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Crioplastia para la enfermedad arterial periférica

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Resumen

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Antecedentes

La angioplastia con balón percutánea es una técnica endovascular para restaurar el flujo sanguíneo a través de una arteria que se ha estenosado o bloqueado por la aterosclerosis. El estrechamiento de la arteria después de la angioplastia (reestenosis) es la causa principal del fracaso a largo plazo. La crioplastia ofrece un enfoque diferente para mejorar los resultados de la angioplastia a largo plazo. Combina la fuerza de dilatación de la angioplastia con balón con el enfriamiento de la pared vascular. Esta revisión sistemática evaluó la crioplastia en la enfermedad arterial periférica y proporciona una guía para la realización de estudios de investigación adicionales en el campo. Ésta es una actualización de una revisión publicada por primera vez en 2007.

Objetivos

Evaluar la eficacia y las complicaciones asociadas con la crioplastia para mantener la permeabilidad en las arterias ilíaca, femoropoplítea y crural a corto y medio plazo.

Métodos de búsqueda

Para esta actualización, el coordinador de búsqueda de ensayos del Grupo Cochrane de Enfermedades Vasculares Periféricas (Cochrane Peripheral Vascular Diseases Group) realizó búsquedas en el registro especializado (última búsqueda en octubre de 2012) y en CENTRAL (2012, número 10). Se realizaron búsquedas de estudios no publicados o en curso en bases de datos de ensayos. Además, se buscó en las listas de referencias de artículos pertinentes.

Criterios de selección

Se consideraron todos los ensayos controlados aleatorios en los cuales a los participantes con enfermedad arterial periférica (EAP) de los miembros inferiores o estenosis del injerto de derivación del miembro inferior, se les asignó al azar a crioplastia con o sin otro procedimiento versus un procedimiento sin crioplastia. Lo anterior incluyó ensayos donde todos los participantes recibieron angioplastia y la asignación al azar fue a crioplastia versus ninguna crioplastia y los ensayos donde la crioplastia se utilizó como complemento al tratamiento convencional (por ejemplo, colocación de stent) contra un control.

Obtención y análisis de los datos

Dos revisores de forma independiente seleccionaron los ensayos, extrajeron los datos y evaluaron el riesgo de sesgo.

Resultados principales

En esta revisión, se incluyeron siete ensayos (seis de crioplastia primaria y un ensayo de crioplastia coadyuvante) con 478 pacientes. Los ensayos informaron la permeabilidad y la reestenosis por participante, lesión o ubicación del vaso. El seguimiento osciló entre 30 días y tres años.

La permeabilidad de la lesión objetivo medida en diversos puntos temporales en dos ensayos de crioplastia primaria no mostró diferencias estadísticamente significativas entre los grupos de tratamiento. El estudio de crioplastia coadyuvante mostró que la crioplastia se asoció con mejor permeabilidad solo a los seis meses (OR 5,37; IC del 95%: 1,09 a 26,49; n = 90).

La reestenosis medida por paciente (dos ensayos de crioplastia primaria) no mostró diferencias estadísticamente significativas entre los tratamientos. La reestenosis medida por lesión (dos ensayos de crioplastia primaria) mostró una diferencia estadísticamente significativa solo a las 24 horas después del procedimiento (OR 0,08; IC del 95%: 0,04 a 0,18; n = 192) que favoreció a la crioplastia.

La necesidad de reintervención no fue significativamente diferente en los participantes del ensayo de crioplastia primaria (por participante: OR 0,27; IC del 95%: 0,05 a 1,52, n = 241; I2 = 89%; por lesión: OR 0,59; IC del 95%: 0,06 a 5,69; n = 307; I2 = 94%) El ensayo de crioplastia coadyuvante no informó la necesidad de intervención.

El éxito inmediato del procedimiento (en el transcurso de 24 horas) no fue significativamente diferente en los participantes del ensayo de crioplastia primaria (por participante: OR 1,63; IC del 95%: 0,14 a 19,55; n = 340; I2 = 95%; por lesión: OR 1,81; IC del 95%: 0,19 a 17,36; n = 397; I2 = 90%). El ensayo de crioplastia coadyuvante informó un éxito del 100%.

La pérdida de miembros, las muertes por todas las causas y el riesgo de complicaciones inmediatamente después del tratamiento no mostraron diferencias estadísticamente significativas entre los tratamientos.

