INTRODUCCIÓN

Once the database searches had been completed, the total number of reference hits from each database was recorded and all hits from databases that were compatible with importing into the “Refworks” database program were combined (all except the occupational databases and PEDro). Imported references were screened for duplicates that were subsequently removed. The next stages

involved systematically screening titles, abstracts and full text against the inclusion and exclusion criteria using a pre-piloted study eligibility prompt sheet (Appendix I). Irrelevant articles were excluded at each stage. At all stages screening was carried out independently by the author and a second reviewer (one of MH, NF or MT). Where there was disagreement between the two reviewers or uncertainty regarding whether studies met the criteria, the studies were discussed with a third reviewer to aid consensus prior to a final decision. Reference lists of included studies were checked to look for additional relevant studies that may have been missed from the electronic search. These studies were combined with hand searched studies identified from the remaining databases (that were

non-compatible with Refworks) and screened for eligibility criteria, before adding them to the final included study list. One additional paper (Mikesky et al, 2006) was added during the peer review process of the published paper of this review (Quicke et al, 2015).

3.3.4 Systematic review registration

The systematic review was registered with an international database for

prospective registering of systematic reviews (PROSPERO) during the search stage and prior to data extraction. This allows transparency in the planned

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methods and reduces the chance of the work being replicated (PROSPERO 2014:CRD42014006913)

3.3.5 Data extraction

Data on study author, year, participants, study design, physical activity type and intensity, safety outcome domains and safety outcome measure results (as pre-specified in table 3.1) were extracted. Extraction of basic study descriptive detail, cardiovascular intensity and physical activity impact categorisation were carried out by the author. Where target heart rates were stipulated within RCT

interventions, less than 50% of maximum heart rate was defined as low intensity, 50 to 70% as moderate intensity, and more than 70% as vigorous intensity (CDC Measuring physical activity intensity. From:

http://www.cdc.gov/physicalactivity/basics/measuring/heartrate.htm, accessed:

November 2012). In the absence of target heart rate information, physical activities were classified based on metabolic equivalents score (MET). MET scores relate to the ratio of a specific physical activity metabolic work rate to that of a standard resting metabolic rate (Ainsworth et al, 2011), with higher MET scores indicating greater physical activity intensity. A MET score of less than 3 was defined as low intensity, 3 to 6 as moderate intensity, whilst a score greater than 6 was considered vigorous (Ainsworth et al, 2011). Physical activity impact was categorised into high and low impact on a case by case judgement based on the likely amount of compressive load and whether both feet were intermittently off the ground (Hunter & Eckstein, 2009). Safety outcome results were extracted by the author, and double checked independently by one of three reviewers (MH, NF, and MT). If more than one paper provided data from the same study, data were included only once and treated as part of the original study. Within RCTs,

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baseline and also primary post-intervention time point follow-up data (over three months) were utilised, whilst in observational studies baseline characteristics and primary study endpoint data (over three months) were extracted.

Adverse events reported in included studies were extracted and were also standardised, where possible, into three ordered categories (mild, moderate and severe) to allow comparison across studies. Adverse event severity descriptors were: a) “mild” defined as bothersome but requiring no change in therapy, b)

“moderate” defined as requiring change in therapy, additional treatment, or hospitalisation, and c) “severe” defined as disabling or life-threatening (Calis &

Young, 2004). This classification was chosen over the more common “non-serious” and ““non-serious” adverse event dichotomy (ICH Harmonised Tripartite Guideline, 1996; Ioannidis et al, 2004) as it is more information rich and allows greater category discrimination. Within RCTs, pain and physical function data were extracted if a study either: a) carried out statistical comparison testing between physical activity and non-physical activity intervention groups at post-intervention follow-up, or; b) carried out statistical comparison testing within the physical activity intervention group over time from baseline to post-intervention.

Where 95% confidence intervals (95% CI) were available without p values for treatment effect or within group change over time, these were extracted and interpreted. Outcome measure data were not extracted if they spanned multiple safety outcome domains without individual domain scoring, for example, data from a paper that only reported on combined pain and function using the Lequesne index, which is a composite pain and function index (Lequesne et al, 1987), would not be extracted. When multiple outcome measures were used in a study for an individual safety outcome domain, only one was utilised. Priority was first given to

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the study’s primary outcome measure and then to OA specific, previously published and validated outcome measures. If the results of primary outcome measures were in different directions this was noted as “inconsistent” in the results. Numbers and proportions of TKRs occurring in participants within

exercise and non-exercise groups within RCTs were extracted along with adjusted odds ratios and confidence intervals for progression to TKR amongst case-control studies for varying levels of physical activity exposure.

3.3.6 Risk of bias of included studies

Bias is “a systematic error or deviation from the truth in results or inferences” and can lead to underestimation or overestimation of the true intervention or exposure effect (Higgins & Green, 2009). A key source of potential bias in systematic reviews is bias related to the limitations of the original studies contained within it (Sanderson et al, 2007; Higgins & Green, 2009). Hence, assessing risk of bias within primary studies is an essential part of conducting systematic reviews (Sanderson et al, 2007; Higgins & Green, 2009). It allows the author to make informed judgements about the potential limitations of individual study results and draw inferences regarding their internal validity which is then used to inform the overall review critical analysis discussion, evidence synthesis and strength of conclusions (Egger et al, 2001; Higgins & Green, 2009).

Including several different study designs in a systematic review poses challenges for consistently assessing risk of bias, since risk of bias tools designed specifically for one study design are often inappropriate for other designs. There is no current gold standard or clear consensus for choice of risk of bias tool for either RCTs or for observational studies (Moher et al, 1995; Katrak et al, 2004; Mallen et al, 2006;

Sanderson et al, 2007; Shamliyan et al, 2012). Therefore, two commonly used risk

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of bias tools specifically designed for each study design were piloted by the

author, and one other reviewer (NF), on three studies before making a decision on the final tool selection for each study type (Jadad et al, 1996; Higgins et al, 2011;

Hayden et al, 2013; Wells et al. From:

http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp, accessed December 2013). The pilot and rationale for the selection of risk of bias assessment tools is described in more detail in Appendix II.