Objective There are few effective treatments for acute whiplash-associated disorders (WAD). Early symptoms of postinjury stress predict poor recovery. This randomised controlled trial (StressModex) investigated whether physiotherapist-led stress inoculation training integrated with exercise is more effective than exercise alone for people with acute WAD.
Methods 108 participants (<4 weeks) at risk of poor recovery (moderate pain-related disability and hyperarousal symptoms) were randomly assigned by concealed allocation to either physiotherapist-led stress inoculation training and guideline-based exercise (n=53) or guideline-based exercise alone (n=55). Both interventions comprised 10 sessions over 6 weeks. Participants were assessed at 6 weeks and at 6 and 12 months postrandomisation. Analysis was by intention to treat using linear mixed models.
Results The combined stress inoculation training and exercise intervention was more effective than exercise alone for the primary outcome of pain-related disability at all follow-up points. At 6 weeks, the treatment effect on the 0–100 Neck Disability Index was (mean difference) −10 (95% CI −15.5 to −4.48), at 6 months was −7.8 (95% CI −13.8 to −1.8) and at 12 months was −10.1 (95% CI −16.3 to −4.0). A significant benefit of the stress inoculation and exercise intervention over exercise alone was also found for some secondary outcomes.
Conclusion A physiotherapist-led intervention of stress inoculation training and exercise resulted in clinically relevant improvements in disability compared with exercise alone—the most commonly recommended treatment for acute WAD. This contributes to the case for physiotherapists to deliver an early psychological intervention to patients with acute WAD who are otherwise at high risk of a poor outcome.
Trial registration number ACTRN12614001036606.
- exercise rehabilitation
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What are the findings?
Physiotherapist-delivered stress inoculation training integrated with guideline-based exercise results in greater and clinically relevant improvements in pain-related disability compared with guideline-based physiotherapy exercise alone.
The treatment benefit was maintained at 12-month follow-up.
Physiotherapist-delivered stress inoculation training integrated with guideline-based exercise results in clinically relevant improvements in stress, depressive symptoms, pain self-efficacy, perceived recovery and pain compared with guideline-based physiotherapy exercise alone.
How might it impact on clinical practice in the future?
These results support the use of physiotherapist-delivered stress inoculation training and exercise for people with acute whiplash-associated disorders at risk of poor recovery.
Physiotherapists are the most commonly used practitioner delivering care to patients with acute whiplash-associated disorder, and with some additional training this approach to early management could be considered for all whiplash-injured patients at risk of poor recovery.
Whiplash-associated disorders (WADs) are the most common non-hospitalised injuries following a road traffic crash (RTC)1 and are a large public health problem in Western countries incurring significant economic and social costs.1 2 Systematic reviews have demonstrated that approximately 50% of those injured will continue to report symptoms years after the injury, with 30% having moderate to severe pain and disability.3 4 As most recovery, if it occurs, takes place in the first 2–3 months postinjury,4 appropriate early treatment may prevent later chronic pain and disability.
Current clinical guidelines recommend exercise and activity for acute WAD,5 but several systematic reviews conclude that exercise/activity-based interventions provide only small effects.6–8 Those interventions have followed a traditional biomedical approach and not addressed psychological responses to the injury. WADs are heterogeneous conditions and patients present with varying levels of pain, disability and psychological distress. Acute symptoms of postinjury stress predict poor recovery at long-term follow-up,9 10 and these symptoms may contribute to pain developing and persisting.11 12 We postulated that targeting early stress symptoms in patients identified at risk of poor recovery13 might limit disability and alleviate pain compared with exercise alone.
Non-psychologist practitioners such as physiotherapists are increasingly being used to deliver psychological interventions for musculoskeletal pain. Most trials using physiotherapists in this role have focused on already chronic conditions such as chronic WAD,14 chronic low back pain and arthritis, and have targeted mainly pain-related cognitions.15 16 Few trials have investigated physiotherapists delivering a psychological intervention in the acute stage of injury and none have addressed stress-related symptoms. Stress inoculation training is a cognitive behavioural approach that facilitates general problem solving and coping strategies to manage stress-related anxiety.17 It has shown positive effects in randomised trials of sexual assault victims and orthopaedic inpatients.17 18
Therefore, we tested a physiotherapist-delivered stress inoculation training integrated with guideline-based exercise compared with guideline-based exercise alone for people with acute WAD at risk of poor recovery.
