Intermittent pneumatic compression for critical limb ischaemia
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of intermittent pneumatic compression for treatment of individuals with critical limb ischaemia.
Background
Description of the condition
Peripheral arterial disease (PAD) is a common disease that affects the blood supply of the limbs. It affects 3% to 10% of the population. It is more common among elderly patients and affects 15% to 20% of people over the age of 70 years (Dua 2016). PAD is caused by progressive narrowing and occlusion of the arteries due to atherosclerosis. Atherosclerosis is a progressive and chronic process whereby fat accumulates in the inner layer of blood vessel walls. This process leads to hardening of the vessel wall and eventually a significant reduction in the flow of blood to target tissues (Peach 2012).
Despite the relatively high prevalence of PAD, most patients are asymptomatic and have no major walking disability (McDermott 2001). However, as the disease burden increases, patients can present with intermittent claudication (IC), which is a cramp‐like pain in a specific muscle group that is brought on by exertion (i.e. walking or exercise) and is rapidly relieved by rest. This can lead to reduced mobility, which has a direct effect on patients' quality of life (Peach 2012).
In 5% to 10% of patients, asymptomatic PAD or IC will progress to the severe presentation of critical limb ischaemia (CLI) over a five‐year period. CLI, also referred to as chronic limb‐threatening ischaemia (CLTI), is defined as rest pain for longer than two weeks or tissue loss attributed to arterial occlusion (Slovut 2008). The prevalence of CLI has been reported as 1% in the adult population (Norgren 2007). CLI occurs when significant arterial insufficiency impairs the nutritive requirements of tissues at rest, leading to limb loss if not urgently investigated and treated (Slovut 2008).
Critical limb ischaemia has a major impact on patients' quality of life. Rest pain affects patients' sleep rhythm and daily activities (Sprengers 2010). Furthermore, these patients are at high risk of limb loss. A recent insurance registry of 41,882 patients with PAD revealed four‐year amputation rates between 35% and 67% among those with CLI and tissue loss (Reinecke 2015).
Description of the intervention
Interventions for treating CLI aim to improve circulation within the limb by means of an operation, which could take the form of a bypass or a minimally invasive balloon procedure, when patients are suitable for these procedures. The standard treatment for CLI is revascularisation by bypass surgery or angioplasty and stenting (Norgren 2007). However, revascularisation is not always a valid option, as the absence of a suitable vessel runoff makes reconstruction of blood flow impossible. Furthermore, some patients have extensive comorbidities that preclude their undergoing a revascularisation procedure (Adam 2005). These patients are usually left with no option other than medical therapy alone, or amputation when medical therapy fails. The bleak outcome of patients with CLI who are not suitable for revascularisation has led to the emergence of alternative therapies that can be used in conjunction with medical therapy.
Intermittent pneumatic compression
Intermittent pneumatic compression (IPC) is an alternative treatment for patients with CLI in the absence of reconstructable anatomy. IPC involves sequential inflation and deflation of pneumatic pressure cuffs placed on the patient's limb. An automatic air source is connected to the cuff to allow intermittent inflation of the cuffs to pressures close to systolic pressure, followed by rapid deflation (van Bemmelen 1994).
Intermittent pneumatic compression is used in combination with medical therapy, which aims to reduce cardiovascular risk on a systemic basis. Medical therapy can include any of the following: antiplatelet therapy, lipid‐lowering therapy, antithrombotic therapy, antihypertensive therapy, or smoking cessation therapy, as detailed in the reporting standards of the Society for Vascular Surgery (SVS) for endovascular treatment of chronic lower extremity PAD (Stoner 2016).
How the intervention might work
Intermittent pneumatic compression works through three interconnected mechanisms (Labropoulos 2005).
Increasing the arteriovenous pressure gradient
The veno‐arteriolar reflex (VAR) is related to precapillary sphincter stricture and causes an increase in venous pressure. Application of the cuffs to the calves and feet empties the venous system and reduces venous pressure. This promotes perfusion of the limbs by increasing blood flow through the capillary bed (Delis 2005).
Reversing vasomotor paralysis
Repeated compression of the sympathetic nerve receptors is an important effect of IPC, as it can influence peripheral blood flow by controlling precapillary sphincter tension (Henriksen 1974).
Enhancing the release of nitric oxide
IPC mediates release of nitric oxide (NO) from the endothelial cells. This increases the shear stress of blood in the affected vessel (Dai 2002). NO is a potent vasodilator as the primary endothelium‐derived relaxing factor (EDRF). Furthermore, it inhibits platelet activation and aggregation, thus playing an important role in preventing formation of thrombosis (Dai 2002).
