Description of the condition
Lower extremity peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and is considered as a major cause of morbidity in the elderly population (Vogt 1992). Intermittent claudication (IC), the most frequent symptomatic presentation of PAD, is defined as discomfort in the legs with exertion that resolves after a short period of rest. Intermittent claudication is highly prevalent in Western countries, affecting an estimated 4.5% of the general population aged 40 years and older (Norgren 2007), and is likely to become more prevalent given the ageing population. Although individuals with IC have a relatively benign prognosis for their affected limb, with a major amputation risk of only 1% to 3% over a five-year period (Norgren 2007), their functional performance deteriorates significantly and this results in a sedentary lifestyle (Sieminski 1997) and severely limited quality of life (QoL) (Khaira 1996; Spronk 2007). Additionally, IC is associated with a significantly increased risk of all cause and cardiovascular mortality independent of other atherosclerotic risk factors (Smith 1990; Golomb 2006).
Description of the intervention
The treatment of IC should be made up of multiple components, focusing on the prevention of future cardiovascular events and related mortality as well as on ameliorating claudication symptoms. Pharmacotherapy and exercise therapy are established as effective first line conservative treatment options, improving walking distance and QoL in patients with IC (Hiatt 2001; Watson 2008; Fakhry 2012). However, in clinical practice endovascular revascularisation (EVR) is being considered as an attractive first line alternative due to its immediate effect and relatively low complication rates. EVR of the lower extremities was first performed and reported on by Dotter and Judkins in 1964 (Dotter 1964). Since then, important technological developments including the introduction of balloon angioplasty and (drug-eluting) balloon and stents have advanced EVR as a safe and durable treatment option in the the management of symptomatic PAD. EVR is performed under local anaesthesia and access to the stenosed or occluded peripheral artery is usually gained via the common femoral artery. Subsequently, an angioplasty procedure is performed which involves (balloon) dilatation of a stenosed peripheral artery or recanalisation of an occluded peripheral artery. This is followed by stent placement if suboptimal results are achieved with angioplasty only (Tetteroo 1998). After a successful EVR procedure, patients are usually ambulatory on the same day and they are able to resume all normal activities within a few days. Furthermore, procedure-related morbidity and mortality are lower than 0.5% (Stewart 2002) with haematoma at the puncture site and embolization being reported as the most common procedure-related complications (Matsi 1998).
How the intervention might work
After successful revascularisation, where the obstruction or occlusion in the peripheral artery is resolved and normal blood flow is restored, the arterial perfusion in the lower extremity improves significantly. This is confirmed by a significant improvement in the ankle brachial index (ABI) immediately after the procedure. Randomised controlled trials (RCTs) have demonstrated the effectiveness of EVR to improve functional performance (that is walking distance, ABI) and QoL in individuals with IC (Bosch 1999; Spronk 2009; Mazari 2012).
Why it is important to do this review
Intermittent claudication (IC) is a serious lifestyle limiting symptom of PAD, with great impact on patients' functional performance and QoL. Conservative treatment strategies, including pharmacotherapy and supervised exercise therapy, are recommended as first line therapy for IC (Norgren 2007; Rooke 2011). Yet their value in clinical practice remains uncertain as medical drugs for IC (for example cilostazol, pentoxifylline, naftidrofuryl) have limited effects (Berger 2012) and supervised exercise programs are under utilised in clinical practice due to limited access (Makris 2012), reimbursement issues and poor patient compliance (Fakhry 2012). Consequently, an enormous increase in the use of EVR as first line therapy for IC is being observed (Anderson 2004; Beckman 2007). Nonetheless, the (long-term) effectiveness of EVR as first line therapy for IC remains debatable. The only Cochrane review on this topic, including two trials with a total of 98 patients comparing angioplasty with non-surgical therapy, concluded that the limited data suggested a short-term benefit in favour of angioplasty (Fowkes 2000). Since the last update of this review, new randomised trials assessing the efficacy of EVR or comparing EVR versus conservative treatment strategies for IC have been published. Furthermore, the combination of exercise therapy and EVR, which might feature the immediate short-term effects of revascularisation and the long-term benefits of exercise therapy, has been investigated in new clinical studies (Greenhalgh 2008; Mazari 2012). However, clinical studies rarely have sufficient power to detect intervention effectiveness on clinical outcomes such as functional performance, QoL or cardiovascular events. Therefore, a Cochrane review identifying these studies systematically, evaluating their results independently, and updating the results when new trials are published is important to reduce the uncertainty on the (added) value of EVR in the management of patients with IC.
