Medtronic to attend the Vascular Society annual meeting 2012 in the form of registration fees and accomodation costs. I am a co-founder of UKETS, a not-for-profit trainee initiative which receives funding through sponsorship from endovascular technology and simulation companies (major funding from Medtronic and Mentice). The majority of this sponsorship is non-financial (that is the companies supply trainers on the courses or allow use of their simulators), although some direct financial input is received from Medtronic and Mentice and is used to run events. No profit is derived from this initiative.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institue of Health Research (NIHR), UK.

    AA is supported by a programme grant from the NIHR.

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

    The PVD Group editorial base is supported by the Chief Scientist Office.

  • National Institute of Health Research (NIHR), UK.

    The PVD Group editorial base is supported by a programme grant from the NIHR.

Differences between protocol and review

The assessment of the methodological quality of the included studies was updated according to the updated recommended 'Risk of bias' tool of The Cochrane Collaboration (Higgins 2011).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Banerjee 2012

MethodsProspective, randomised, multicentre clinical evaluation of the PolarCath® system versus conventional balloon post-dilation of nitinol self-expanding stents (nSES) implanted in the superficial femoral artery (SFA) of patients with diabetes mellitus, presenting with life-style limiting claudication
Participants

No of participants: 74 patients with 90 stented SFA lesions (45 randomised to receive cryoplasty, and 45 received conventional angioplasty)

Country: USA

Inclusion criteria
1. Diabetics, insulin or non-insulin dependent above 21 years of age, able to provide an informed consent, and life expectancy > 1 year

2. Presenting with moderate claudication (Rutherford stage 2), severe intermittent claudication (RB stage 3), chronic critical limb ischaemia with rest pain (RB stage 4), or chronic critical limb ischaemia with ischaemic ulcers (RB stage 5)
3. Placement of > 5 mm in diameter self-expanding nitinol stent in the SFA, with at least 1 vessel infra-popliteal run-off

4. Placement of > 60 mm in length self-expanding nitinol stent in the SFA, with at least 1 vessel infra-popliteal run-off

Exclusion criteria
1. Serum creatinine ≥ 2.0 mg/dl
2. Absence of at least 1 vessel brisk infra-popliteal run-off to the foot
3. LV ejection fraction ≤ 25%
4. Allergy to iodinated contrast
5. Allergy to aspirin or clopidogrel
6. Relative or absolute contraindication to anticoagulation
7. WBC < 3000 K/UL; platelet count < 100,000 K/UL; Hgb < 10 g/dl

Interventions

Intervention: Cryoplasty

Control: Conventional balloon angioplasty

Outcomes

Primary outcome:

Rate of binary restenosis, at 12 months, as determined by duplex ultrasound.

Secondary outcome:

Resting ankle-brachial index (at 6 months and 1 year)

Notes

Location: superficial femoral artery

All patients received stents in both arms of the trial (74 patients with 90 stented lesions)

Outcomes were reported as:

  • per patient: limb loss, immediate success of procedures, cardiovascular deaths, deaths, complications, ABI, mean walking impairment scores, Rutherford stages

  • per lesion: binary restenosis, patency, immediate success of procedures

Antiplatelet/anticoagulant agents (clopidogrel, aspirin, warfarin) used by patients in both groups at randomisation, but no information is given regarding the usage of these agents during the trial

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskRandomisation after stenting, method not described
Allocation concealment (selection bias)High riskAllocation after stenting, concealment not given
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo information provided on blinding participants. Personnel not blinded to treatment allocation
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided on blinding outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted for (9 deaths/90 participants)
Selective reporting (reporting bias)Low riskExpected outcomes presented
Other biasHigh riskStudy design required to randomise the patients after stenting

Diaz 2011

Methods

RCT

Eighty-six patients were randomised according to the operator’s preference to receive cryoplasty, and 69 received conventional angioplasty

Participants

Country: Spain

No of participants: 155 patients (86 randomised to receive cryoplasty, and 69 received conventional angioplasty). The cryoplasty group had 39 lesions at 29 sites (19 superficial femoral artery and 10 popliteal artery), while the angioplasty group had 45 lesions at 31 sites (22 superficial femoral artery and 9 popliteal artery)

