Criteria for considering studies for this review
Types of studies
We will consider all randomised controlled trials (RCTs) or quasi-RCTs which compare autologous whole blood or PRP injection therapy to another therapy (placebo or active treatments, including non-pharmacological therapies) for lateral elbow pain. We will only include published trials available as full articles or full trial reports.
Types of participants
Adult participants (>16 years) who have been determined to have lateral elbow pain on the basis of specific criteria as defined by the trial authors. These criteria usually include clinical features such as pain that is maximal over the lateral epicondyle, and reproducibility of pain by two or more of the following tests: palpation of the lateral epicondyle and/or the common extensor origin of the elbow, gripping, resisted wrist or second or third finger extension (dorsiflexion). They may also include criteria such as the presence of focal hypoechoic areas or frank tears or alterations in the normal fibrillary pattern in the common extensor origin when examined by ultrasound or MRI. We will review the inclusion criteria of included trials.
In addition, we will include trials that include participants with tendonitis at other sites provided that the lateral elbow pain results are presented separately or at least 90% of participants in the trial have lateral elbow pain.
Types of interventions
For comparisons that include a co-intervention (such as a physical therapy), we will only consider studies that contain the co-intervention in both experimental and control groups.
Types of outcome measures
There is considerable variation in the outcome measures reported in clinical trials of interventions for pain. However there is general agreement that outcome measures of greatest importance to patients should be considered.
The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has published consensus recommendations for determining clinically important changes in outcome measures in clinical trials of interventions for chronic pain (Dworkin 2008). Reductions in pain intensity of ≥ 30% and ≥ 50% reflect moderate and substantial clinically important differences, respectively, and it is recommended that the proportion of patients that respond with these degrees of pain relief be reported.
Continuous outcome measures in pain trials (such as mean change on a 100 mm visual analogue scale) may not follow a Gaussian distribution. Often, a bimodal distribution is seen instead, where patients tend to report either very good or very poor pain relief (Moore 2010). This creates difficulty in interpreting the meaning of average changes in continuous pain measures. For this reason, a dichotomous outcome measure (the proportion of participants reporting ≥30% pain relief) is likely to be more clinically relevant and will be the main measure of the benefits of the intervention in this review.
NICE have recommended that trials of tendinopathy include functional and quality of life outcomes with a minimum follow-up of one year (NICE 2013).
Participant reported pain relief of 30% or greater
Function/disability as measured by disease-specific disability measures such as the Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaire (Rompe 2007), or the upper-limb specific Disabilities of the Arm, Shoulder and Hand (DASH) outcome questionnaire (Gummesson 2003)
Mean pain or mean change in pain score on a visual analogue scale or numerical rating scale
Participant's perception of overall effect as measured by a global rating of treatment satisfaction such as the Patient Global Impression of Change (PGIC) scale or overall treatment success
Proportion of withdrawals due to adverse events
Proportion with any adverse event
Health-related quality of life as measured by either generic measures (such as components of the Short Form-36 (SF-36), or disease-specific tools
Other pain measures including participant-reported pain relief of 50% or greater; proportion achieving pain score below 30/100 mm on a visual analogue scale (VAS); PGIC in pain much or very much improved
Grip strength (preferably pain-free maximum grip strength)
Proportion with serious adverse events (defined as adverse events that are fatal, life-threatening, or require hospitalisation)
Timing of outcome assessment
For the purpose of this review, if multiple time points are reported, we will group outcomes up to six weeks; over six weeks to six months; over six months to a year; and more than a year. If trials include outcomes at more than one time point within these time periods we will extract the latest time point. Adverse event data will be extracted at the end of the trials.
Search methods for identification of studies
We will search the following electronic databases, unrestricted by date, or language:
Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library);
MEDLINE (Ovid 1946-present) (Appendix 1);
EMBASE (Ovid 1947-present);
ISI Web of Science (Web of Knowledge);
Clinical trials registers such as ClinicalTrials.gov (http://clinicaltrials.gov/) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/) for ongoing trials.
We will adapt the search strategy developed for MEDLINE as appropriate for use in the other databases.
Searching other resources
We will screen reference lists of retrieved review articles and trials to identify potentially relevant studies.
Data collection and analysis
Selection of studies
Two review authors (MS, EO) will independently review the search results and identify trials that appear to fulfil our inclusion criteria. All articles selected by at least one of the review authors will be retrieved for closer examination. The review authors will not be blinded to the journal or authors. Disagreement about inclusion or exclusion of individual studies will be resolved by consensus or if consensus cannot be reached by a third review author (RB or RJ).