Conclusiones de los autores

No es posible establecer el efecto beneficioso de la crioplastia sobre la angioplastia convencional porque el número de ensayos controlados aleatorios es pequeño y su calidad no es suficientemente alta. Las tasas de éxito técnico y permeabilidad primaria observadas en estos ensayos no son consistentes y no indican necesariamente una función futura de la crioplastia en el tratamiento de la EAP, pero no se pueden interpretar de manera confiable. Actualmente, no hay datos suficientes para apoyar el uso habitual de la crioplastia sobre la angioplastia de balón convencional en el tratamiento de la EAP.

Resumen en términos sencillos

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Crioplastia para la enfermedad vascular periférica

La enfermedad arterial periférica se debe al estrechamiento o al bloqueo de las arterias principales de las piernas, generalmente debido a aterosclerosis. La reducción resultante del flujo sanguíneo causada por una arteria bloqueada o estrechada puede causar dolor al caminar o hacerse tan grave que amenace con la pérdida de la pierna. La cirugía endovascular incluye la inserción de un balón pequeño mediante una punción con aguja en la arteria afectada. El balón se infla posteriormente para extender la arteria abierta (lo que se denomina angioplastia de balón percutánea). Lamentablemente, la arteria a menudo se estrecha nuevamente con el transcurso del tiempo, lo que se conoce como reestenosis. La crioplastia enfría la pared del vaso a la vez que realiza la angioplastia de balón y puede reducir el engrosamiento de la capa muscular interna del vaso sanguíneo para mejorar los resultados de la angioplastia a largo plazo y evitar la reestenosis.

El efecto beneficioso de la crioplastia sobre la angioplastia de balón convencional todavía está por establecerse definitivamente porque existen pocos ensayos controlados aleatorios que evalúen este método. Las tasas de éxito técnico y las tasas de arterias no obstruidas (permeabilidad primaria) en comparación con la angioplastia convencional observadas en siete ensayos (478 pacientes), no fueron consistentes. En particular, los resultados a largo plazo aún están por evaluar completamente. Actualmente, no hay datos suficientes para apoyar el uso habitual de la crioplastia sobre la angioplastia de balón convencional en el tratamiento de la enfermedad arterial periférica.

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.

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.


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

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


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

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.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 1

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

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 1 Patency per patient (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.1

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 2 Patency per lesion (adjunctive cryoplasty trials).
Figuras y tablas -
Analysis 1.2

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 3 Restenosis per patient (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.3

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 4 Restenosis per lesion (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.4

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 5 Need for re‐intervention per patient ‐ no time interval (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.5

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 6 Need for re‐intervention per lesion ‐ no time interval (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.6

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 7 Limb loss (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.7

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 8 Limb loss (adjunctive cryoplasty trials).
Figuras y tablas -
Analysis 1.8

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 9 Immediate success of procedure per patient ‐ within 24 hours (primary cryoplasty trials)).
Figuras y tablas -
Analysis 1.9

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 10 Immediate success of procedure per patient ‐ within 24 hours (adjunctive cryoplasty trials).
Figuras y tablas -
Analysis 1.10

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 11 Immediate success of procedure per lesion ‐ within 24 hours (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.11

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 12 Immediate success of procedure per lesion ‐ within 24 hours (adjunctive cryoplasty trials).
Figuras y tablas -
Analysis 1.12

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 13 Death from all causes (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.13

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 14 Deaths from all causes (adjunctive cryoplasty trials).
Figuras y tablas -
Analysis 1.14

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 15 Complications ‐ Immediate post treatment (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.15

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 16 Complications ‐ immediate post treatment (adjunctive cryoplasty trials).
Figuras y tablas -
Analysis 1.16

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 17 Ankle brachial index (primary cryoplasty trials).
Figuras y tablas -
Analysis 1.17

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

Comparison 1 Cryoplasty versus angioplasty, Outcome 18 Ankle brachial index (adjunctive cryoplasty trials).
Figuras y tablas -
Analysis 1.18

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

Comparison 1. Cryoplasty versus angioplasty

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Patency per patient (primary cryoplasty trials) Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 3 months

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

0.84 [0.30, 2.37]

1.2 6 months

2

241

Odds Ratio (M‐H, Fixed, 95% CI)

0.62 [0.36, 1.07]

1.3 9 months

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

1.35 [0.58, 3.17]