StressModex is a parallel-group, assessor-blinded, randomised controlled trial with participants recruited from sites in Queensland, Australia, between 3 October 2014 and 23 January 2017, and follow-up at 6 weeks and at 6 and 12 months. The trial was prospectively registered at the Australian New Zealand Clinical Trials Registry, and the study protocol has been previously published.19
Two protocol deviations were made. The original protocol specified that the Acute Stress Disorder Scale (ASDS) was to be used as a screen for inclusion/exclusion and as a secondary outcome measure at each follow-up point. Due to its overlap with the Posttraumatic Stress Diagnostic Scale (PDS) and to reduce participant burden, the ASDS was only used for inclusion/exclusion and not as a secondary outcome. The sample size proposed in the original protocol included a 15% loss to follow-up. We decided prior to the trial commencement to increase this to 20%, and this increased the sample size from 100 to 108.
Setting and participants
Community-dwelling participants were recruited by advertisement in local and metropolitan newspapers, radio and online media, from primary care practices (general practitioner and physiotherapy) as well as from the Emergency Department of the Gold Coast University Hospital.
Participants were eligible for inclusion if they met all of the following criteria: grade 2 or 3 WAD less than 4 weeks in duration; currently experiencing at least moderate pain-related disability (Neck Disability Index [NDI]: ≥32%) and hyperarousal symptoms (≥3 hyperarousal subscale of the PDS)13 20; not currently receiving care for whiplash (excluding medications); aged 18–65 years; and proficient written and spoken English.
The exclusion criteria were known or suspected serious spinal pathology (eg, metastatic disease of the spine); confirmed fracture or dislocation at time of injury (WAD grade 4);21 fracture or injuries to other body regions; spinal surgery in the past 12 months; meeting the criteria for probable acute stress disorder diagnosis on the ASDS 22screening positive for a current major depressive episode on the Patient Health Questionnaire-9 (PHQ-9); and a history of psychosis, bipolar disorder or depression.
Randomisation and masking
Volunteers were screened by telephone by a research physiotherapist. If eligible they completed baseline assessment via online forms sent via the RedCap (Research Electronic Data Capture) program. Participants were mailed the forms to complete if they did not have internet access. After baseline assessment, eligible participants were randomised using a computer-generated randomisation schedule consisting of random permuted blocks of 4–8, produced before the trial start by an independent statistician, to receive one of the following interventions:
Stress inoculation training and guideline-based exercise delivered by a physiotherapist.
Guideline-based exercise alone delivered by a physiotherapist.
To ensure allocation was concealed, participants were randomly assigned immediately after baseline assessment by opening the next sealed, sequentially numbered, opaque envelope. Participants were deemed to have entered the study at the time that the envelope was opened.
The research staff who were involved in the baseline and follow-up assessments were blinded to the treatment allocation of the participants.
All participants were provided with the patient educational booklet entitled whiplash injury recovery: a self-management guide which provides information and advice about WAD and self-management.23
Participants in both groups were asked not to seek other treatments and where possible not to change current medications for the 6-week intervention period. The participants’ nominated general practitioner was notified in writing of the individual’s participation in the trial. The general practitioners were asked within reason to refrain from referring or suggesting additional or alternative treatments for the initial 6 weeks after randomisation.
The exercise programme adheres to the recommendations of the current Australian guidelines for the management of acute whiplash.17 The 6-week (10 sessions) exercise programme was carried out under the supervision of the physiotherapist (2 sessions/week in weeks 1–4 and 1 session/week in weeks 5 and 6). The physiotherapists first assessed the participant and then tailored the exercises for each individual. The programme comprised specific exercises to improve movement, strength and endurance of the neck and shoulder girdle muscles, as well as exercises to improve eye/head coordination. The exercises were progressed by the physiotherapist in terms of increasing difficulty and load. At the same time the physiotherapist advised and guided the participant’s return to normal activities including work and on undertaking general aerobic exercise in a submaximum and progressive manner. Participants were encouraged to perform the exercises at home, once per day. Written and illustrated exercise instructions were provided. A logbook was completed by participants to record compliance with the exercises. At the physiotherapist’s discretion, manual therapy (but not grade V manipulation) was allowed, but it was emphasised that this was not a major component of the intervention. The exercise programme has been described in detail elsewhere19 and is available in online supplementary appendix 1.
