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Anabolic steroids for treating pressure ulcers

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine the effects of anabolic steroids on the healing of pressure ulcers of any grade, in any care setting; to establish whether anabolic steroids are an effective treatment; whether there is an optimal anabolic steroid, treatment duration and dosage; and which anabolic steroid has fewest side effects.

Background

Description of the condition

Globally, pressure ulcers (also known as bed sores, pressure sores or decubitus ulcers) are a common medical problem amongst people confined to a bed or a wheelchair for long periods of time. A pressure ulcer is commonly defined as "a localized injury to the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure or in combination with shear" (EPUAP & NPUAP 2009). Pressure ulcers are a complication associated with acute illness, injuries and immobility (Kaltenthaler 2001). They develop rapidly and are dependent upon the amount of time soft tissue is compressed against underlying bone, as well as the amount of pressure exerted on the patient's skin (Versluysen 1986). Both of these factors eventually result in ischaemia (lack of blood flow to an area) and necrosis (tissue death). It has been estimated that, at any point in time, pressure ulcers affect between 4.7% and 32.1% of hospital patients and between 4.6% and 20.7% of people in nursing homes (Kaltenthaler 2001).

Although it is difficult to determine the true incidence of pressure ulcers, an empirical study has estimated that annually in the UK alone, around 412,000 people are likely to develop a new pressure ulcer. This equates to one in every 150 of the general population, and one in 23 of the population over 65 years of age (Bennett 2004), being at risk of developing pressure ulcers. In a prospective cohort study with 658 participants carried out in the USA, approximately one‐third of hip‐fracture patients (36.1%, standard error (SE) 2.5%) experienced one or more new pressure ulcers in the course of 32 days following hospitalisation (Baumgarten 2009).

The classification of pressure ulcers agreed by the international National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel (NPUAP‐EPUAP) consists of four stages (EPUAP & NPUAP 2009): stage I ‐ non‐blanchable redness of intact skin; stage II ‐ partial thickness skin loss or blister; stage III ‐ full thickness skin loss, fat visible; and stage IV ‐ full thickness tissue loss, with muscle/bone visible (See Appendix 1 for details).

A cost analysis study in the UK documented that treatment costs depend upon the time taken to heal and the incidence of complications. It estimated that costs per ulcer healed ranged from GBP 1064 (grade 1, comparable to stage I) to GBP 10,551 (grade 4, comparable to stage IV) (Bennett 2004). Treating pressure ulcers represents a very significant resource cost to the health and social care system in the UK and elsewhere (Bennett 2004). For instance, from 1999 to 2000 the cost of pressure ulcer care was estimated to be in the range of GBP 1.4 billion to GBP 2.1 billion, which was roughly equal to the total National Health Service expenditure on mental illness or community health services. The majority of these costs were attributable to nursing time; any reduction in the nursing time required to manage pressure ulcers could provide a reduction in overall cost of treatment. Unless properly managed at an early stage, the long‐term costs of managing pressure ulcers and related complications are extremely high. In order to reduce morbidity and mortality from pressure ulcers, early detection and treatment to halt progression to stage IV ulcers are required (Brem 2010).

In addition to costs, pressure ulcers, regardless of underlying causes, can impair the quality of life of the affected individuals, and the burden extends to their family, society and nation as a whole. Patients' suffering is an intangible cost, which is not possible to measure in monetary terms, regardless of countries of origin or settings of care. Additionally, it is noted that people with pressure ulcers are usually at risk of developing additional pressure ulcers (EPUAP & NPUAP 2009). The impact on the cost of patient management of the transition from having no pressure ulcers to having the first pressure ulcer is greater than the impact of any increase in the number of pressure ulcers beyond the first. This is because a first pressure ulcer triggers the need for treatment interventions, as well as the prevention of consequent pressure ulcers (Baumgarten 2009). In brief, the impact of pressure ulcers on functional recovery, quality of life, and cost of care is challenging.

