Description of the condition
Haemodialysis, the most common treatment for kidney injury globally, requires reliable access to the bloodstream by means of a vascular access. The native arteriovenous (AV) fistula and the AV graft (AV accesses) are universally recognised (Allon 2008; Besarab 2008) as the best types of access because large observational studies have shown that their use is associated with better patient outcomes than central venous catheters (Dhingra 2001; Pastan 2002). This belief was reinforced by a recent meta-analysis by our group, in which we showed that people using catheters had the highest risk of death from all causes, infections and cardiovascular disease (Ravani 2013). AV accesses are internal accesses because they are inserted in the arm of a patient and consist of a direct surgical connection between an artery and a vein (fistula), or a bridge conduit between an artery and a vein (graft), usually made of synthetic material.
Description of the intervention
Remodelling of blood vessels after surgical creation of an AV access is an important part of the maturation and enlargement of the access (Roy-Chaudhury 2006) to facilitate flow sufficient for haemodialysis. However, scarring and abnormal remodelling may also contribute to vascular access stenosis, dysfunction and thrombosis, a leading cause of hospitalisation in haemodialysis patients (Manns 2005). While early complications within the first few months after access creation are more common in fistulas than in grafts (Dember 2008) late complications of an established and functioning access are more common in grafts, and include venous outflow, graft-vein, graft-artery and intra-graft lesions in grafts, and venous outflow and arterial inflow in fistulas (Roy-Chaudhury 2006). Additional procedures are performed in 80% of newly-created fistulas to salvage access function (1.45 to 3.3 procedures/access-year, three times higher than in grafts), with an overall cost to facilitate fistula maturation (CAD 7740 in the first year) similar to that of a successful graft creation (CAD 8130 in the first year) (Lok 2007). About half of the fistulas that mature without additional interventions (20% of all fistulas) require some revisions in the long-term (0.17 to 0.57 procedures/access-year) (Lok 2007). Since these rates are six times lower than in grafts in the long-term, fistulas are considered the most cost-effective access (USD 4862/year) (Besarab 2008) available for dialysis access.
How the intervention might work
In most haemodialysis programs, different methods are routinely used for early identification of a haemodynamically significant stenosis of a fistula or graft (NKF 2006). These include physical examination (monitoring) and different surveillance techniques, such as sequential measurements with trend analysis of intra-access flow measurements, measured or calculated static arterial and venous dialysis pressure, and/or duplex ultrasound. In the presence of a trend toward critical values of access flow or pressure, guidelines recommend patient referral for an imaging study and pre-emptive correction of stenoses greater than 50% to prevent further progression of vessel narrowing and thrombosis of the access (Jindal 2006; NKF 2006; Polkinghorne 2008; Tordoir 2007). These pre-emptive radiological intervention procedures (angioplasty with or without stenting) or surgical corrections of a stenosis are expected to result in increased longevity of the AV access, improved suitability for dialysis, increased dialysis dose delivery, and reduced subsequent access-related procedures and cost. However, the evidence in support of such practice is controversial (Tonelli 2008). Implementation of access screening strategies has been found to reduce the risk of thrombosis but not patency rates in fistulas, and to have no benefits in grafts (Tonelli 2008). In addition, information regarding access loss, costs, and hospitalisation rates following implementation of these screening strategies (a measure of potential harm) is insufficient.
Why it is important to do this review
Current guidelines recommend routine screening of permanent AV access (NKF 2006) but several trials and a systematic review (Tonelli 2008) have been published since these guidelines were last updated. Given the considerable morbidity associated with access dysfunction but also the important resource implications and uncertain benefits and harms of these screening strategies (Tonelli 2008) knowledge synthesis about optimal ways to improve outcomes of a functioning access remains a priority for patients, clinicians and health policy makers. In this systematic review we will summarise data from clinical trials on the benefits and harms of pre-emptive correction of AV access stenosis on the risk of major patient-centred endpoints.
- To evaluate whether pre-emptive correction of an AV access stenosis improves clinically relevant outcomes:
- Vascular access outcomes: suitability for haemodialysis, risk of thrombosis, and overall patency rates and access survival (access loss)
- Patient-centred outcomes: hospitalisation rates, need for diagnostic or intervention procedures to maintain access patency; all-cause mortality, cause-specific mortality (cardiovascular or infection-related), fatal and non-fatal cardiovascular events (myocardial infarction or stroke); and surrogate outcomes (measures of heart function and structure, of access flow, and of haemodialysis adequacy)
- To evaluate whether the effects of pre-emptive correction of an AV access stenosis differ by access type (fistula versus graft); and
- To evaluate whether other factors (dialysis vintage, access location, configuration or materials, algorithm for referral for intervention, intervention strategies (surgical versus radiological or other), or study design explain the heterogeneity that might exist in effect estimates.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) and quasi-RCTs (trials in which allocation to treatment was obtained by predictable methods such as alternation, use of alternate medical records, or date of birth) evaluating the benefits and harms of a pre-emptive strategy to correct AV access stenosis in adults treated with haemodialysis or planned to start haemodialysis for end-stage kidney failure (ESKD) and have an AV fistula or graft will be eligible. Studies of any follow-up duration will be included.