Stress inoculation training and exercise
The exercise programme provided was identical to that described above.
In addition, the physiotherapist provided six sessions (one per week) of stress inoculation training, teaching strategies to assist participants in managing acute stress responses. It consisted of three phases: (1) identify and understanding stress—identifying specific stressors and how these affect pain, behaviour, emotions, physical performance and thoughts; (2) developing skills for managing stress, such as relaxation, problem solving and helpful coping self-statements; and (3) applying skills in various stressful situations to develop tolerance and confidence. Participants were encouraged to practise these skills on a weekly basis with home practice. Further details of the stress inoculation training intervention are provided in online supplementary appendix 1.
For both study arms, all sessions were for a maximum of 50 min.
Physiotherapist training and treatment fidelity
To avoid contamination, different physiotherapists were used to deliver the stress inoculation training and exercise (10 physiotherapists) or standard physiotherapy exercise (11 physiotherapists) interventions. Those who delivered the exercise-alone intervention had never been trained in the stress inoculation training intervention.
All treatments were delivered by physiotherapists with experience in the delivery of treatments as part of clinical trials and in the delivery of the exercise programme used in the trial. Before the start of the trial, physiotherapists were again trained in the exercise intervention with a half-day workshop, with the physiotherapists who delivered the combined intervention receiving an additional 1.5 days training in stress inoculation. The exercise training was provided by MS, an experienced musculoskeletal physiotherapist, and the stress inoculation training by JK, a clinical psychologist, and RS, a rehabilitation physician. After the training, the physiotherapists delivering the stress inoculation intervention audiotaped the practice sessions of each of the six components. These were audited by JK and RS and the physiotherapists provided with feedback. The physiotherapists could not commence delivering the trial treatments until it was deemed that they could successfully deliver the intervention. Midway through the trial, a refresher training session of 1 day was provided to the physiotherapists delivering the combined intervention.
The physiotherapists completed a session-by-session checklist of adherence to protocol and were required to provide audio recordings of their stress inoculation sessions, a random sample of which was formally evaluated by an independent psychologist. The physiotherapy exercise sessions were audited twice per physiotherapist (MS) to check for adherence.
All outcome measures were completed online through the RedCap platform or via mail. Investigators following up participants in any way to complete outcome measures were blinded to group allocation. Demographic characteristics such as age, educational level, working status, medical history, present medications, previous investigations and treatment, as well as information about symptoms, injury event and compensation status, were obtained at baseline.
Secondary outcomes included the following: PDS25; the Depression, Anxiety and Stress Scale (DASS)26; the Pain Catastrophizing Scale27; the Pain Self-Efficacy Questionnaire (PSEQ)28; the Coping Strategies Questionnaire29; self-rated global impression of recovery measured using an 11-point scale that ranges from −5 (vastly worse) to +5 scale (completely recovered), with 0 indicating unchanged30; the average pain intensity over the last week and the last 24 hours measured with 0 (no pain) and 10 (worst possible pain) in a Numeric Rating Scale and the physical and mental subscales of the Short-Form 36.31 All secondary measures are described in online supplementary appendix 2.
Participants also completed a process measure, the Credibility/Expectancy Questionnaire (CEQ)32 33 following the initial session with the treating physiotherapist. The CEQ provides a measure of how the participant thinks and feels about the treatment (online supplementary appendix 2).
We identified serious adverse events (defined as an event that is life-threatening, requires inpatient hospitalisation, or will result in persistent or significant disability or incapacity) and adverse effects (defined as an exacerbation of a pre-existing condition such as neck pain or headache) of treatment with open-ended questioning at the 6-week follow-up assessment.
An independent study statistician undertook the analyses and was blinded to group allocation. Sample size calculations were based on the ability to detect a clinically important difference of 10 points24 34 on the 100-point NDI between the two treatment groups. This was determined using a two-sided t-test with a type 1 error rate of 0.05, power of 0.80 and allowing for 20% loss to follow-up by 12 months with an assumed SD of 16, based on previously collected pilot data and data from recent trials. Using these parameters, the calculated total sample size was 108 participants (54 participants per group).
