Cryoplasty for peripheral vascular disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy of, and complications associated with, cryoplasty for maintaining patency in the iliac or infra‐inguinal arteries.
Background
In the United Kingdom, symptomatic peripheral arterial disease (PAD) occurs in 5% to 7% of people over the age of 55 years (Dewhurst 1991; Fowkes 1991). In 25% of these people, the condition will deteriorate and require treatment, and 5% will go on to develop limb threatening critical limb ischaemia (CLI) (Dormandy 1991). More than 50% of those who require treatment will be suitable candidates for endovascular methods of intervention (London 1995).
Percutaneous balloon angioplasty is a radiological 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 femoro‐popliteal arteries. Five year patency rates for iliac and femoro‐popliteal angioplasty are 55% to 60% and 52%, respectively (Adar 1989; Leu 1999; Long 1991; Martin 1995; Murphy 1995).
A recent Cochrane review of trials (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 (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 eagerly being sought to regulate this process (Clowes 1983; Dilley 1988; Mintz 1996; Sottiurai 1983).
Cryoplasty offers a new approach to improving long‐term angioplasty results. It combines the dilation force of balloon angioplasty with the delivery of cold thermal energy to the vessel wall. Cryotherapy is already widely adopted in other fields of medicine as an effective method of treatment. Previous studies have demonstrated a benign histological response in arteries in response to cold thermal energy, with no interruption in the function of the vessel (Gage 1967). Cryoplasty is thought to provoke apoptosis (natural cell death) rather than necrosis (pathological cell death) in the arterial smooth muscle cells, thus has the theoretical advantage of reduced myointimal hyperplasia in long‐term patency (Fava 2004).
As it is an emerging therapy, many questions remain regarding the safety and efficacy of cryoplasty. This meta‐analysis 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 or infra‐inguinal arteries.
Methods
Criteria for considering studies for this review
Types of studies
Trials in which patients with peripheral arterial disease (PAD) of the iliac or infra‐inguinal arteries are randomised to cryoplasty with, or without, another procedure versus a procedure without cryoplasty.
Types of participants
Males and females of any age, diagnosed with PAD by an expert clinician, through clinical and investigative assessment (ankle‐brachial pressure index (ABPI), duplex, exercise testing or angiography), and who require vascular intervention that could be appropriately managed with cryoplasty and are deemed fit to undergo such an intervention. If possible these patients will be stratified on a symptomatic basis (e.g. rest pain, tissue loss, claudication distance) or by TASC criteria (TASC).
Types of interventions
Trials including any form of therapy that involved the use of cryoplasty for the treatment of PAD will be considered for inclusion. Trials will be divided into subgroups according to the indication for intervention (critical limb ischaemia, intermittent claudication); and de novo or repeat procedures. Additional therapies, in particular, the adjuvant use of antiplatelet or anticoagulant agents will also be assessed.
Types of outcome measures
The following primary outcome measures will be considered:
• patency, restenosis or occlusion at various timepoints (e.g. 30 days, 3 months, 6 months, 12 months) using imaging studies or haemodynamics;
• need for reintervention;
• limb loss.
The following secondary outcome measures will be considered:
• immediate success of procedures (within 24 days);
• 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);
• ABPI;
• walking distance;
• maximum walking distance on treadmill;
• grading of patency on duplex scanning or angiography;
• time to restenosis;
• quality of life assessments.
Cost‐effectiveness in terms of morbidity (presence of disease), mortality (death), and use of resources (e.g. bed days) will also be considered.
Search methods for identification of studies
This review will draw on the search strategy developed for the Cochrane Peripheral Vascular Diseases Group as a whole. Publications describing (or which might describe) RCTs of cryoplasty for PAD will be sought through electronic searches of the Cochrane Peripheral Vascular Diseases Specialised Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL).
Briefly, the Specialised Trials Register of the Group has been constructed from regular electronic searches of MEDLINE (1966 onwards), EMBASE (1980 onwards), and the Cochrane Central Register of Controlled Trials (CENTRAL); and through handsearching 38 relevant journals and numerous conference proceedings. Relevant trials are entered into the Register. The full list of journals and conference proceedings, as well as the search strategies for the electronic databases, are described in the 'Search strategies for the identification of studies' section within the editorial information about the Cochrane Peripheral Vascular Diseases Group in The Cochrane Library.
In addition, JM will search MEDLINE (1966 onwards) and EMBASE (1980 onwards) using the MeSH terms 'angioplasty', 'peripheral vascular disease', 'cryosurgery' and 'cryotherapy' alone and in combination to look for relevant articles. The manufacturers of the cryoplasty device will also be contacted to obtain any unpublished, missed or forthcoming trial work.
Data collection and analysis
Selection of trials
All three authors will select trials for inclusion in the review.
Quality of trials
JM and GS will independently assess the methodological quality of each trial, with arbitration in the event of disagreement from a co‐author (SM), using the checklist recommended by the Cochrane Peripheral Vascular Diseases Review Group. JM and GS will give each trial an allocation score of A (clearly concealed), B (unclear if concealed), C (clearly not concealed) and also a summary score of A (low risk of bias), B (moderate risk of bias) and C (high risk of bias). Trials scoring A for concealment or bias will be included, C excluded and B discussed in more detail with the third author (SM).
Data extraction
Data collection will be carried out by JM and crosschecked by GS and SM, including information on participants (age and sex distribution, measures of severity of disease such as ABPI), interventions and outcomes (as above). Any information absent in the publications will be sought directly from the authors.
Statistical analysis
The trials will be assessed and measures used for statistical pooling according to the guidelines published by the Cochrane Peripheral Vascular Diseases Review Group. Subgroup analysis will be performed if possible and as necessary, including type and length of lesion, and initial presentation (TASC criteria and symptoms) (TASC). Patients with vessels requiring re‐intervention (with stratification for time from intervention to re‐intervention) will also be analysed as a subgroup.