These three mechanisms combine to improve perfusion in ischaemic limbs. In association with appropriate risk factor modification, this can provide a feasible method of treatment not only for patients with non‐reconstructable CLI, but also for those who are physiologically unfit for surgical intervention (Labropoulos 2005).
For patients with non‐reconstructable CLI, IPC therapy may be associated with improved amputation‐free survival, fewer minor amputations, and reduced rest pain in comparison with no use of IPC (Moran 2015; Zaki 2016).
Why it is important to do this review
CLI results in pain at rest and ischaemic leg ulcers/gangrene with substantial deterioration in quality of life (QoL) (Matsumoto 2016). Ischaemic leg pain limits activities and tends to isolate patients from social connections, with consequent stagnating effects on emotional and mental health (Sprengers 2010). Improving the QoL of patients with CLI has become as important as improving their clinical status in terms of setting a treatment goal (Norgren 2007).
Not all patients are suitable for revascularisation. As reported in the BASIL trial, 34% of patients were not offered any revascularisation, as they did not have reconstructable options, lacking proper runoff or suitable anatomy. Furthermore, 7% of the total number of patients were deemed unfit for any surgical option owing to their other comorbidities (Adam 2005).
No pharmacological therapy has proved effective as a single treatment modality (Hiatt 2001), and ultimately, amputation is often the only option left. Therefore, new therapies are urgently needed (Sprengers 2010). With the ageing population and the associated rise in prevalence of CLI, the social and economical burden continues to increase. Establishing high‐quality evidence to evaluate the use of IPC in CLI treatment is imperative. This Cochrane Review will investigate available evidence to establish the effectiveness of IPC for treatment of CLI.
Objectives
To assess the effects of intermittent pneumatic compression for treatment of individuals with critical limb ischaemia.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing the effects of intermittent pneumatic compression (IPC) for treatment of critical limb ischaemia (CLI).
Types of participants
We will include all participants with a diagnosis of CLI, including those with Fontaine classification stage III or IV ‐ as in Fontaine 1954 ‐ or Rutherford‐Baker category 4, 5, or 6 (Rutherford 1997). Diagnosis of CLI will be based on relevant diagnostic modalities (i.e. clinical examination, ankle‐brachial index (ABI), duplex ultrasonography, computed tomography angiography (CTA), and/or magnetic resonance angiography (MRA)). We will not exclude trials based on age or gender of participants nor on treatment settings. We will exclude patients with PAD who do not have CLI, such as patients with Fontaine classification stage I or II or Rutherford‐Baker category 0, 1, 2, or 3.
We will include patients if they received IPC for:
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non‐reconstructable CLI, defined as CLI with no peripheral run‐off vessels that could be treated through bypass or angioplasty approaches;
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reconstructable CLI and were physiologically unfit, that is, if deemed to be at high risk of mortality if they proceed with revascularisation owing to extensive comorbidities (Prause 1998); or
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reconstructable CLI for which IPC is used as an adjunct to revascularisation before or after surgery.
We will examine these groups in further detail by conducting subgroup analysis.
Types of interventions
We will include any comparison of IPC intervention versus medical therapy in which IPC is the differentiating factor between groups.
IPC involves sequential inflation and deflation of pneumatic pressure cuffs placed on the patient's lower limbs. Different therapy protocols are available in which IPC is applied for various lengths of time. Inflation/deflation frequency also differs according to the commercially available device. We will include any study that reports on use of IPC, regardless of the protocol implemented. IPC may be applied differently to patients' lower limbs. IPC may be used on the feet only (Pawlaczyk 2015), calves only, feet and calves (Labropoulos 2005), or feet, calves, and thighs (Dillon 1986). We will include any study reporting on any of these therapy modalities. IPC is usually administered in conjunction with medical therapy, which is administered to modulate risk factors and control comorbidities among patients with CLI.
We will include medical therapy as the comparator.
The definition of medical therapy is guided by the reporting standards of the SVS (Stoner 2016). Medical therapy can include any combination of antiplatelet therapy, antithrombotic therapy, lipid‐lowering therapy, antihypertensive therapy, smoking cessation therapy, or a lifestyle modification programme. Randomisation in the included studies should produce comparable groups at baseline, with similar medication regimens reported between comparator and intervention groups, thus making IPC the only differentiating factor between groups.