Statistical analyses were conducted on an intention-to-treat basis using IMB SPSS Statistics V.24. To account for repeated outcome measurement, a linear mixed modelling approach was employed. The effect of the intervention was analysed separately for each outcome with time as a repeated factor, treatment condition as a fixed factor and an unstructured covariance matrix used to specify the within-participant correlation over time. For each outcome, the difference in estimated marginal means (95% CI) between the groups was obtained at each time point, after adjustment for baseline measurement. All outcomes were continuous. A p value <0.05 was used to define statistical significance. Effect sizes (Cohen’s D) were also produced for all continuous outcomes at each time point.
Additional analyses were undertaken at 6 weeks, with a Fisher’s exact test used to determine group differences in self-rated global impression of recovery when dichotomised into success defined as much to very much improved (score +4 or +5).35
A patient representative of the National Health and Medical Research Council of Australia (NHMRC) Centre of Research Excellence in Road Traffic Injury Recovery was involved in the initial discussions of the intervention to be tested. They were not involved in the development of the plans for recruitment, design, outcome measures or the conduct of the study. No patients were asked to advise on the interpretation or writing of results. The burden of the intervention was not assessed, but patients were asked at each follow-up if they had any concerns with the treatment and we also assessed the credibility of the interventions and patient expectations of outcome. We intend to disseminate the trial results to the participants and will pursue patient and other relevant stakeholder involvement in the development of a dissemination plan.
Enrolment and follow-up
All participants were classified as grade 2 WADs. Figure 1 outlines the flow of participants through the trial. A total of 108 participants consented and were randomised. Of the 53 participants randomised to the stress inoculation and exercise group, the primary outcome measure (NDI) was completed by 51 (96%) participants at 6 weeks, 49 (92%) at 6 months and 50 (94%) at 12 months. Of the 55 participants randomised to the exercise-only group, NDI was completed by 51 participants (93%) at 6 weeks, 49 (89%) at 6 months and 48 (87%) at 12 months. There was some variation in the number of participants completing the secondary outcome measures over time in both groups, with these differences noted in table 3. Twenty-one physiotherapists (10 delivered the integrated intervention and 11 the standard exercise) delivered the trial treatments across 12 private physiotherapy clinics.
Table 2 shows the baseline characteristics for both groups. Participants were mainly middle-aged and predominantly female. The average time since their RTC injury was 16.4 (7.7) days. In both groups, approximately one-third of the participants had lodged a claim for compensation, with a compulsory third-party motor vehicle claim being the most common claim type. Twenty per cent of participants had engaged a solicitor. Queensland operates under a fault-based third-party compensation scheme, where only those deemed not at fault for the motor vehicle crash (MVC) can claim for compensation. Participants reported moderate levels of pain and disability and lower quality of life than Australian norms (table 3). Scores on all items of the CEQ were the same for both groups (table 2).
No serious adverse events were reported. One participant in each group recorded an adverse effect in the form of neck pain exacerbation. Neither of these participants withdrew from the trial because of adverse effects.
Adherence with treatment was good, with the median (IQR) number of sessions attended for both the stress inoculation and exercise and exercise-only groups being 109 10 out of a maximum of 10 sessions. Eight participants in the exercise-only group did not attend the full 10 sessions but attended a mean (SD) of 6.5 (2.4) sessions. Nine participants in the stress inoculation and exercise group did not attend the full 10 sessions, with the mean (SD) attendance being 6 (2.2). Physiotherapist adherence to the trial treatment protocols was excellent based on independent review of randomly selected sessions. For the audiotaped stress inoculation training sessions, 10% of the sessions were audited and adherence to the protocol was 94.6%±10.6%. For the completed proformas of the exercise sessions, adherence was 93%±4%.
In the primary analysis, the stress inoculation and exercise group improved significantly more than the exercise-alone group at each time point (estimated mean difference between groups at 6 weeks=−10.0 points [95% CI −15.5 to −4.48, Cohen’s D=−0.7, p<0.01]; at 6 months=−7.8 points [95% CI −13.8 to −1.8, D=−0.52, p<0.05]; at 12 months=−10.1 points [95% CI −16.3 to −4.0, D=−0.66, p<0.01]). Based on an estimated minimal clinically important difference for the NDI of 7–10 percentage points,24 34 36 the difference between the interventions is clinically important at each time point. Table 3 and figure 2 show the unadjusted NDI scores for each group, and table 4 shows the treatment effect for the stress inoculation and exercise group compared with the exercise-alone group at each follow-up time point.