Data extraction and management
Two review authors (MS, EO) will extract the following data from the included trials and resolve any differences by consensus:
trial characteristics including size and location of the trial, and source of funding;
characteristics of the study population including age and comorbidities;
characteristics of autologous whole blood or PRP injection therapy such as dose and frequency of injections, schedule of treatment, total number of treatment sessions;
characteristics of the control interventions;
risk of bias domains as outlined in Assessment of risk of bias in included studies; and
outcome measures: the measurement scale, and direction of the scale, and the mean and standard deviation, and number of participants per treatment group for continuous outcomes (such as mean pain, function, quality of life), and number of events and number of participants per treatment group for dichotomous outcomes (such as proportion with 30% or more pain relief, treatment success, withdrawals due to adverse events, adverse events) as outlined in Types of outcome measures.
We will note in the 'Characteristics of included studies' tables if outcome data are not reported in a form suitable for meta-analysis, and where missing data are calculated or estimated from a graph, or imputed.
Our a priori decision rules to extract data in the event of multiple outcome reporting in trials are as follows.
Where trialists report both final values and change from baseline values for the same outcome, we plan to extract final values.
Where trialists report both unadjusted and adjusted-for-baseline values for the same outcome, we plan to extract adjusted values.
Where trialists reported data analysed based on the intention-to-treat (ITT) sample and another sample (e.g. per-protocol, as-treated), we plan to extract ITT-analysed data.
For cross-over RCTs, we plan to extract data from the first period only.
Where trials do not include a measure of overall pain but include one or more other measures of pain, for the purpose of pooling data, we will combine overall pain with other types of pain in the following hierarchy: unspecified pain; pain with activity; or daytime pain.
If multiple time points are reported within our time frames (up to six weeks; over six weeks to six month; over six months to a year; and over one year), we will extract the latest time point (e.g., if data are reported at four weeks, five weeks, three months and six months, we will extract outcomes at five weeks and six months).
Assessment of risk of bias in included studies
Two review authors (MS, EO) will assess the risk of bias of each included trial and resolve any disagreements by consensus, or consult a third review author (RB or RJ) if necessary.
We will assess the following methodological domains, as recommended by the Cochrane Collaboration (Higgins 2011a):
sequence generation (to determine if the method of generating the randomisation sequence was adequate, such as random-number tables, computer-generated random numbers, minimisation, coin tossing, shuffling of cards and drawing of lots);
allocation sequence concealment (to determine if adequate methods were used to conceal allocation, such as central randomisation and sequentially numbered, sealed, opaque envelopes);
blinding of participants, personnel and outcome assessors;
incomplete outcome data;
selective outcome reporting; and
other potential threats to validity, such as inappropriate analysis in cross-over trials.
Each of these criteria will be explicitly judged as low risk of bias, high risk of bias, or unclear risk (either lack of information or uncertainty over the potential for bias). We will consider blinding objective outcomes separately from blinding of subjective participant-reported outcomes (e.g. pain, function). We will present the figures generated by the risk of bias tool to provide summary assessments of the risk of bias.
Measures of treatment effect
When possible, the analyses will be based on intention-to-treat data (outcomes provided for every randomised participant) from the individual trials. For each trial, we will present outcome data as point estimates with mean and standard deviation for continuous outcomes and risk ratios (RRs) with corresponding 95% confidence intervals (CIs) for dichotomous outcomes.
For continuous data, results will be presented as mean differences (MDs) if possible. However, where different scales are used to measure the same outcome or concept, standardised mean differences (SMDs) will be used. The SMD will be re-expressed as a mean difference on a typical scale (e.g. 0 to 10 for mean pain) by multiplying by a typical among-person standard deviation (e.g. the standard deviation of the control group at baseline from the most representative trial) (Schünemann 2011b).
Unit of analysis issues
If we identify trials that injected both forearms, but the trialists report outcomes per participant without accounting for the bilateral correlation, we will only report results from one arm where possible. If we are unable to obtain the data for a single arm, or adjust the outcome data, we will include the data as reported by the trialists and comment on the validity of such analyses, and assess the effect of including such data using sensitivity analyses.
If we identify trials that employ a cross-over design, only data from the first time point will be included.
Where multiple treatment arms are reported in a single trial, we will include only the relevant arms. If two comparisons (e.g. autologous whole blood versus placebo and PRP versus placebo) are combined in the same meta-analysis, we will halve the placebo group to avoid double-counting.
Dealing with missing data
Where data is missing or incomplete, further information will be sought from the study authors.