Types of participants
We will include trials that enrolled patients who had an AV access (either a fistula or a graft) for haemodialysis because they were planned to start haemodialysis for ESKD or were receiving any form of haemodialysis, haemofiltration, or haemodiafiltration as a renal replacement therapy (RRT) for ESKD using an AV access (either a fistula or a graft) irrespective of their dialysis vintage. Both studies of pre-emptive stenosis correction in a mature access and in a non-maturing access will be included.
We will exclude studies of patients who were receiving RRT in acute kidney injury settings or who used a central venous catheter for haemodialysis instead of an AV access.
Types of interventions
We will consider any study with pre-emptive correction of a documented or suspected stenotic lesion of an AV fistula or graft in patients with ESKD. All pre-emptive strategies will be considered including surgery (open or endovascular surgery) or imaging assisted (radiological or ultrasound) procedures (angioplasty), without or with stenting. Any diagnostic criteria for eligibility for correction will be considered, including monitoring method, surveillance technique and imaging tests, critical value for a documented stenosis or a lesion clinically suspected.
Controls will include active comparators (e.g. a different diagnostic strategy with or without pre-emptive correction) or inactive comparator (no strategy). In addition, for the comparator we will consider any diagnostic criteria for eligibility for correction, including monitoring method, surveillance technique and imaging tests, critical value for a documented stenosis or a lesion clinically suspected.
Types of outcome measures
Primary outcomes will be the achievement of access suitability for cannulation and access survival.
- The ability to successfully use the AV access with two needles and without catheters. As there are different ways to define suitability (the most popular being use for at least two thirds of the haemodialysis runs after a maturation period of one to two months with a minimum blood flow of 300 mL/min using two needles) (Lok 2006), we will consider the definition chosen by the triallists. Outcome description will be tabulated considering the following items:
- Cannulation yes/no (the most liberal)
- Two needle cannulation yes/no
- Cannulation with some blood-flow cut off
- Some combination of the above for a period of a certain length
- Some measure of consistency (e.g. two out of three, four out of six)
- Reliable use for sufficient duration to allow catheter removal (the most objective but also the most conservative)
- Use of catheters as a measure of access reliability.
Access survival or time to remediable access failure (thrombosis)
- Defined as the need for the first procedure on the access to prolong survival, or access abandonment without vascular access procedures, or as defined by the triallists (primary survival); and time to irremediable access failure (thrombosis) defined as abandonment of the access despite prior procedures performed to prolong access survival (secondary survival), or as defined by the triallists.
Secondary outcomes related to access:
- Need for access evaluation defined as a formal assessment to determine if diagnostic imaging study and intervention are required to achieve maturation, maintain function, or correct dysfunction of an AV access, or as defined by the triallists.
- Surgical interventions on the AV access defined as a vascular access procedure to achieve maturation, maintain function, or correct dysfunction of an AV access, or as defined by the triallists.
- Diagnostic or interventional radiological procedures on the access defined as a fistulogram or angioplasty of an AV access, or as defined by the triallists.
- Any access complications (including infection, aneurysm, high flow and steal syndrome), which may include bacteraemia, sepsis, endocarditis, endovascular infection, osteomyelitis, discitis, skin/soft tissue infection, access-infection or infection as defined by the triallists.
Secondary outcomes related to patients:
- All-cause mortality.
- Cause specific mortality (from infection or cardiovascular disease as evaluated by the triallists).
- Non-fatal cardiovascular events:
- Myocardial infarction or acute coronary syndrome as defined by the triallists
- Cerebrovascular accident of transient Ischaemic attack as defined by the triallists
- Exacerbation of heart failure as defined by the triallists
- Ventricular arrhythmia or sudden death or cardiac conduction disorder as defined by the triallists.
- All-cause hospitalisation and hospitalisation for any specific cause defined as admission to a hospital for any reason or as defined by the triallists.
- Quality of life measured with the SF-36 scale or any kidney disease specific quality of life tool or any other measure provided by the triallists.
- Measurements of heart function and structure used to predict patient outcomes including left ventricular (LV) hypertrophy, LV mass index, LV systolic ejection fraction, and LV end diastolic dimension determined using any technique or threshold as defined by the triallists.
- Measurements of access function including access blood flow, dynamic or static venous pressure monitoring using the techniques and thresholds to determine dysfunction as defined by the triallists.
- Adequate dialysis dose delivery defined as a urea reduction ratio > 70%, single-pool Kt/V ≥ 1.2, or any other measure of dialysis adequacy as defined by the triallists.
