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Cost-effectiveness of surgical treatments compared with early structured physiotherapy in secondary care for adults with primary frozen shoulder

Aims A pragmatic multicentre randomized controlled trial, UK FROzen Shoulder Trial (UK FROST), was conducted in the UK NHS comparing the cost-effectiveness of commonly used treatments for adults with primary frozen shoulder in secondary care. Methods A cost utility analysis from the NHS perspective was performed. Differences between manipulation under anaesthesia (MUA), arthroscopic capsular release (ACR), and early structured physiotherapy plus steroid injection (ESP) in costs (2018 GBP price base) and quality adjusted life years (QALYs) at one year were used to estimate the cost-effectiveness of the treatments using regression methods. Results ACR was £1,734 more costly than ESP ((95% confidence intervals (CIs) £1,529 to £1,938)) and £1,457 more costly than MUA (95% CI £1,283 to £1,632). MUA was £276 (95% CI £66 to £487) more expensive than ESP. Overall, ACR had worse QALYs compared with MUA (-0.0293; 95% CI -0.0616 to 0.0030) and MUA had better QALYs compared with ESP (0.0396; 95% CI -0.0008 to 0.0800). At a £20,000 per QALY willingness-to-pay threshold, MUA had the highest probability of being cost-effective (0.8632) then ESP (0.1366) and ACR (0.0002). The results were robust to sensitivity analyses. Conclusion While ESP was less costly, MUA was the most cost-effective option. ACR was not cost-effective. Cite this article: Bone Jt Open 2021;2(8):685–695.


Introduction
Adhesive capsulitis or frozen shoulder is a common disorder affecting 8.2% of men and 10.1% of women of working age, 1 with an estimated cumulative incidence of 2.4 per 1,000 population per year. 2 The capsule of the shoulder joint becomes inflamed, then scarred and contracted, causing pain, stiffness, and loss of function. 3 A range of treatment options of varying effectiveness and costs are available for the management of frozen shoulder in secondary care. 4 A survey of specialist health professionals conducted in the UK in 2009 identified three interventions as being most commonly used: physiotherapy; manipulation under anaesthesia; and arthroscopic capsular release. 5 The UK national physiotherapy guidelines for frozen shoulder recommend exercise and manual therapy either in isolation, or to supplement with an intra-articular steroid injection. 6 Both manipulation under anaesthesia and capsular release are expected to facilitate quicker recovery, but are costly and invasive, and there is a lack of rigorous evidence. [7][8][9] The UK FROzen Shoulder Trial (UK FROST) was conducted to provide evidence of clinical effectiveness and cost-effectiveness of manipulation under anaesthesia (MUA), arthroscopic capsular release (ACR), and a specific non-surgical pathway designed for the trial to include intra-articular steroid injection and structured physiotherapy using the best available evidence and consensus from expert shoulder physiotherapists. 6,7,10 We have called this 'Early' Structured Physiotherapy (ESP) as it is more quickly accessible than the surgery interventions and the similarly developed pathway of post-procedural physiotherapy that followed surgery. Therefore, specifically for the purposes of the trial, participants underwent standardized physiotherapy programmes in all three groups as described in detail elsewhere, ESP in the non-surgical group, and post-procedural physiotherapy in the two surgical groups. 11 The clinical effectiveness results of UK FROST have been reported. 12 In summary, we sought a target difference of five points on the Oxford Shoulder Score (OSS) 13 between early structured physiotherapy (ESP) and either surgical treatment, or a difference of four points between the two surgical treatments. Mean group differences on the OSS at one year were 2.01 points between participants randomized to capsular release and MUA (95% confidence interval (CI) 0.10 to 3.91), 3.06 points between capsular release and ESP (95% CI 0.71 to 5.41), and 1.05 points between MUA and ESP (95% CI -1.28 to 3.39). All of the mean differences on the assessment of shoulder pain and function (OSS) at the primary endpoint of one year were less than the target differences. Therefore, none of the three interventions were considered to be clinically superior.