Description of the intervention

The treatment of pressure ulcers involves a variety of regimens and anabolic steroids have become an option for an adjuvant therapy (that supplements 'usual' treatment). Anabolic steroids are synthetic derivatives of the hormone testosterone that have anabolic ('building up') and androgenic (male) properties. The USA lists many derivatives of anabolic steroids in the Designer Anabolic Steroid Control Act of 2012 (The United States Congress 2012); however, only a few are in therapeutic use, and these include nandrolone, oxandrolone, and oxymetholone, which are synthetic derivatives of testosterone. Androgenic effects are linked to male sex characteristics. Anabolic effects enhance the effectiveness of protein synthesis in tissues ‐ including skeletal muscle ‐ for example, the anabolic effect of oxandrolone is used in patients with severe burns (Hart 2001). As there are no separate receptors for anabolic and androgenic effects, the anabolic effect cannot be entirely separated from the androgenic effect. In principle, some are more anabolic, for example, oxandrolone has six‐times the anabolic potency of methyltestosterone (Fox 1961).

Studies report that weight loss associated with protein depletion is directly related to poor wound healing and increased surgical risk (Windsor 1988; Bauman 2013). Clinically the anabolic effect on the growth of skeletal muscle (and bone) is potentially beneficial for restoration of muscle mass in patients. This is particularly useful in patients with cachexia (loss of weight and muscle wastage) attributable to chronic illness such as HIV/AIDS (Bhasin 2000), rheumatoid arthritis (Lemmey 2013), and in the elderly with wasting (Morley 2008). Anabolic androgenic steroids are widely abused in the sports world, and among high school students (FDA 2013), because of these muscle mass effects (Franke 1997).

How the intervention might work

Most, if not all, people with severe pressure ulcers suffer from weight loss and lean body mass resulting from a catabolic ('breaking down') state. Until these catabolic process are corrected, it is highly possible that wound healing will be delayed (Collins 2004). Anabolic steroids are sometimes used to correct these catabolic states. Studies on anabolic steroids have identified that their actions stimulate protein synthesis in cells, including cells with androgen receptors (Forbes 1989). Androgen receptors are present most prominently in skin fibroblasts (Demling 2000); skin fibroblast is one of the components of the regenerating process.

Although the exact mechanism is not fully understood, animal studies have shown that anabolic steroids (testosterone in this case) act on protein synthesis by regulating the availability of template RNA (Dixon 1964), this leads to increased protein synthesis, which is mostly seen in skeletal muscle (Demling 2000; White 2009; White 2013). Testosterone also has a documented ability to modulate the activity of components of the regeneration process, specifically, immune, fibroblast, and myogenic precursor cells (that precede muscle development) (White 2009). Furthermore, animal studies have demonstrated that testosterone and androsterone possess anti‐staphylococcal antimicrobial activity (Yotis 1968), which could prevent colonisation of the ulcerated area by bacteria.

One concern associated with oxandrolone administration is the effect of an increase in liver enzymes (Jeschke 2007). This effect causes many to question the use of anabolic steroids for the management of pressure ulcers in people with impaired liver function, for example, the elderly or people with chronic illness. A prospective study of 27,892 postmenopausal women showed evidence that hormone replacement therapy (oral oestradiol in combination with testosterone‐like progestin) may increase the risk of cholecystectomy (i.e. gallbladder removal ‐ often a result of impaired liver function) (Nordenvall 2014).

Why it is important to do this review

In the USA, Medicare do not reimburse treatments associated with hospital acquired pressure ulcers (Medicare Program 2007; Rosenthal 2007). One of the objectives of this decision was to provide incentives to hospitals to prevent occurrence of these ulcers (Rosenthal 2007). Therefore, it is important to implement effective treatment options for existing pressure ulcers in order to prevent development of further ulcers. Investigators have suggested that treatment of pressure ulcers with anabolic steroids might be effective for promoting lean body mass and appendicular skeletal muscle mass (combined lean body mass from all four limbs) (Sattler 2011), healing of a wound after a major operation (Jiang 1989), chronic and cutaneous and wounds (Demling 1998; Demling 2000, respectively), and for stage IV ulcers (Collins 2004).