Inclusion criteria: lifestyle-limiting claudication (Rutherford-Becker categories 1–3), and rest pain or ischaemic skin changes of the feet (Rutherford- Becker categories 4–5) induced by atheromatous lesions involving the femoropopliteal region

Exclusion criteria: patients with contraindications to the administration of contrast and patients with renal failure

Interventions

Intervention: Cryoplasty

Control: Conventional balloon angioplasty

OutcomesThe primary study endpoint was target lesion patency
Secondary endpoints were initial treatment success with > 30% residual stenosis, absence of haemodynamically relevant dissection, and recoil without the need for stent placement
Notes

Location: femoropopliteal arteries

Patients from both arms of the trial received stents in case of > 30% residual stenosis or luminal narrowing by dissection was detected

Outcomes were reported as:

  • per patient: patency, target lesion patency, need for re-intervention, immediate success of procedures, deaths, complications, ABI

  • per lesion: restenosis, need for re-intervention, immediate success of procedures

Information on antiplatelet/anticoagulant agents used by patients before enrolment in the study is not given. All patients received heparin intra-arterially before the procedure and a loading dose of clopidogrel on the day of the intervention. At discharge, a lifetime regimen of oral acetylsalicylic acid and an 8-week regimen of clopidogrel was prescribed.

Author sent additional data by e-mail

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskPatients were randomised according to the operator’s preference to receive cryoplasty
Allocation concealment (selection bias)High riskPatients were randomised according to the operator’s preference to receive cryoplasty
Blinding of participants and personnel (performance bias)
All outcomes
High riskStudy personnel not blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned
Incomplete outcome data (attrition bias)
All outcomes
High risk48 out of 155 patients were not accounted for at the 36 month follow-up date when the study was published
Selective reporting (reporting bias)High riskOutcomes were not reported at all defined time points
Other biasHigh riskOperator selection of patient

Fossaceca 2011

Methods

RCT

Twenty-four patients were allocated to receive cryoplasty, and 24 received conventional angioplasty

Participants

Country: Italy

No of participants: 48 patients (24 patients were allocated to receive cryoplasty, and 24 received conventional angioplasty). The cryoplasty group had 39 lesions located at 29 sites, while conventional angioplasty group had 45 lesions located at 31 sites

Inclusion criteria:

diabetes mellitus and peripheral atherosclerotic disease with severe claudication or CLI (Rutherford stages 2-6); haemodynamically significant stenosis (70%) or occlusion of the superficial femoral artery (SFA) and/or popliteal artery (PA) as assessed by preliminary colour Doppler ultrasound (CDUS)

Exclusion criteria:

patients with a history of severe allergy or hypersensitivity to contrast material, intolerance to aspirin and/or clopidogrel, coagulation disorders, acute ischaemia of the lower limbs, Buerger’s disease, deep vein thrombosis, loss of infected tissue and absence of outflow

Interventions

Intervention: Cryoplasty

Control: percutaneous angioplasty

OutcomesThe primary study endpoints were immediate technical success (residual restenosis < 30%) and distal run-off as assessed on post-procedural angiography, and degree of restenosis and distal run-off at 6 and 12 months, as assessed with either colour Doppler ultrasound (CDUS) or digital subtraction angiography (DSA)
Notes

Location: Femoropopliteal arteries. The cryoplasty group had 29 sites (19 SFA, 10 PA) and 39 lesions for 24 patients, while the percutaneous angioplasty group had 31 sites (22 SFA, 9 PA) and 45 lesions for 24 patients.

Treatment failures were defined as lesions requiring additional conventional balloon angioplasty owing to a suboptimal result or requiring stent placement due to vessel dissection, and were not considered in the follow-up.