The main objective of this systematic review is to summarise the (added) effect of EVR on functional performance and QoL in the management of intermittent claudication.
Criteria for considering studies for this review
Types of studies
We will systematically search for and include only RCTs with parallel-group design in patients with IC comparing outcomes of EVR (with and without conservative therapy) versus conservative therapy (that is exercise, pharmacotherapy) or no therapy.
Only trials comparing EVR (± conservative therapy) with conservative therapies or no therapy will be included. We will exclude studies providing any kind of surgical revascularisation in the comparison group. We will also exclude trials comparing different types of EVR procedures (for example angioplasty versus angioplasty plus stenting).
Types of participants
We will include patients with stable IC, according to Rutherford category 1 to 3 or Fontaine stage II (Norgren 2007), who are eligible for both EVR and conservative management.
Types of interventions
In the intervention group, patients should receive EVR (± conservative therapy). All percutaneous EVR procedures will be considered and can include angioplasty (any type, for example balloon, laser) or angioplasty plus (selective) stent placement (any type of stent including drug-eluting) for atherosclerotic lesion(s) in the lower extremity arteries. In the comparison group, patients should receive only conservative therapy or no therapy. Conservative therapy may include pharmacotherapy for IC (for example cilostazol, pentoxifylline, naftidrofuryl), exercise therapy (supervised and non-supervised) or a combination of exercise and pharmacotherapy.
We will consider the following comparisons:
- EVR versus no therapy;
- EVR versus conservative therapy;
- EVR plus conservative therapy versus conservative therapy.
Where cardiovascular risk factor modification (for example lipid control, hypertension control, or anti-smoking advice) is provided in the intervention group, it should also be provided equally in the comparison group.
Types of outcome measures
- Functional performance:
- maximum walking distance (MWD), assessed on a treadmill;
- pain free walking distance (PFWD), assessed on a treadmill.
2. Secondary invasive interventions during follow up:
- endovascular or surgical revascularisation;
- Quality of life (QoL), including health-related (general and disease-specific) QoL measures and utility measures
- Procedure-related complications (e.g. local haematoma, embolization)
- Cardiovascular events (e.g. myocardial infarction, stroke)
- Functional performance measures not assessed on a treadmill (e.g. six-minute walk test)
Search methods for identification of studies
We will not apply any language restrictions.
The Cochrane Peripheral Vascular Diseases (PVD) Group Trials Search Co-ordinator (TSC) will search the PVD Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL), part of The Cochrane Library (www.the cochranelibrary.com). See Appendix 1 for details of the search strategy which will be used to search CENTRAL. The PVD 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 PVD Group module in The Cochrane Library (www.thecochranelibrary.com).
The following trial databases will be searched by the TSC for details of ongoing and unpublished studies:
- World Health Organization International Clinical Trials Registry platform (http://apps.who.int/trialsearch/);
- ClinicalTrials.gov (http://clinicaltrials.gov/);
- Current Controlled Trials (http://www.controlled-trials.com/);
- Nederlands Trials Register (http://www.trialregister.nl/trialreg/admin/rctsearch.asp)
Searching other resources
We will handsearch the reference lists of all eligible studies for additional studies.
Data collection and analysis
Selection of studies
Identified studies will initially be selected by two review authors (FF and HF) independently reviewing titles and abstracts. The final selection will be based on full text evaluation of the selected studies by the two review authors (FF and HF) working independently. Disagreements between the review authors will be discussed and resolved by consensus. If no consensus is reached, a third review author (MH) will act as arbiter.
Data extraction and management
Two review authors (FF and HF) will extract all the required data from each included study using a standardised form, which will consist of: 1) Study characteristics including study design, year of publication, study location and applied inclusion and exclusion criteria; 2) patient baseline characteristics including number of patients in each group, mean age and gender distribution; 3) intervention characteristics and losses to follow up; 4) primary and secondary outcomes, as specified in Types of outcome measures.
Assessment of risk of bias in included studies
Two review authors (FF and HF) will independently assess the methodological quality of the included studies, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), for the following domains:
- randomisation, sequence generation;
- allocation concealment;
- blinding (of participants, personnel and outcome assessors);
- incomplete outcome data;
- selective outcome reporting;
- publication and other sources of bias.
For each of the six domains, the risk of bias will be assessed as 'low risk', 'high risk' or as 'unclear risk of bias' where there is insufficient information available to permit judgement on risk of bias.