The stress inoculation and exercise group also improved significantly more than the exercise-alone group on several secondary outcomes at various time points. Tables 3 and 4 show the results for the secondary outcomes. A significantly greater proportion of participants in the stress inoculation and exercise group (41%, n=21) reported that their condition was improved/much improved compared with the exercise-only group (18%, n=9) (Fisher’s exact test χ2=8.01, p<0.05).
Some of these effects are clinically important, although it should be noted that the minimal clinically important differences have been defined in conditions other than WAD. These include DASS stress scores at 6 weeks and DASS depression scores at 6 weeks and 6 months (minimal clinically important difference—DASS stress score of 5.55 and DASS depression score of 3.8621); PSEQ scores at 12 months (PSEQ minimal clinically important difference is 5.522); and global perceived recovery at 6 weeks (minimal clinically important difference is 1.3537). Group differences in Mental Health Component Scores (MCS) at 6 weeks and 6 months were greater than 4.95 (ie, half the SD seen in the Australian population38) and may reflect a clinically important difference.
The StressModex trial found that physiotherapist-led stress inoculation training and exercise results in greater improvements in neck pain-related disability compared with exercise alone for patients with acute WAD. Clinically relevant benefits of the combined intervention were found for the primary outcome (NDI)24 34 in the short (6 weeks), medium (6 months) and long (12 months) term, indicating a sustained effect of the intervention over time. Significant effects of the combined intervention were also found for many secondary outcomes, including pain and mental health outcomes. No serious adverse events related to the interventions were reported.
Comparison with other trials
Previous trials of treatment for acute WAD have predominantly focused on exercise treatments and found mostly small effects.6 7 One large high-quality trial conducted in the UK (Managing Injuries of Neck Trial (MINT) trial) showed a small effect of a six-session physiotherapy exercise package over advice alone at 4 months’ follow-up (NDI −3.7 [−6.1 to −1.3]) but not in the longer term of 8 and 12 months.39 Much greater effects were found for the same outcome in the StressModex trial. This might be due to our objective of specifically targeting stress-related symptoms, a known risk factor for poor recovery after whiplash injury.9 The MINT trial intervention included simple strategies for dealing with psychological factors where the physiotherapists questioned patients to identify treatment targets, such as beliefs about pain and coping strategies. Subsequent management included goal setting, pacing, education about pain and recovery, facilitation of effective coping strategies, and reassurance. Physiotherapists also screened for post-traumatic stress symptoms and referred when necessary, although details of how decisions around this process were made were not explained.40 It is possible that the approach used in the MINT trial was too broad, and although attempted to address psychosocial factors lacked the specificity to be effective. Physiotherapists report difficulty identifying and lack confidence to manage psychological factors in people with musculoskeletal pain,41 most likely due to a lack of training in these aspects. The fact that our trial specifically targeted one psychological risk factor and trained physiotherapists in its management as opposed to a more broad approach may be the reason for the stronger effects seen.
Additionally, all clinical trials to date have considered the condition as homogeneous and included all patients regardless of their presentation. However, there are consistent data to show WAD, particularly grade 2 disorders, is heterogeneous with varying levels of pain, disability and psychological factors,4 with some of these factors being prognostic for poor recovery.9 In StressModex, we specifically included patients at risk of poor recovery.13 20 Those with good potential for recovery (eg, lower levels of pain, disability and stress) would be unlikely to benefit from strategies to target stress-related symptoms that they do not report, and we propose that these low-risk patients will recover well with less intensive intervention. Further to this, a greater number of treatments provided to people with acute WAD may lead to poorer outcomes,42 indicating the importance of differentiating patients on their risk or not of developing chronic pain. By providing more concerted targeted treatments to those who need them most (patients at risk of poor recovery), the iatrogenic effects of providing the same treatment to those who do not need it may be avoided.
One previous trial found no effect of an early multidisciplinary (medication, physiotherapy and psychology according to their presentation) versus usual care for acute WAD.43 In this trial, patients in the multidisciplinary arm were less compliant with psychology treatment compared with physiotherapy. Patients in the acute stage of a physical injury may not see the relevance of seeing a psychologist for what they perceive is a physical injury. This factor may also explain the smaller effects found in the MINT trial, where patients with post-traumatic stress symptoms were referred to a psychologist.40 The StressModex trial attempted to overcome these barriers by using physiotherapists to deliver early psychological care, and we have demonstrated greater effect on later disability, pain and mental health outcomes. We have also shown that with training, physiotherapists can successfully and effectively deliver a psychological type of intervention.