Outcomes were reported as

  • per site: patency, (re)stenosis, occlusion, immediate success of procedures

  • per patient: deaths

All patients were premedicated with aspirin and clopidogrel for at least 3 days before the procedure. No information is given about the antiplatelet/anticoagulants agents after the procedure.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described
Blinding of outcome assessment (detection bias)
All outcomes
Low riskIndependent assessors for study outcomes
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly one patient excluded at follow-up due to technical failure of the procedure
Selective reporting (reporting bias)Low riskExpected outcomes presented
Other biasLow riskPost-procedural angiograms and follow-ups evaluated by independent radiologists

Jahnke 2010

Methods

RCT

Sealed envelope containing the treatment modality

Participants

Country: Germany

No. of participants: 86 (40 Cryoplasty; 46 Conventional angioplasty)

Inclusion criteria:

lifestyle-limiting claudication (Rutherford-Becker categories 1-3); rest pain; ischaemic skin changes of the feet (Rutherford-Becker categories 4-5) induced by focal atherosclerotic stenoses or occlusions of the popliteal artery

Exclusion criteria:

haemodynamically relevant lesions (> 50% luminal stenosis) of the arterial in- and/or outflow; previous stent or stent-graft placement into the popliteal artery; lesions induced by former vascular surgery; fresh embolic occlusions; contraindications to the administration of contrast media; renal failure; hyperthyroidism; allergic diathesis

Interventions

Intervention: Cryoplasty

Control: Conventional balloon angioplasty

Outcomes

Primary outcome: target lesion patency

Secondary outcomes: initial anatomic treatment success with < 30% residual stenosis; absence of haemodynamically relevant dissection or recoil without the need for stent placement; complications

Notes

Location: Popliteal artery

The rate of stent placement for dissection and/or residual stenosis was 30% after cryoplasty and 39% after conventional angioplasty.

Outcomes were reported as:

  • per patient: patency, target lesion patency, restenosis, need for re-intervention, immediate success of procedures, complications, ABI

No information is given about antiplatelet/anticoagulation agents either before or after procedure.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe patients were randomly assigned by opening a sealed envelope containing the treatment modality
Allocation concealment (selection bias)Low riskSealed envelope containing the treatment modality
Blinding of participants and personnel (performance bias)
All outcomes
Low riskTreatment assigned by opening sealed envelopes
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned
Incomplete outcome data (attrition bias)
All outcomes
High riskOnly 29 patients (40 patients recruited) reached 9 months follow-up, no explanation given about the missing patients
Selective reporting (reporting bias)Low riskAll expected outcomes presented
Other biasLow riskNot evidence of other bias

Shammas 2012

Methods

RCT

Sealed envelope containing the treatment modality

Participants

Country: USA

No. of participants: 40 (20 Cryoplasty; 20 Primary balloon angioplasty)

Inclusion criteria:

patients had de novo lesions, were > 18 years of age and referred for claudication (Rutherford Becker I–III) or critical limb ischaemia (Rutherford Becker IV–V)

Exclusion criteria:

1. heavily calcified vessels (as subjectively determined by the operator)

2. total occlusions longer than 10 cm, any lesion less than 3 cm, or non-femoropopliteal lesions

3. inability to take aspirin or adenosine diphosphate receptor antagonists

4. bleeding disorder or platelet count less than 100,000 per μl

5. creatinine over 3.5 mg/dl

6. unwilling to give consent or return for future follow-up visits

7. decompensated congestive heart failure or acute coronary syndrome

8. staged vascular procedure during the same hospital stay or one week after the index procedure

Interventions

Intervention: Cryoplasty

Control: Primary balloon angioplasty

Outcomes

Primary outcome: target lesion revascularisation at 6 months

Secondary outcomes:

1. The rate of bail out stenting because of suboptimal acute angiographic results defined as a residual stenosis of ≥ 30% or the presence of type C–F dissection. Dissections were classified according to the National Heart, Lung, and Blood Institute classification for coronary artery dissections
2. Final acute angiographic results in each arm at the end of the procedure
3. Target vessel revascularisation (TVR) at 6 months
4. Major adverse events including major amputation, death, distal embolisation, vascular complications (arteriovenous fistula, pseudoaneurysm, or perforation), major bleeding (loss of 3 units of packed red blood cells with a source of bleed, or intracranial bleed or retroperitoneal bleed), unplanned urgent revascularisation of the treated vessel in the same hospital stay, stroke, and acute renal failure (an increase in creatinine clearance by 25% over pre procedure baseline)
5. Change in the ankle brachial index at 6 month post procedure from baseline.

Notes

Location: Femoropopliteal arteries

Bailout stenting was performed in patients with procedural failures, but were not permitted for procedural success.