In cases where individuals are missing from the reported results, we will assume the missing values to have a poor outcome. For dichotomous outcomes that measure adverse events (e.g. number of withdrawals due to adverse events), the withdrawal rate is calculated using the number of patients that received treatment as the denominator. For dichotomous outcomes that measure benefits (e.g. proportion of subjects with 30% or more reduction in pain), the proportion will be calculated using the number of randomised subjects as the denominator. For continuous outcomes (e.g. pain), we will calculate the MD or SMD based on the number of patients analysed at the time point. If the number of patients analysed are not presented for each time point, the number of randomised patients in each group at baseline will be used.
Where possible, missing standard deviations will be computed from other statistics such as standard errors, confidence intervals or P values, according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If standard deviations cannot be calculated, they will be imputed (e.g. from other studies in the meta-analysis) (Higgins 2011c).
Assessment of heterogeneity
We will first assess included trials for clinical homogeneity in terms of participants, interventions and comparators. For studies judged as clinically homogeneous, we will assess and quantify the possible magnitude of inconsistency (i.e. heterogeneity) across studies, using the I2 statistic with a rough guide for interpretation as follows: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100% considerable heterogeneity (Deeks 2011). In cases of considerable heterogeneity (defined as I2 ≥ 75%), we will explore the data further by comparing the characteristics of individual studies and any subgroup analyses. We will report any differences when interpreting the results of this review or we will report I2 values wherever there is unexplained statistical heterogeneity.
Assessment of reporting biases
In order to determine whether reporting bias is present, we will determine whether the protocol of the trial was published before recruitment of patients for the study. For studies published after 1 July 2005, we will screen the WHO's ICTRP search portal as described in Electronic searches. We will evaluate whether selective reporting of outcomes is present (outcome reporting bias).
We will compare the fixed-effect estimate against the random-effects model to assess the possible presence of small sample bias in the published literature (i.e. in which the intervention effect is more beneficial in smaller studies). In the presence of small sample bias, the random-effects estimate of the intervention is more beneficial than the fixed-effect estimate (Sterne 2011). The potential for small-study effects in the main outcomes of the review will be further explored using funnel plots if at least 10 studies reporting pain are included in a meta-analysis (Sterne 2011).
For studies with similar participant and intervention characteristics and a common comparator, we will pool outcomes in a meta-analysis using the random-effects model as a default, and perform a sensitivity analysis with the fixed-effect model.
Summary of findings table
We will present the main results of the review in a summary of findings table which provides key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes (proportion reporting pain relief of 30% or greater; total number of withdrawals due to adverse effects; number of adverse events; function; mean (or mean change) in pain score; success of treatment; quality of life), as recommended by the Cochrane Collaboration (Schünemann 2011a). Because some comparators might exert an immediate but short-lived benefit (e.g. glucocorticoid injection) while autologous blood and PRP injections might exert a more delayed onset of benefit we will consider both the six week and six month endpoints. The summary of findings table includes an overall grading of the evidence related to each of the main outcomes, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Schünemann 2011b).
We will provide the absolute percent difference, the relative percent change from baseline, and for outcomes with statistically significant differences between intervention groups, the number needed to treat (NNT).
For dichotomous outcomes, the absolute risk difference will be calculated using the risk difference statistic in the Cochrane Collaboration's statistical software, Review Manager 2013, and the result expressed as a percentage. The relative percent change for dichotomous data will be calculated as the RR - 1 and expressed as a percentage. The NNT will be calculated from the control group event rate and the relative risk using the Visual Rx calculator (Visual Rx 2008).
For continuous outcomes, the absolute change will be calculated as the MD between the intervention and control group, expressed in the original measurement units (divide by the scale), and as a percentage; the relative change will be calculated as the absolute change (MD) divided by the baseline mean of the control group from a representative trial. The NNT for continuous measures will be calculated using the Wells calculator (available at the CMSG Editorial office, (http://musculoskeletal.cochrane.org/). We will assume a minimal clinically important difference (MCID) of 1.5 points on a 10 point continuous pain scale, and 10 points on a 100 point scale for function or disability for input into the calculator (Gummesson 2003).
Subgroup analysis and investigation of heterogeneity
If there are sufficient data, we plan to carry out the following subgroup analyses, to assess if pain and function differ between the following groups:
participants who receive whole blood compared to those who receive PRP; and
participants with a lateral collateral ligament tear or large (≥ 6 mm) intrasubstance tear compared to participants without these tears.
We will use the formal test for subgroup interactions in Review Manager 2013.
We will assess the robustness of the pain results to selection and detection biases, by excluding trials from the meta-analysis with inadequate or unclear allocation concealment; and trials with unclear or inadequate participant blinding.