To inform decision-making, it is important to identify the cost-effective intervention for the treatment of frozen shoulder in secondary care. This paper reports on the economic evaluation conducted alongside the UK FROST trial, which aimed to assess the health-related quality of life, costs and cost-effectiveness of surgical treatments (MUA and capsular release followed by post-procedural physiotherapy) versus non-surgical treatment (ESP) for the management of adults with frozen shoulder within the NHS.

Methods
Overview. Individual patient data (IPD) collected alongside the UK FROST trial were used to perform a cost utility analysis. Costs and health benefits were compared for the three groups over one year, and hence discounting was not required. Costs (2018 price base) were evaluated from the UK NHS and Personal Social Services perspective. Health benefits were expressed in terms of quality-adjusted life years (QALYs), based on patient's health-related quality of life using the EuroQol five-dimension five-level questionnaire (EQ-5D-5L). 14,15 Adjusted differences in mean costs and mean QALYs at one year were used to estimate the cost-effectiveness of the three treatment options. The base-case analysis was conducted on the multiple imputed dataset and followed an intention-to-treat (ITT) approach; thus the treatment groups were compared based on their initial random allocation irrespective of protocol deviations or withdrawal. The National Institute for Health and Clinical Excellence (NICE) guidelines were applied to all methods used for this economic analysis. 16 All analyses and modelling were conducted in StataTM 16 (StataCorp LP, College Station, Texas, USA).
Trial design, interventions, and economic data collection. UK FROST recruited 503 adults with a clinical diagnosis of frozen shoulder from 35 hospital sites in the UK between April 2015 and December 2017. Detailed inclusion and exclusion criteria are published elsewhere. 17 Patients were randomized on a 2:2:1 basis to manipulation under anaesthesia with steroid injection (n = 201), arthroscopic capsular release (n = 203), or ESP with steroid injection (n = 99).
For the purposes of the trial, physiotherapy programmes were standardized in all three groups using the best available evidence and consensus of expert shoulder physiotherapists. 6,7,10,11 Physiotherapy in all three groups was to be up to 12 sessions unless, exceptionally, the physiotherapist decided that more than 12 sessions were needed. Patients were also offered an intra-articular steroid (glucocorticoid) injection at the earliest opportunity in the ESP pathway. The injection was administered with or without imaging guidance depending on usual practice of the hospital site, as current evidence did not support superiority of either approach. 18 We did not anticipate that a steroid injection was normally given as part of post-procedural physiotherapy that followed the two surgical interventions. All participants were provided with instructions on a graduated home exercise programme progressing from gentle pendular exercises to firm stretching exercises according to stage, as is accepted good practice. 6,11 The development of the standardized physiotherapy programmes for UK FROST are described in detail elsewhere. 11 MUA and capsular release were performed as day case surgical procedures. With MUA, the surgeon manipulated the affected shoulder in a controlled fashion to stretch and tear the tight capsule when the patient was under general anaesthesia; and that was supplemented by an intra-articular steroid injection. If the manipulation was judged to be incomplete, the surgeons were asked not to cross over intraoperatively to do capsular release in order to allow assessment of the outcome of the manipulation. ACR was performed under general anaesthesia to surgically divide the contracted anterior capsule in the rotator interval, and that was supplemented with manipulation to complete and confirm optimal capsular release. Procedures like posterior capsular release were permitted at the discretion of the operating surgeon and were recorded.
All interventions were delivered either by participating surgeons who were familiar with the surgical procedures or by qualified physiotherapists (i.e. not students or †Community Health Services, Physiotherapist, adult, one to one (currency code A08A1). ‡Sum of total expenditure on excess bed days (elective and non-elective) divided by total activity for HRG codes relating to shoulder: MUA (HD24E; non inflammatory, bone or joint disorders, with CC score 8 to 11)); ACR (HN53A, HN53B, HN53C, HN54A, HN54B, HN54C; major and intermediate procedures for non-trauma with CC score 4+, 2 to 3, and 0 to 1).