Outcomes were reported as

  • per patient: restenosis, limb loss, deaths, complications, ABI

  • per lesion restenosis, need for re-intervention, immediate success of procedures

Clopidogrel 600 mg and aspirin 324 mg were administered orally immediately prior to the procedure in patients not taking antiplatelet agents. Patients already receiving clopidogrel and aspirin continued to take 75 mg oral clopidogrel and 324 mg oral aspirin daily. The exclusive anticoagulant administered during the procedure was intravenous bivalirudin.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by envelopes
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted for
Selective reporting (reporting bias)Low riskAll outcomes presented
Other biasLow riskNo evidence for other bias

Spiliopoulos 2010

Methods

RCT

Allocation: pooled 1:1 envelopes, which were opened only after lesions were successfully crossed

Blinded: no

Participants

Country: Greece

No. of participants: 50 (24 Cryoplasty; 26 Conventional balloon angioplasty)

Inclusion criteria:

non-insulin or insulin dependent diabetes mellitus; severe claudication or CLI (Rutherford stage 3 to 6); stenosis ≥ 70% or occlusion of the SFA and/or the PFA; de novo and ISR lesions

Exclusion criteria:

diet-controlled diabetes; history of severe contrast allergy or hypersensitivity; intolerance to aspirin and/or clopidogrel; systemic coagulopathy or hypercoagulation disorders; acute limb ischaemia; Buerger disease; deep vein thrombosis; infected tissue loss; absent pedal arch run-off

Interventions

Intervention: Cryoplasty

Control: Conventional balloon angioplasty using commercially available semi-compliant or non-compliant balloon catheters

Outcomes

Primary outcome: technical success < 30% residual stenosis without any adjunctive stenting; primary patency; binary in-lesion restenosis (> 50%); freedom from target lesion recanalisation

Secondary outcome: 30-day complications; patient mortality; limb salvage; minor amputation of the treated limbs

Notes

Location: Femoropopliteal arteries

Stenting was reserved for bail-out in case of elastic recoil, post-dilatation residual stenosis 30%, or
severe flow-limiting dissection (type C). Technical success was defined as 30% residual stenosis without any adjunctive stenting.

Outcomes were reported as

  • per patient: limb loss, deaths

  • per lesion: binary restenosis, need for re-intervention, immediate success of procedures

No information is given on the usage of antiplatelet/anticoagulant agents before the patients' enrolment in the study.

All patients were premedicated with aspirin and clopidogrel for at least 3 days before the procedure. After procedure, patients received were prescribed with a dual antiplatelet therapy (aspirin and clopidogrel) for 6 weeks and solely clopidogrel or aspirin indefinitely thereafter.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPooled 1:1 envelopes
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding of participants and personnel (performance bias)
All outcomes
High riskPatients randomised only after lesions were successfully crossed
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted for
Selective reporting (reporting bias)High riskOne secondary outcome (30 day complications) not presented
Other biasLow riskNo evidence of other bias

Wang 2011

Methods

RCT

Patients with peripheral arterial disease (PAD) of the iliac or infra-inguinal arteries or lower limb bypass graft stenoses

Participants

Country: China

No. of participants: 25 (10 Cryoplasty; 15 Conventional balloon angioplasty)

Inclusion criteria:

1. Diagnosed with atherosclerotic peripheral arterial disease according to the Trans-Atlantic Inter-Society Consensus (TASC) classification

2. With lesions involving the iliac and femoropopliteal regions, but having no outflow tract obstruction below the knee

3. With Fontaine class II and greater

4. ABI < 0.6

5. TcPO2 < 30 mmHg

Definite atherosclerotic plaque formation, haemodynamically significant stenosis (> 50%) or total occlusion of the arteries, as documented by CDFI, CTA or MRA

Exclusion criteria:

1. Acute limb ischaemia/thrombus formation

2. Previous bypass surgery or stenting procedures

3. With outflow tract narrowing or total obstruction below the knee

4. Intolerance to contrast

5. History of  contrast allergy or hypersensitivity and intolerance to antiplatelet and/or anticoagulation drugs

6. Infected tissue loss

Interventions

Intervention: Cryoplasty

Control: Conventional balloon angioplasty

Outcomes

1. Technical success: residual stenosis < 30%

2. Changes in clinical characteristics between baseline and follow-up; postoperative changes in clinical characteristics using Rutherford classification 7