1.4 12 months

1

155

Odds Ratio (M‐H, Fixed, 95% CI)

0.72 [0.38, 1.36]

1.5 24 months

1

155

Odds Ratio (M‐H, Fixed, 95% CI)

0.74 [0.39, 1.40]

1.6 36 months

1

155

Odds Ratio (M‐H, Fixed, 95% CI)

0.78 [0.41, 1.47]

2 Patency per lesion (adjunctive cryoplasty trials) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 2 months

1

90

Odds Ratio (M‐H, Fixed, 95% CI)

3.07 [0.12, 77.32]

2.2 4 months

1

90

Odds Ratio (M‐H, Fixed, 95% CI)

3.14 [0.31, 31.42]

2.3 6 months

1

90

Odds Ratio (M‐H, Fixed, 95% CI)

5.37 [1.09, 26.49]

2.4 8 months

1

90

Odds Ratio (M‐H, Fixed, 95% CI)

2.64 [0.90, 7.73]

2.5 10 months

1

90

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [0.68, 4.25]

2.6 12 months

1

90

Odds Ratio (M‐H, Fixed, 95% CI)

1.91 [0.82, 4.48]

3 Restenosis per patient (primary cryoplasty trials) Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Within 24 hours (immediate)

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

1.03 [0.35, 2.98]

3.2 6 months

1

40

Odds Ratio (M‐H, Fixed, 95% CI)

1.59 [0.24, 10.70]

4 Restenosis per lesion (primary cryoplasty trials) Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Within 24 hours (immediate)

1

192

Odds Ratio (M‐H, Fixed, 95% CI)

0.08 [0.04, 0.18]

4.2 6 months

1

50

Odds 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) Show forest plot

2

241

Odds 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) Show forest plot

3

307

Odds Ratio (M‐H, Random, 95% CI)

0.59 [0.06, 5.69]

7 Limb loss (primary cryoplasty trials) Show forest plot

2

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.1 6 months

1

40

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 12 months

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.3 24 months

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

1.09 [0.14, 8.42]

7.4 3 years

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

1.09 [0.14, 8.42]

8 Limb loss (adjunctive cryoplasty trials) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

8.1 12 months

1

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)) Show forest plot

3

266

Odds 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) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11 Immediate success of procedure per lesion ‐ within 24 hours (primary cryoplasty trials) Show forest plot

3

307

Odds 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) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

13 Death from all causes (primary cryoplasty trials) Show forest plot

4

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

13.1 30 days

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.2 3 months

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

13.3 6 months

3

245

Odds Ratio (M‐H, Fixed, 95% CI)

3.32 [0.36, 30.38]

13.4 12 months

3

253

Odds Ratio (M‐H, Fixed, 95% CI)

2.34 [0.60, 9.13]

13.5 24 months

2

205

Odds Ratio (M‐H, Fixed, 95% CI)

1.52 [0.57, 4.01]

13.6 3 years

2

205

Odds Ratio (M‐H, Fixed, 95% CI)

1.11 [0.48, 2.59]

14 Deaths from all causes (adjunctive cryoplasty trials) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

14.1 12 months

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

15 Complications ‐ Immediate post treatment (primary cryoplasty trials) Show forest plot

4

306

Odds Ratio (M‐H, Fixed, 95% CI)

2.26 [0.70, 7.37]

16 Complications ‐ immediate post treatment (adjunctive cryoplasty trials) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

17 Ankle brachial index (primary cryoplasty trials) Show forest plot

4

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

17.1 Within 24 hours

2

241

Mean Difference (IV, Fixed, 95% CI)

‐0.05 [‐0.12, 0.03]

17.2 2 days

1

25

Mean Difference (IV, Fixed, 95% CI)

0.02 [‐0.11, 0.15]

17.3 30 days

1

25

Mean Difference (IV, Fixed, 95% CI)

0.0 [‐0.13, 0.13]

17.4 3 months

1

86

Mean Difference (IV, Fixed, 95% CI)

0.13 [0.02, 0.24]

17.5 6 months

1

40

Mean Difference (IV, Fixed, 95% CI)

0.03 [‐0.11, 0.17]

17.6 9 months

1

86

Mean Difference (IV, Fixed, 95% CI)

0.02 [‐0.06, 0.10]

18 Ankle brachial index (adjunctive cryoplasty trials) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

18.1 12 months

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 1. Cryoplasty versus angioplasty