§Post procedural physiotherapy form is featured to record staff at or above Band 8. Hence unit cost for physio at or above Band is estimated as averaged Band 8a (£66) and Band 8b (£78). ARC, arthroscopic capsular release; MUA, manipulation under anaesthesia. assistants). There was no minimum number of surgical procedures that the surgeon had to have performed and no grades of surgeon were excluded. No additional training was required for either programme of physiotherapy. However, a standardized booklet was used to record the physiotherapy that participants received in all three trial arms, which provided instructions for delivering the ESP or post-procedural physiotherapy pathways. NHS ethical approval was obtained on 18 November 2014 from the National Research Ethics Service (NRES Committee North East -Newcastle & North Tyneside 2; Research Ethics Committee Reference 14/NE/1176). Local site-specific NHS research and development approvals were obtained from each participating site. The study was adopted to the UK Clinical Research Network portfolio (17719). Written informed consent was obtained from all trial participants by suitably qualified local study personnel at each participating site.
As detailed in the trial protocol, 17 cost and health outcome data were collected prospectively via patient questionnaires at three months, six months, and one year; and via hospital forms (baseline characteristics, details of surgery, physiotherapy, complications, and hospital care due to additional and further treatments received before/during/after completing randomized treatment). Copies of these forms will be included in the Supplementary Material published alongside the NIHR Health Technology Assessment report. 19 Health outcomes and quality adjusted life years. The main outcome measure for the economic analysis was QALYs based on the EQ-5D-5L questionnaire. The EQ-5D has been validated for a range of shoulder conditions. 20,21 The EQ-5D-5L was completed by trial participants at baseline, three and six months, and one year. The EQ-5D-5L defines health-related quality of life in terms of five dimensions: 'mobility', 'self-care', 'usual activities', 'pain/discomfort', and 'anxiety/depression'. Responses in each dimension are divided into five ordinal levels coded 1) no problems, 2) slight problems, 3) moderate problems, 4) severe problems, and 5) extreme problems/unable to perform. We used the Van Hout et al 22 2012 mapping function to derive utilities. QALYs were calculated by combining the utility estimates by the duration of time in each health state using the area under the curve (AUC) method. 23 The difference in mean QALYs between treatments groups was adjusted for baseline utility. 24 Table II. Average primary and community resource use (shoulder-related) and lost days off work per treatment group. 19 Resource type

MUA (n = 201) ACR (n = 203) ESP (n = 99) n Mean (SD) Median Missing (%) n Mean (SD) Median Missing (%) n Mean (SD) Median Missing (%)
GP Resource use and costs. The cost for each trial participant was calculated by multiplying health care resource use by the associated unit costs. Total cost comprises the cost of the initial intervention; hospital stays and outpatient appointments after initial intervention, including physiotherapy; and visits to primary and community health care professionals over one year. Costs relating to the surgical interventions was based on operation times, staff, consumables, and length of stay. The hospital-based staff cost per minute was estimated using PSSRU 2018 (Personal Social Services Research Unit) data. 25 These unit cost estimates included staff salaries, salary oncosts, overheads, and capital overheads. Drug tariff per milligram for medications (i.e. anaesthesia, antibiotics, and steroid injections) were obtained from the British National Formulary. 26 To cost length of stay we used NHS Reference costs, 27 taking the weighted mean inpatient bed day for all major and intermediate shoulder procedures. Physiotherapy data (i.e. session duration and staff delivering the session) was collected using physiotherapy forms designed for the trial. Physiotherapists cost per hour was estimated using PSSRU 2018 (Bands 5 to 8).