There have been reports of the negative health effects of the use of anabolic steroids. Studies have highlighted that testosterone, as treatment, also produces a modest increase in prostate‐specific antigen levels, but does not cause changes in the signs or symptoms of prostate hyperplasia (enlargement) (Kenny 2011). A non‐Cochrane systematic review that included 27 randomised controlled trials (RCTs) and 2994 participants reported that testosterone administration to older men increased the risk of a cardiovascular‐related event by 54% (Xu 2013), while a recently published study of men who underwent coronary angiography reported that the use of testosterone therapy had the potential risk of adverse outcomes (Vigen 2013). The generalisability of these findings, however, to the population of people with pressure ulcers is not known. It is, therefore, important to undertake a comprehensive assessment of all the available high level data on the benefits and harms of anabolic steroids on the healing of pressure ulcers.

Objectives

To determine the effects of anabolic steroids on the healing of pressure ulcers of any grade, in any care setting; to establish whether anabolic steroids are an effective treatment; whether there is an optimal anabolic steroid, treatment duration and dosage; and which anabolic steroid has fewest side effects.

Methods

Criteria for considering studies for this review

Types of studies

We will only consider randomised controlled trials (RCTs) of anabolic steroids for healing pressure ulcers.

Types of participants

We will include trials with participants of any age described as having a pressure ulcer (bed sore, pressure sore or decubitus ulcer) of any grade in any healthcare setting.

We will exclude trials in which participants with a pressure ulcer are receiving systemic corticosteroids, immunosuppressive agents, anticancer agents, or any radiation therapy.

Types of interventions

Eligible interventions will include: an anabolic steroid compared with another anabolic steroid, non‐anabolic steroid therapy, placebo or alternative treatments (with or without usual pressure ulcer management). We will consider different regimens of the same anabolic steroid and different mode(s) of anabolic steroid administration.

The term 'anabolic steroid' will include testosterone and its esters, nandrolone (as the decanoate ester), mesterolone and oxymetholone, which are used clinically. Studies will only be eligible for inclusion if the use of an anabolic steroid (or an aspect of anabolic steroid use) is the only systematic difference between treatment arms. If people in different treatment arms within a trial experience other systematic differences in co‐interventions the study will be excluded.

Types of outcome measures

Primary outcomes

Wound healing measured by:

  • time to complete healing/rate of healing (as defined in the trial);

  • proportion of wounds completely healed in a specified time period (as defined in the trial);

  • all reported adverse events.

Healing is defined as "re‐epithelialization to a cicatrix [area of new connective tissue] with a dry surface and 0 cm square of open area for a minimum of 96 hours" (Bauman 2013).

Secondary outcomes

If data permit, we will assess the following secondary outcomes:

  • pain (as measured by a validated pain measurement scale);

  • length of hospital stay;

  • change in wound size or wound surface area;

  • change in pressure ulcer volume;

  • incidence of different type of infection(s);

  • cost;

  • quality of life (as measured by the trialists or measured by a validated scale).

Search methods for identification of studies

Electronic searches

We will search the following databases to identify relevant RCTs:

  • The Cochrane Wounds Group Specialised Register;

  • The Cochrane Central Register of Controlled Trials (CENTRAL) The Cochrane Library (latest issue);

  • Ovid MEDLINE (1946 to present);

  • Ovid MEDLINE (In‐Process & Other Non‐Indexed Citations) (to present);

  • Ovid EMBASE (1974 to present);

  • EBSCO CINAHL (1982 to present).