Search methods for identification of studies
We will search the Cochrane Renal Group's Specialised Register through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from:
- Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
- Weekly searches of MEDLINE OVID SP
- Handsearching of renal-related journals and the proceedings of major nephrology conferences
- Searching of the current year of EMBASE OVID SP
- Weekly current awareness alerts for selected nephrology journals
- Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
- Reference lists of clinical practice guidelines, review articles and relevant studies.
- Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. Titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however studies and reviews that might include relevant data or information on trials will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.
Data extraction and management
Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non-English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.
Assessment of risk of bias in included studies
- Was there adequate sequence generation (selection bias)?
- Was allocation adequately concealed (selection bias)?
- Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
- Participants and personnel
- Outcome assessors
- Were incomplete outcome data adequately addressed (attrition bias)?
- Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
- Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For dichotomous outcomes (suitability for cannulation, access thrombosis, diagnostic, radiological and surgical procedures, all-cause mortality, cause-specific mortality, adverse patient events, fatal and non-fatal cardiovascular events, hospitalisation) results will be expressed as risk ratios (RR) with 95% confidence intervals (CI).
Where continuous scales of measurement are used to assess the effects of treatment (quality of life scores, measurements of heart function and structure, measurements of access function, and measurements of adequacy of dialysis dose), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.
Unit of analysis issues
Studies with non-standard designs, such as cross-over studies, cluster-RCTs, repeated accesses within subjects, and studies with multiple intervention groups, will be analysed as described in Chapter 16 of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Dealing with missing data
We will contact authors for any missing data. Strategies for dealing with missing data will be followed according to Chapter 16 (Section 16.1) and intention-to-treat issues in Chapter 16 (Section 16.2) (Higgins 2011).
Assessment of heterogeneity
Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with P value of 0.05 used for statistical significance, and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium, and high levels of heterogeneity.
Assessment of reporting biases
If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).
Data will be pooled using the random-effects model but the fixed-effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
Heterogeneity among participants could be related to study population characteristics such as publication year, gender, diabetes, presence of cardiovascular disease, age, time on dialysis, haemodialysis technique (including haemofiltration and haemodiafiltration). Heterogeneity due to interventions (strategies for pre-emptive stenosis diagnosis and correction) could be related to the anatomical location, material, AV access configuration, or diagnostic criteria or type of intervention (angioplasty or surgery). Heterogeneity could also be related to study risk of bias. Subgroup analyses will be conducted for these features if heterogeneity is detected. We will conduct separate analyses for fistulas and grafts and combine these where no evidence of subgroup differences exist.
Heterogeneity will be explored due to the following features used in meta-regression:
- Characteristics of the study population
- Baseline age
- Comorbidities (diabetes and cardiovascular disease)
- Use of antiplatelet agents
- Duration of dialysis
- Previous access history (number of access or access interventions)
- Current use of catheters
- Characteristics of the vascular access type and definition of intervention
- Material (autologous vein; allogeneic vein; animal vein; or synthetic - including polytetrafluoroethylene, Dacron, modified Dacron, or other)
- Configuration (loop or straight)
- Anatomical location (forearm, upper arm, femoral and the arterial and venous vessels as for graft)
- Type of anastomosis (end-side or side-side)
- Transposition of vein (present or absent)
- Diagnostic method: monitoring, surveillance strategy (Duplex US, US dilution, dynamic or static, venous pressure)
- Surgical versus angioplasty
- Potential biases of the study
- Allocation concealment.
We acknowledge the importance of other factors, but will not include them in the pre-specified analyses to avoid inflation of the type I error rate (Higgins 2003): haemodialysis dialysis modality, number and duration of dialysis sessions per week, anatomical location of the access, size of anastomoses, artery and vein, duration from creation to cannulation, training of surgeon, vessel mapping prior to creation and size of the vessels, randomisation method, intention-to-treat, proportion lost to follow-up, blinding of study assessors, and single centre versus multicentre.
We will perform sensitivity analyses to explore the influence of the following factors on effect size:
- repeating the analysis excluding unpublished studies
- repeating the analysis taking account of risk of bias
- repeating the analysis excluding any very long or large studies to establish how much they dominate the results
- repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.
The authors would like to acknowledge the referees for their comments and the editorial team of the Cochrane Renal Group for their assistance.
Appendix 1. Electronic search strategies
Appendix 2. Risk of bias assessment tool
Contributions of authors
- Draft the protocol: PR
- Study selection: PR, MJ
- Extract data from studies: PR, MJ
- Enter data into RevMan: PR
- Carry out the analysis: PR
- Interpret the analysis: PR, MJ, SP, JM, MO, RQ, GS
- Draft the final review: PR
- Disagreement resolution: GS
- Update the review: PR
Declarations of interest
Sources of support
- University of Calgary, Canada.Division of Nephrology
- No sources of support supplied