The cost of other hospital-based care and for the primary care and community-based services were estimated by applying unit costs from national tariffs to resource volumes. Other costs included lost productivity measured as number of days off work. The costs of time taken off work were estimated by applying costs from the Office National Statistics (ONS) 28 to occupational information derived from self-reported work status information. Table I presents the unit costs used to calculate the total cost per patient in the trial. The base-case analysis included only shoulder-related resource use, except for hospital stay, which included both shoulder and general medical complications that could apply to the affected shoulder. Handling missing data. We have previously reported details of the approach applied to handle missing data, 19,29 and we have used the same methods in this study, as described below. Complete case analysis (CCA) excludes all participants with any missing or incomplete data. Excluding patients with missing data leads to loss of statistical power and can bias the results. 30 Multiple imputation (MI) has been recommended as the appropriate method to reflect the uncertainty in the results of an economic evaluation attributable to missing data. 31 Multiple imputation assumes that data are missing at random (MAR), i.e. that the probability that data are unobserved is dependent only on observed variables. 32 We conducted a comprehensive investigation following missing data guidelines, 30,33,34 to prove that MAR was a plausible assumption fitting UK FROST dataset. Thus, incomplete data on costs and QALYs were imputed using multiple imputation with chain equations and predictive mean matching over 60 imputations. Age, sex, baseline OSS score, diabetes (yes/no) at baseline, baseline utility, and all predictors of missingness were included as an explanatory variable in the imputation models. Mean estimates of costs and QALYs, variances, and CI were obtained using Rubin's rules. 35 The MI model was validated using graphical plots to visualize whether the distribution of imputed data resembles the distribution of original data. We explored possible departures from the MAR assumption by means of sensitivity analyses, including complete case analysis. Additionally, a mixed model, which does  not require an imputation process, is also presented as per the sensitivity analysis. Base case analysis. The base case analysis was conducted on the imputed dataset on an ITT basis. Cost-effectiveness was estimated as the difference in mean costs divided by the difference in mean QALYs between the trial comparators at twelve months follow-up, using conventional decision rules and estimating ICERs as appropriate. 36 The mean difference estimates and their 95% CIs were generated by means of seemingly unrelated regression (SUREG) adjusted for age, sex, baseline EQ-5D-5L score, baseline OSS score, and diabetes (yes/no). In order to compute the probability of each intervention being cost-effective at a given cost-effective threshold, the SUREG was conducted with a bootstrapping approach on five imputed datasets to generate 10,000 replicates of incremental costs and benefits. These replicates were represented graphically as cost-effectiveness acceptability curves (CEACs). The probability that each intervention is cost-effective is reported at the cost-effectiveness thresholds applied by NICE of £20,000 to £30,000/QALY, 15 and a threshold of £13,000/QALY as suggested by recent research. 37,38 The ICER was re-expressed in terms of net monetary benefit (NMB) as an estimate of the gain (or loss) in resources of investing in the intervention when those resources might be used somewhere else. Analyses of uncertainty. The uncertainty around the cost-effectiveness results was explored using sensitivity analyses, all of which controlled for the same covariates: (Scenario 1) recalculating costs including non-shoulder costs (ITT approach); (Scenario 2) adopting a broader perspective that includes productivity and private care costs; (Scenario 3) restricting the analyses to complete cases (ITT approach); (Scenario 4) imputing QALY data at aggregated level rather than at the index-score level; (Scenario 5) mix model approach; and (Scenario 6) missing not at random scenario, which allocated higher costs or worse health outcomes to patients with missing data.

Results
Study population and missing data. The baseline study population for the economic analysis was 503 patients: ESP (n = 99), MUA (n = 201), and capsular release (n = 203). A total of 19 participants fully withdrew from the trial, for whom we used multiple imputation techniques to impute missing economic data. There were 16 participants who crossed over from their initial randomization, i.e. from ESP to capsular release (n = 7), from MUA to ESP (n = 4), from capsular release to ESP (n = 2), and from capsular release to MUA (n = 3  Figure a). Missing data were non-monotonic, since in all groups, individuals with missing data at one follow-up point may provide data subsequently (i.e. more individuals are observed at year one than in month 6). The results of logistic Resource use related to primary and community care was slightly higher for the capsular release group, although differences between the groups appeared small (Table II). Over the entire follow-up period, a higher proportion of participants in the capsular release group had more days lost off work. Inpatient hospital costs related to complications after initial treatment up to one year was greater for the manipulation group. However, participants who received ESP were more likely to need further treatment following their index intervention and accumulated greater outpatient costs after discharge. Participants in the capsular release group received fewest further treatments, however, they accumulated greater total costs over the trial follow-up; as expected, costs of the surgery were the major cost driver for this group (Table III). Participants waited a median of 14 days for ESP, a median of 56.5 days for MUA, and a median of 71.5 days for capsular release. 