Measures of treatment effect
To analyse the treatment effect of EVR in each study for the continuous outcome measures, including the primary outcomes MWD, PFWD and the secondary outcome QoL, we will extract the post-intervention value of each outcome measure for both the intervention and comparison groups. Subsequently we will calculate and report the mean difference (MD) between the two treatment groups as treatment effect for each study. If studies used different treadmill protocols with great variation in the intensity of the protocol to assess MWD and PFWD we will convert the walking distances to metabolic equivalents (METS) by simulating the reported data and using the American College of Sports Medicine (ACSM 2006) metabolic walking equation to calculate the associated METS.
For the dichotomous outcome measures, including secondary intervention, procedure-related complications, cardiovascular events or death during follow up in each treatment group, we will use hazard rate ratios (HRs), if reported, or we will compute risk ratios (RRs) as measures of treatment effect.
Unit of analysis issues
In this systematic review only RCTs with parallel-group design will be included. The unit of randomisation is the individual participant.
Dealing with missing data
In the case of missing data on dropouts, withdrawals and outcome measures, we will try to contact the original investigators and request the data where appropriate. Missing data indicating the variance of the outcome measures (for example standard deviations (SD), confidence intervals (CI)) are to be expected, in which case we will use the methods as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to calculate or impute these data.
Assessment of heterogeneity
We will assess statistical heterogeneity of the outcome measures by calculating the Q statistics and the I² statistic as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of reporting biases
If enough studies are included, we will plot a funnel plot for each outcome measure with effect size on the x-axis and precision on the y-axis to investigate possible publication bias.
We will calculate treatment effects with the corresponding 95% confidence intervals (CIs) for both the continuous and dichotomous outcome measures using either fixed-effect or random-effects models depending on the heterogeneity of the data. Subsequently, where appropriate, we will calculate the pooled treatment effect size in a random-effects model meta-analysis and present a forest plot for each outcome measure separately. Two-sided P ≤ 0.05 will be considered statistically significant and all data analysis will be performed using RevMan 5.2, where appropriate.
Subgroup analysis and investigation of heterogeneity
We will perform the following subgroup analyses, providing enough studies for each subgroup are identified:
- types of conservative therapy (i.e. exercise or pharmacotherapy);
- types of EVR procedures (e.g. angioplasty, angioplasty plus stenting);
- types of pharmacotherapy (e.g. cilostazol, pentoxifylline, naftidrofuryl);
- types of exercise therapy (i.e. supervised or non-supervised programme);
- separate segments (i.e. aortoiliac, femoropopliteal, infrainguinal or mixed).
The pooled treatment effect for all subgroups will be presented as a subgroup meta-analysis in a single forest plot for each outcome measure separately.
If enough studies are included for each analysis, we will evaluate the individual study effect on the results by excluding each study separately from the analysis to examine whether exclusion of an individual study will significantly change the results. In addition, we will perform sensitivity analyses by removing studies with high risk of (methodological) bias to observe whether excluding studies with high risk of bias will significantly change the results.
Appendix 1. CENTRAL search strategy
Contributions of authors
FF: wrote the protocol; will select relevant studies, assess methodological quality of included studies, extract and analyse the data, write the review.
HF: contributed to the protocol; will select relevant studies, assess methodological quality of studies, extract data, contribute to the text of the review.
ER: contributed to the protocol and will contribute to the text of the review.
JT: contributed to the protocol and will contribute to the text of the review.
SS: contributed to the protocol and will contribute to the text of the review.
MH: contributed to the protocol; will resolve any disagreements regarding inclusion of studies and will contribute to the text of the review.
Declarations of interest
MH's institution has received funding from ZonMW, Netherlands Organization for Scientific Research, National Institutes of Health, and Stichting Technische Wetenschappen for MH's research projects not related to this review. MH also reports receiving royalties from Cambridge University Press from the textbook 'Decision Making in Health and Medicine' and travel/meeting expenses from the 2010 and 2011 Clinical Update on Cardiac CT and MRI 2010 meetings, the 2011 International Society for Strategic Studies in Radiology (ISSSR) meeting and the 2012 ESR Referral Guidelines for Imaging workshop.
Sources of support
- No sources of support supplied
- Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.The PVD Group editorial base is supported by the Chief Scientist Office.
- National Institute for Health Research (NIHR), UK.The PVD Group editorial base is supported by a programme grant from the NIHR.