3. ABI

4. Arterial stenosis using  the colour Doppler flow image (CDFI)

Notes

Location: Iliac or infrainguinal arteries

Outcomes were reported as

  • per patient: immediate success of procedures, complications, ABI

No information is given on the usage of antiplatelet/anticoagulant agents before or after the patients' enrolment in the study.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskGenerated random numbers
Allocation concealment (selection bias)Low riskGenerated random numbers allocated to patients
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll outcome data presented
Selective reporting (reporting bias)Low riskAll outcomes presented
Other biasLow riskStudy appears to be free of other sources of bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    PA: popliteal artery
    SFA: superficial femoral artery

Bakken 2008Retrospective review of patients
Banerjee 2009Non-randomised study
Basco 2012Retrospective cohort study
Bosiers 2010Multicentre registry evaluating the use of the PolarCath peripheral dilatation system
Das 2009Not a randomised controlled trial, but prospective, multicentre study of 111 patients with stenoses of occlusions of infrapopliteal vessels
Fava 2004Case series of 15 patients with stenoses and/or occlusions of the SFA and PA
FIX-IT RetroRetrospective analysis
Gisbertz 2009Prospective cohort study of 17 patients treated with cryoplasty
Gonzalo 2010Prospective study of 11 patients
Karthik 2007Prospective, single centre follow-up case series of arterial restenosis in 10 patients with graft risk or in stent restenosis
Korteweg 2009Pilot study without a control arm
Laird 2006Prospective, multicentre registry of 102 claudicants with lesions of the SFA and PA. Results to nine months reported
Samson 2008Case series of 47 lesions in 32 consecutive patients with lesions in the SFA, PA and vein bypass grafts
Schmieder 2010 Retrospective review of patients
Shin 2010Retrospective record review
Silva 2011Retrospective analysis

Characteristics of ongoing studies [ordered by study ID]

ATHERO

Trial name or titleATHERO: Advanced technology halting early re-stenosis and occlusion
Methods

Study design

Allocation: Randomised
Control: Active control
Endpoint classification: Safety/efficacy study
Intervention model: Parallel assignment
Masking: Open label
Primary purpose: Treatment

Participants

Number: 100

Inclusion criteria:

- The subject must give written informed consent and possess decision making capacity free of sedative or hypnotic agents

- Age 18 years or older

- Candidate for angiography with intent to treat as determined by the principle investigator

- On angiography, ipsilateral to a symptomatic limb, a stenotic or occluded de novo or restenotic lesion in the common femoral artery, superficial femoral artery or above the knee popliteal artery measuring no longer than 10 cm (the upper limit of treatment in cryoplasty pre-marketing)

- On angiography lesion stenoses between 50% and 100% (inclusive)

- At least one run-off vessel - available for follow-up assessments

Exclusion criteria:

- Contraindication to systemic anticoagulation e.g. history of documented haemorrhage requiring treatment within the past 30 days; history of a hereditary bleeding disorder or known bleeding diathesis; major surgery or trauma, open chest massage, ocular surgery or haemorrhagic retinopathy within the past 30 days; puncture at a non-compressible site within 48 hours prior to planned procedure; history of stroke, intracranial haemorrhage, or central nervous system structural abnormalities within the past 3 months

- History of endovascular surgery procedure or open vascular surgery on the index limb within the last 30 days

- History of significant acute or chronic kidney disease that would preclude contrast angiography - known allergy to contrast agents

- History of heparin-induced thrombocytopenia (HIT)

- Participation in any study of an investigational device, medication, biologic, or other agent within 30 days prior to randomisation

- Any thrombolytic therapy within 30 days of randomisation

- Pregnancy, lactation, or possession of any child bearing potential without evidence of surgical infertility or passage of 12 months since the last day of the subject's last menstrual period

- Target lesion involving a Dacron prosthesis or a prosthetic of unknown material

- Target lesion extending into the orifice of the profunda femoris artery

- Prisoner status

- Any other subject feature that in the opinion of the investigator should preclude study participation

Age minimum: 18 years
Age maximum: N/A
Gender: Both

InterventionsDevice: Lower extremity atherectomy and cryoplasty - Silverhawk™ Atherectomy and CryoPlasty® Therapy for Lower Extremity Claudication
Outcomes

Primary outcomes:

Primary target patency at 12 months. The 'target' is the index stenotic lesion(s). Primary patency is defined as < 50% residual stenosis by duplex (colour-flow Doppler) scan analysis, with antegrade flow to the target vessel

Secondary outcomes:

Ankle-brachial index (ABI) improvement by = 0.15 at 3, 6 and 12 months compared to baseline

Change in walking impairment questionnaire (WIQ) functional status scores from baseline at 3, 6 and 12 months

Complications: defined as adverse events (AEs) or serious adverse events (SAEs). Complications may or may not be device related

Cost to patient and hospital: Including operating room times and duration of hospitalisation

Starting dateDecember 2006
Contact information

Joshua I Greenberg, MD: Telephone: 619-543-6222

Email: jigreenberg@ucsd.edu (not a valid emailed address; 10 May 2012)

Ahmed Suliman, MD: Telephone: 619-543-6222

Email: asuliman@ucsd.edu (not a valid email address; 10 May 2012)

Principal Investigator: Niren Angle, MD; University of California, San Diego

Notes

Still recruiting patients (as off 26 March 2013)

AA emailed: 20 December 2011; 10 May 2012 - emailed to N Angle; sent request http://www.niren-angle.com/Contact-Us.aspx on 31 January 2013

Other contact: Dr Niren Angle nangle@ucsd.edu (not valid 10 May 2012); fherrera00@yahoo.com (from ResearchGate)

The SFA Study CLASE

Trial name or titleA Randomized Trial for Femoropopliteal Arteries (Prime Time for Superficial Femoral Artery (SFA) - The SFA Study CLASE)
Methods

Randomised trial

Allocation: Randomised

Endpoint classification: Safety/efficacy study

Intervention model: Parallel assignment

Masking: Double blind (subject, investigator)

Primary purpose: Treatment

Participants

Number: 130

Inclusion criteria:

- Stenosis > 70% or total occlusion of the femoropopliteal segment that do not include the origin of the SFA - SFA and popliteal of > 4 mm in diameter

- TASC classification A, B, and C

- At least one vessel run-off

Exclusion criteria:

- Age < 18 years old

- Medical condition that may cause the patient not to be compliant with follow-up (excl. terminal cancer)

- Pregnancy

- Unwilling or unable to comply with the follow-up

- Inability or refusal of informed consent

- Medical exclusion criteria - Systemic Infection (sepsis) - Bleeding diathesis unable to use anticoagulation. - Untreatable reaction to contrast material

- Anatomical endovascular exclusion criteria - SFA/popliteal artery < 4 mm diameter - Total occlusion of femoral artery with non-visualization of the origin of the SFA - Previous SFA/popliteal intervention (PTA, stenting etc.) - Acute ischaemia and/or acute thrombosis of the SFA-popliteal segment - TASC type D

Age minimum: 18 years
Age maximum: N/A
Gender: Both

Interventions

Device: Viabahn endograft

Procedure: Angioplasty/stent (Guidant "Absolute" stent)

Procedure: Cryoplasty (PolarCath peripheral balloon catheter)

Procedure: Laser angioplasty (Spectranetics)

Procedure: SilverHawk Atherectomy

Outcomes

Primary outcome(s):

Determine if the devices (laser, atherectomy, Polarcath, and Viabahn endograft) offer better treatment, better outcome, and better patency than the angioplasty/stent treatment to the femoral artery

Time frame: 2 weeks, 3, 6, and 12 months

Starting dateNovember 2004
Contact information

Julio Rodriguez-Lopez, M.D.; Arizona Heart Institute

Email: jrodriguez@azheart.com

Notes

Study terminated: no funding

AA emailed for data/update: 20 December 2011 and 10 May 2012 - no reply received.

A thesis was submitted by Hester F. Shieh in 2012 for partial fulfilment of the requirements for the degree of Doctor of Medicine (University of Arizone College of Medicine - Phoenix) entitled: 'The CLASE Study: Endovascilar Management of the Superficial Femoral Artery'. It stated that the study is a retrospective review of patients that underwent endovascular management of the femoropopliteal segment and evaluated patency. (http://arizona.openrepository.com/arizona/bitstream/10150/221411/1/Shieh,%20Hester.pdf (accessed 11 July 2013)

Ancillary