Types of outcome measures
Primary outcomes
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Major amputation: above‐ankle amputation of the affected limb
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Major adverse limb events (MALE): defined as any major amputation (transtibial or above) or any major vascular intervention (thrombectomy, thrombolysis, or major surgical procedure (new bypass graft, jump/interposition graft revision)) (Stoner 2016)
Secondary outcomes
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Amputation‐free survival: a composite endpoint used as a measure of the number of patients who are still alive without above‐ankle amputation of the index limb (Stoner 2016)
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Major adverse cardiovascular events (MACE): myocardial infarction, stroke, death (any cause) (Stoner 2016)
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Ulcer healing: complete healing of lower limb ulcers for patients with Fontaine IV (Stoner 2016)
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Death: any cause
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Health‐related quality of life (HRQoL): measured by validated Qol instruments (e.g. EuroQol Five Dimension (EQ5D), Short Form 36 (SF36))
For all outcomes, we will include the time points reported by individual studies. Clinically relevant time points will be three months and 12 months.
Search methods for identification of studies
Electronic searches
The Cochrane Vascular Information Specialist (CIS) will search the following databases for relevant trials.
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Cochrane Vascular Specialised Register.
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Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online.
The Cochrane Vascular Specialised Register is maintained by the CIS and is constructed from weekly electronic searches of MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Allied and Complementary Medicine Database (AMED), and through handsearching of relevant journals. The full list of databases, journals, and conference proceedings that have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Vascular Module in the Cochrane Library (www.cochranelibrary.com).
The CIS will search the following trial registries for details of ongoing and unpublished studies.
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ClinicalTrials.gov (www.clinicaltrials.gov).
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World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch).
Searching other resources
We will search the reference lists of all included studies.
Data collection and analysis
Selection of studies
Two review authors (RE and WT) will independently screen all titles and abstracts identified via searches to identify those that might meet the review inclusion criteria. We will retrieve the full text of studies identified as potentially relevant by at least one review author. The same review authors will independently screen full‐text articles for inclusion or exclusion. We will resolve disagreements by discussion, or, if necessary, we will consult a third review author (NH). We will list as excluded studies all studies excluded at the full‐text review stage, and we will present reasons for their exclusion in the 'Characteristics of excluded studies' table. We will depict the screening and selection process in an adapted PRISMA flowchart (Liberati 2009).
Data extraction and management
Two review authors (RE and WT) will independently extract data from eligible studies using an adapted data extraction form provided by Cochrane Vascular. We will resolve disagreements by discussion, or, if necessary, we will consult with a third review author (NH). One review author (RE) will enter all extracted data into RevMan ‐ Review Manager 5.3 software (RevMan 2014), and a second review author (NH) will check entered data for accuracy and consistency against the data extraction sheets.
We will aim to describe studies according to the following.
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Trial design.
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Diagnosis of CLI.
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Demographic characteristics of participants.
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Types of interventions and comparators.
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Outcomes reported.
Assessment of risk of bias in included studies
Two review authors (RE and WT) will independently assess the risk of bias of all included studies. We will assess the following domains as having low, high, or unclear risk of bias.
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Selection bias (random sequence generation and allocation concealment).
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Performance bias (blinding of participants and personnel).
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Detection bias (blinding of outcome assessors).
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Attrition bias (incomplete outcome data).
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Reporting bias (selective outcome reporting).
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Other sources of bias.
We will resolve disagreements by discussion, or, if necessary, we will consult with a third review author (NH).
Owing to the nature of the type of intervention, blinding of participants and personnel (i.e. patients, clinicians, and outcome assessors) will not be possible; therefore we will deem these domains to be at high risk of bias.
Measures of treatment effect
Dichotomous data
We will express results for dichotomous outcome measures using risk ratio (RRs) and associated 95% confidence intervals (CIs) to reflect uncertainty of the point estimate of effects.
Continuous data
For continuous outcome measures, we will calculate mean and standard deviation (SD) with corresponding 95% CI. We will use standardised mean differences (SMDs) with 95% CIs to combine outcomes from trials that measure outcomes using different scales (Higgins 2011).
Time‐to‐event data
We will use survival analysis to report time‐to‐event data and will express the intervention effect as a hazard ratio (HR) with associated 95% CI. Methods used to analyse time‐to event data will be guided by those described by Parmar 1998 and Tierney 2007.
Unit of analysis issues
For primary endpoints the unit of analysis will be each limb, and for secondary endpoints the unit will be the participant.
Dealing with missing data
We will record missing and unclear data for each included study. If possible, we will perform all analyses using an intention‐to‐treat approach, that is, we will analyse all participants and their outcomes within the groups to which they were allocated, regardless of whether they received the intervention. If necessary, we will contact study authors to request missing data.
Assessment of heterogeneity
We will assess the degree of heterogeneity by visually inspecting forest plots and by examining the Chi² test for heterogeneity. We will assess heterogeneity of the overall results for main outcomes by using Chi², I², and Tau² statistics, according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), which states that 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity, and 75% to 100% may show considerable heterogeneity.