We will use the following search strategy in The Cochrane Central Register of Controlled Trials (CENTRAL) and will adapt it appropriately for other databases:

#1 MeSH descriptor [Pressure Ulcer] explode all trees
#2 (pressure NEXT (ulcer* or sore* or injur*)):ti,ab,kw
#3 decubitus NEXT (ulcer* or sore*)):ti,ab,kw
#4 (bedsore* or (bed next sore*)):ti,ab,kw
#5 {or #1‐#4}
#6 MeSH descriptor: [Anabolic Agents] explode all trees
#7 MeSH descriptor: [Testosterone] explode all trees
#8 MeSH descriptor: [Oxandrolone] explode all trees
#9 MeSH descriptor: [Nandrolone] explode all trees
#10 MeSH descriptor: [Mesterolone] explode all trees
#11 MeSH descriptor: [Oxymetholone] explode all trees
#12 (anabolic next (steroid* or agent*)):ti,ab,kw
#13 testosterone:ti,ab,kw
#14 oxandrolone:ti,ab,kw
#15 nandrolone:ti,ab,kw
#16 mesterolone:ti,ab,kw
#17 oxymetholone:ti,ab,kw
#18 {or #6‐#17}
#19 #5 AND # 18

We will adapt this strategy to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. We will combine the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐and precision‐maximising version (2008 revision) (Lefebvre 2011). We will combine the EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). We will combine the CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (SIGN 2011). We will not restrict studies with respect to language, date of publication or study setting.

We will search the following clinical trials registries:

Searching other resources

We will search the reference lists of relevant reviews and included studies to identify further relevant trials. We will handsearch conference proceedings from the European Pressure Ulcer Advisory Panel and European Wound Management Association for any relevant trials. We will also contact experts in this field and drug manufacturers to enquire about any unpublished or on‐going trials.

Data collection and analysis

Selection of studies

Two review authors (CN, MAW) will screen titles and abstracts identified according to the selection criteria set for this review and retrieve full‐text copies of all articles that might satisfy the inclusion criteria. The two review authors will check the full articles for eligibility. Any disagreement will be resolved by consensus, and by referral to a third review author, if needed.

Data extraction and management

We, the reviewers, will extract information from the included studies using a piloted data extraction sheet. We will contact the corresponding authors for any missing information. We will also contact the drug manufacturer(s) to obtain information to complement any on‐going or unpublished studies. Where studies have duplicate publications, we will extract the maximum amount of available data from the available publications. Disagreements will be resolved by discussion and with a third review author, if needed.

Independently, two review authors will extract the following data:

  • author;

  • country and publication year of study;

  • setting of study (e.g. primary care, hospital);

  • participants characteristics;

  • intervention and comparison;

  • co‐interventions (if present);

  • treatment regimen (drug, dosage, route of administration, frequency, duration);

  • outcomes and method of measurement;

  • risk of bias assessment (e.g. methods of randomisation, allocation concealment, blinding, follow‐up, dropouts);

  • duration of follow‐up;

  • adverse events;

  • pain data; quality of life data;

  • length of hospital stay;

  • cost of treatment (if provided).

Assessment of risk of bias in included studies

Independently, two review authors will assess each included study using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011a). The tool addresses six specific domains, namely: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other bias. One other bias specific to this review will be comparability of ulcer surface area between treatment groups at baseline (i.e. extreme baseline imbalance). Blinding (participants, trialists and outcome assessors) and completeness of outcome data will be assessed for each outcome separately, this is because assessment on wound healing can be subjective. We will complete a 'Risk of bias' table for each eligible study. We will discuss any disagreement amongst all review authors to achieve a consensus.

We will present assessment of risk of bias using a 'Risk of bias' summary figure, which presents all of the judgements in a cross‐tabulation of study by entry. This display of internal validity indicates the weight the reader may give to the results of each study.

We will classify each domain as being at high, low, or unclear risk of bias (See Appendix 2 for details).

Measures of treatment effect

We will report effect measures for dichotomous outcomes using the risk ratio (RR) and its 95% confidence intervals (CI). For continuous outcomes, we will report effect measures using the mean difference (MD) ‐ or standardised mean difference (SMD) if the scale of measurement differs across trials ‐ both with corresponding 95% CI.

For studies with time‐to‐event outcomes (e.g. time to healing), we will report hazard ratio (HR) and its 95% CI. If the studies identified for the present review do not report HR, we will compute these following the formulae of Parmar and co‐workers (Parmar 1998), implemented in a spreadsheet (Tierney 2007).