11 The longer waiting times were reflected in the actual days off work and increased productivity costs, which were greater for the capsular release arm. Private costs were similar among the three arms. It should be noted that total cost estimates shown in Table III are unadjusted means, and relate to complete cases, therefore there is limited value in interpreting differences between treatments. Mean differences for each surgical treatment versus ESP and corresponding 95% CIs, adjusted for patient covariates, and taking into consideration the correlation between costs and QALYs, are shown in Table IV (i.e. cost-effectiveness results). Health outcomes and quality-adjusted life years. The overall distribution of the EQ-5D scores (utilities) for the different follow-up assessments is illustrated in Figure 1. Patients allocated to MUA started from a higher utility value compared to the other groups (manipulation (mean 0.456) vs capsular release (mean 0.428) vs ESP (mean 0.402)). Patients allocated to the surgical groups had similar utility values (adjusted for baseline utility) at 12 months' follow-up (capsular release (mean 0.739) vs MUA (mean 0.734)); both MUA and capsular release had better utility values compared to ESP at 12 months (mean 0.693). QALYs estimates at one year, when controlling for baseline utility (for available cases), show that patients allocated to MUA accrued more QALYs than the other two groups: MUA (0.6765) > ESP (0.6492) > capsular release (0.6475). Cost-effectiveness analysis. The incremental analysis for the base case is summarized in Table IV. Compared to ESP, MUA cost a mean of £276 more per patient (95% CI £66 to £487) and marginally improved health outcomes over the 12 months (a mean 0.0396 more QALYs per participant than structured physiotherapy (95% CI -0.0008 to 0.0800)). The resulting incremental cost-effectiveness ratio (ICER) for MUA was £6,984 per additional QALY when compared to ESP. ACR is considerably more costly than ESP (on average £1,734 more expensive per participant (95% CI (£1,529 to £1,938)); and despite the QALY gained by capsular release participants (on average 0.0396 more QALYs per participant than physiotherapy (95% CI -0.0008 to 0.0800)) this was not sufficient to support capsular release as being a cost-effective use of NHS resources when compared with ESP. Similarly, capsular release is dominated by MUA, with higher mean costs and lower QALYs. As illustrated by the CEAC in Figure 2, at a £20,000 per QALY threshold the probability of MUA being cost-effective was high (86%) compared with ESP (13%) and capsular release (0%). Sensitivity analysis. Table V shows that the base case analysis results were robust to including non-shoulder costs, with MUA continuing to be a cost-effective use of NHS resources. In contrast, cost-effectiveness results were sensitive to a broader perspective scenario, suggesting the ICER from a wider perspective was higher than the thresholds that NICE normally considered for reimbursement decisions. Capsular release continued to be dominated by MUA in both costs' scenarios. Given that capsular release was dominated in all scenarios, sensitivity analyses around missing data were restricted to the comparison of MUA compared with ESP (Table VI). Both multiple imputation and the mixed model agree that MUA is the costeffective alternative, although mean difference in costs and QALYs changed according to the method. The mixed

Discussion
Main findings. UK FROST is the largest randomized clinical trial to our knowledge to date that provides robust evidence on the cost-effectiveness of common surgical interventions followed by post-procedural physiotherapy, compared with a non-surgical pathway of ESP and steroid injection for the treatment of patients with a frozen shoulder. Participants' health-related quality of life improved with all three treatments during the trial followup. Overall, participants who had MUA accrued more QALYs compared to those who had capsular release and ESP. The greater costs of capsular release make this intervention difficult to justify. In particular, capsular release was dominated by manipulation, with higher mean costs and lower QALYs. Compared to ESP, participants who had capsular release accrued on average more QALYs, but this was not sufficient to support capsular release as a cost-effective alternative to ESP. At a £20,000 per QALY threshold the probability of MUA being cost-effective was high (86%) compared with early structured physiotherapy (13%) and capsular release (0%). Therefore, from an NHS perspective, this is clear evidence that MUA is the most cost-effective option and would represent good value for money. This analysis presents an up-to-date estimate of the cost-effectiveness of three common treatment pathways for the management of frozen shoulder in the NHS setting. The strengths of this study were the pragmatic design and the recruitment of patients from 35 hospitals across a range of rural and urban areas, involving 90 surgeons and 285 physiotherapists. There were minimal exclusions of patients and the rate of crossovers was low. We also used very detailed hospital forms designed for the trial, together with multiple sources of cost data available for the analyses, to permit an exhaustive microcosting to optimize the accuracy of the estimation of the treatment costs. The UK FROST trial, therefore, provides timely and direct evidence of clinical and resource implications for the NHS that may also be generalizable to other healthcare systems that offer these treatment options.