The stress inoculation intervention included sessions to recognise the effect of stress on pain, strategies to modulate stress, problem solving and coping skills, and focused on the transfer of these skills to daily life. The significant effects on stress symptoms (DASS) at all time points suggest that it was effective in improving patients’ stress symptoms. Whether or not the reduction in stress acts as a mediating variable for the effect on disability cannot be determined from the results of this trial but would warrant further investigation.
Strengths and limitations
The StressModex trial has several strengths and limitations. The trial followed a prespecified protocol and included design features to minimise bias, including assessor blinding, concealed allocation and intention-to-treat analysis. Participant retention was high, participants complied with treatment attendance, and physiotherapists adhered to the treatment protocol. The participants represented people with acute WAD and compared well with cohorts of previous studies.39 43
Strengths also included direct comparing of two non-drug treatments—the exercise component is the most commonly recommended and used treatment for acute WAD.5 What was our innovation? We added a treatment that targeted a known risk factor for poor recovery (stress) in patients with complex whiplash, which is usually resistant to treatment. The number of treatments and the treatment time per session in both interventions were equal.
There are some limitations. Participants were aware of their treatment group assignment. The nature of the intervention also meant that it was not possible to blind the physiotherapist providers. However, treatment expectations were no different between the two groups. In terms of generalisability, participants with a history of mental health diagnoses were excluded as were those who scored highly on the ASDS and the depression screen, the PHQ-9. Thus our findings are not generalisable to those with a diagnosable mental health condition. In these cases, patients would require assessment by a qualified mental health professional, and it was certainly not our aim for physiotherapists to provide treatment to such patients.
When physiotherapists deliver a combined stress inoculation training and exercise, patients report clinically relevant reductions in pain-related disability compared with when physiotherapists deliver guideline-based exercise alone. Our format of integrating stress inoculation training with the guideline-recommended treatment of exercise over 10 sessions fits well with usual care for acute WAD commonly provided throughout the world.
Our results apply to the many jurisdictions worldwide that wrestle with the health burden of WAD. Our findings will interest insurance stakeholders and health insurance policymakers. Physiotherapists are the most commonly used practitioner delivering care to patients with acute WAD, and if they receive some additional training in delivering stress inoculation this approach to early management could be widely feasible in whiplash-injured patients at risk of poor recovery (ie, those who have high levels of stress). We plan to explore the barriers and facilitators to implementing this discovery across health sectors and jurisdictions. With an eye on scaling up the reach of our intervention, we will investigate delivering it in group settings and supplementing it with online delivery of some components.
We would like to acknowledge Joan Carlisle and Tania Manning for their work coordinating recruitment for the trial. We would like to thank the participants who volunteered for the study and the physiotherapy clinics that carried out the treatments.
Contributors MS contributed to the study conception and design, training and auditing of the physiotherapists, recruitment of participants, data management and the drafting and revision of the manuscript. RS and JK contributed to the study conception and design, training and auditing of the physiotherapists and the revision of the manuscript. GK contributed to the recruitment of participants and revision of the manuscript. JW contributed to the data management, data analysis and drafting and revision of the manuscript. MS and JW act as guarantors and take responsibility for the integrity of the data and the accuracy of the data analysis. The corresponding author attests that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted. The senior author (MS) affirms that the manuscript is an honest, accurate and transparent account of the study being reported, that no aspects of the study have been omitted and that any discrepancies from the study as planned/registered have been explained.
Funding The trial was funded by the National Health and Medical Research Council of Australia (Grant ID: APP1069443). The funders of the study had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript or the decision to submit for publication.
Competing interests None declared.
Ethics approval Ethical approval was obtained from the human ethics research committees of The University of Queensland (2011000206), Griffith University (AHS/14/14/HREC) and the Gold Coast University Hospital (HREC/15/QGC/34). All participants gave written informed consent prior to study entry.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The investigators will share data (with associated coding library) used in developing the results presented in this manuscript on request to the corresponding author at firstname.lastname@example.org. Anonymised record-level data will be made available on proposal for analysis by those who have received ethical clearance from their host institution.
Correction notice This article has been corrected since it published Online First. The CI −15.5 to −9.0 has been corrected to −15.5 to −4.48 in the abstract, results and table 4.
Patient consent for publication Not required.
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