We will estimate 'overall effect' across all primary outcomes reported in the included trials.

Unit of analysis issues

We will record whether trials measured outcomes in relation to an ulcer, or a participant, or whether multiple ulcers on the same participant were randomised. We will also record occasions where multiple ulcers on a participant have been incorrectly treated as independent within a study without taking account of the interdependence of the ulcers. We will report this as a part of the 'Risk of bias' assessment. Unless, otherwise stated, where the number of ulcers appears to equal the number of participants, we will treat the ulcer as the unit of analysis.

Dealing with missing data

If individual trials provide data on the proportion of ulcers healed, without including all randomised participants in the analysis, we will assume that the dropouts' wound did not heal (i.e. they would be considered in the denominator, but not in numerator). We will only present complete case data if relevant (e.g. time to heal, other secondary outcomes etc.).

If there are missing standard deviations (SDs) for continuous outcomes, we will attempt to calculate these using case‐analysis. We will impute SDs from SEs, CIs, t values or P values (as appropriate) that relate to the differences between means in two groups following the guidance and recommendation described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

When there is not enough information available to calculate the SDs, we will impute SDs. If SDs are available from other included studies for the change from baseline for the same outcome measures, we will use these in place of the missing SDs. If this approach is not applicable, assuming correlation coefficients from the two intervention groups are similar (which is reasonable for an RCT), we will impute an SD of the change from baseline for the experimental intervention, following a formula as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

Assessment of heterogeneity

We will assess studies for clinical and statistical heterogeneity based on the participants, intervention, control, outcome and study design elements, and will tabulate this in the 'Characteristics of included studies' table. We will also assess statistical heterogeneity using the Chi2 test and the I2 test. The I2 test examines the percentage of total variation across studies due to (statistical) heterogeneity rather than to chance (Deeks 2011). Values of I2 over 50% indicate the presence of a higher level of heterogeneity. In the absence of clinical heterogeneity and in the presence of statistical heterogeneity (where I2 exceeds 50%), we will use a random‐effects model, however, we will not pool studies where heterogeneity is very high (I2 over 75%). When there is no clinical heterogeneity or low statistical heterogeneity (I2 less than 50%), we will use a fixed‐effect model.

Assessment of reporting biases

If there are a sufficient number of studies (minimum 10 RCTs), we will investigate publication bias by constructing a funnel plot. In the absence of publication bias, the plot should resemble a symmetrical inverted funnel. However, an asymmetrical funnel plot may also be due to other biases such as differences in methodological quality among studies. Even when there is a symmetrical funnel plot, it does not necessarily mean there is an absence of publication bias (Stern 2011).

Data synthesis

We will combine studies using a narrative overview of the studies with meta‐analyses of outcome data where appropriate (in Review Manager (RevMan) 5.2) (Review Manager 2012). The decision to include studies in a meta‐analysis depends on the availability of treatment effect data and assessment of heterogeneity. For time‐to‐event data, we will plot log rank observed minus excepted events estimates using a fixed‐effect model (a random‐effects model is not available for this analysis in RevMan 5.2). Where possible, and if relevant, we will conduct sensitivity analysis to investigate the potential impact of studies at high risk of bias on pooled studies.

Subgroup analysis and investigation of heterogeneity

When possible, we will perform subgroup analyses to explore the influence of risk of bias on effect size. We will assess the influence of removing from meta‐analyses studies classed as having high and unclear risk of bias. These analyses will include only studies that are assessed as having low risk of bias in all key domains, namely, adequate generation of the randomisation sequence, adequate allocation concealment and blinding of outcome assessor for the estimates of treatment effect.

'Summary of findings' tables

We will present the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We plan to present the following outcomes in the 'Summary of findings' tables:

  • time to complete ulcer healing where analysed using appropriate survival analysis methods;

  • proportion of ulcers completely healed during the trial period; and,

  • adverse events.