We will regard statistical heterogeneity as substantial if I² is greater than 50% and either T² is greater than zero or the P value is low (less than 0.10) in the Chi² test for heterogeneity.
If we identify substantial clinical, methodological, or statistical heterogeneity across included trials, we will not perform meta‐analysis of data, and we will report results narratively.
Assessment of reporting biases
We will investigate publication bias by using funnel plots if 10 or more studies are included in the review, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Data synthesis
We will carry out statistical analysis by using Review Manager 5.3 software (RevMan 2014). We will use a fixed‐effect model to synthesise data when it is reasonable to assume that trials are estimating the same underlying treatment effect. If clinical heterogeneity is sufficient to expect that underlying treatment effects differ between trials, or if we detect substantial statistical heterogeneity, we will use a random‐effects model to produce an overall summary, when the average treatment effect is clinically meaningful.
Subgroup analysis and investigation of heterogeneity
We will investigate the following subgroups if sufficient data are available.
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Diabetic versus non‐diabetic patients.
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Patients with tissue loss (Rutherford category 5 or 6) versus patients with no tissue loss (Rutherford category 4).
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Effect differences at time points for each outcome.
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Patients with non‐reconstructable CLI, physiologically unfit patients with reconstructable CLI, and patients with reconstructable CLI for whom IPC is used as an adjunct to revascularisation before or after surgery.
Sensitivity analysis
We will repeat the analyses while including high‐quality trials only. For the purposes of this review, we will classify as high‐quality trials those judged as having 'low risk of bias' for sequence generation and allocation concealment. We will also repeat the analyses while including RCTs only.
'Summary of findings' table
We will prepare a 'Summary of findings' table to present the findings for IPC versus medical therapy for patients with CLI. We will include the seven outcomes detailed under Types of outcome measures (see Table 1). We will grade the quality of evidence by using criteria devised by the Grades of Recommendation, Assessment, Developmental and Evaluation Working Group (Atkins 2004), and we will use GRADEprofiler (GRADEpro) software (Guyatt 2008; Higgins 2011; Schunemann 2006). We will assign one of four levels of quality ‐ high, moderate, low, or very low ‐ based on overall risk of bias of the included studies, directness of the evidence, inconsistency of results, precision of the estimates, and risk of publication bias.
| Intermittent pneumatic compression (IPC) compared with medical therapy alone for critical limb ischaemia (CLI) at 12 months | ||||||
| Patient or population: patients with CLI Settings: hospital Intervention: IPCa Comparison: medical therapyb | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Medical therapy | IPC | |||||
| Amputation 12 months | ||||||
| Major adverse limb events (MALE) 12 months | ||||||
| Amputation‐free survival 12 months | ||||||
| Major adverse cardiovascular events (MACE) 12 months | ||||||
| Ulcer healing 12 months | ||||||
| Death 12 months | ||||||
| Health‐related quality of life 12 months | ||||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval (CI)) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CLI: critical limb ischaemia; IPC: Intermittent pneumatic compression; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence. | ||||||
aIPC involves sequential inflation and deflation of pneumatic pressure cuffs placed on the patient's limb. An automatic air source is connected to the cuff to allow intermittent inflation of the cuffs to pressures close to systolic pressure, followed by rapid deflation.
bMedical therapy can include any of the following: antiplatelet therapy, lipid‐lowering therapy, antithrombotic therapy, antihypertensive therapy, or smoking cessation therapy.
| Intermittent pneumatic compression (IPC) compared with medical therapy alone for critical limb ischaemia (CLI) at 12 months | ||||||
| Patient or population: patients with CLI Settings: hospital Intervention: IPCa Comparison: medical therapyb | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Medical therapy | IPC | |||||
| Amputation 12 months | ||||||
| Major adverse limb events (MALE) 12 months | ||||||
| Amputation‐free survival 12 months | ||||||
| Major adverse cardiovascular events (MACE) 12 months | ||||||
| Ulcer healing 12 months | ||||||
| Death 12 months | ||||||
| Health‐related quality of life 12 months | ||||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval (CI)) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CLI: critical limb ischaemia; IPC: Intermittent pneumatic compression; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence. | ||||||
| aIPC involves sequential inflation and deflation of pneumatic pressure cuffs placed on the patient's limb. An automatic air source is connected to the cuff to allow intermittent inflation of the cuffs to pressures close to systolic pressure, followed by rapid deflation. bMedical therapy can include any of the following: antiplatelet therapy, lipid‐lowering therapy, antithrombotic therapy, antihypertensive therapy, or smoking cessation therapy. | ||||||