The EQ-5D instrument has been well validated in patients with a frozen shoulder. 19,20 However, a systematic review identified a lack of use of generic preferencebased measures in existing frozen shoulder clinical studies. 7 The elicitation of the EQ-5D-5L from patients with frozen shoulder is another strength of our study, providing further evidence on the impact of this condition on patient's overall health related quality of life.
There are two potential limitations with the analysis. The first relates to the problem of missing data, which is a common issue in economic evaluations nested within clinical trials. We conducted a comprehensive analysis of missing data and a number of sensitivity analyses to test the assumptions we used to impute missing data in our economic models. Sensitivity analyses showed that results were robust to alternative assumptions on missing data, indicating that MUA continued to be a cost-effective use of NHS resources. It is therefore highly unlikely that such assumptions regarding missing data will change the conclusions of our analysis.
The second limitation relates to the length of follow-up, as one year could be argued to be too short to capture the full effects of all the treatments. Clinical effectiveness results showed that at the primary endpoint of 12 months, many participants had improved to nearly full shoulder functioning, with a median overall OSS of 43 (out of 48), compared with an initial median overall OSS of 20 points. 11 It is notable that the difference in OSS scores and the difference in quality of life are found in the same direction, with only a small difference in QALYs observed across groups. It could be argued that there is a possible trend of the capsular release group improving over time, which might continue with longer time follow-up. This could be explained by the timing of the delivery of the interventions. However, additional analysis adjusting for delivery times of interventions confirmed this did not alter the interpretation of the primary findings, which in turn also suggests that it is unlikely that any important difference in QALYs would emerge beyond the trial follow-up. 12 Regarding costs, we are confident that important costs, including costs of complications, have been captured during the trial follow-up. It is important to consider that all three treatment groups received standardized physiotherapy specifically designed for the purposes of the trial. This is likely to have resulted in patients receiving more physiotherapy and possibly steroid injections in the ESP pathway than would be received routinely in the NHS and consequently increased its costs. More physiotherapy, however, was also likely to have been received in both the surgical pathways than that provided in the NHS. Furthermore, the rationale for the number of physiotherapy sessions that patients were encouraged to receive in the ESP intervention was to give every opportunity for the physiotherapy to be effective. Despite this, ESP was not found to be clinically superior compared with the surgical treatments or to be the most cost-effective option to the NHS.
Finally, it should be noted that this study did not take into consideration the economic impact of hydrodilatation. This is because when we undertook a survey of practice to inform the design of UK FROST, only 6% of UK practitioners were using hydrodilatation. Consequently, this was not identified as a priority intervention for evaluation. 39 Its popularity has increased since then, and although hydrodilatation has been compared with manipulation, capsular release, and intra-articular steroid injections, 40,41 evidence of its effectiveness and costeffectiveness is inconclusive.
In summary, to the best of our knowledge there is very limited evidence regarding the cost-effectiveness of the three commonly used treatments for the frozen shoulder that were compared in UK FROST. We found that while our specifically designed non-surgical pathway of ESP and steroid injection was the least costly intervention, MUA was the most cost-effective management pathway for the NHS as the extra cost was good value for money for the benefits gained by patients. Evidence presented from this economic evaluation should help clinicians discuss treatment options with patients during shared decisionmaking and encourage surgeons to use capsular release more selectively when less costly and less invasive interventions fail. 42

Take home message
-UK FROST is the largest randomized clinical trial to date that provides robust evidence on the cost-effectiveness of common interventions for the treatment of adult patients with a frozen shoulder in secondary care: manipulation under anaesthesia (MUA), arthroscopic capsular release (ACR), and physiotherapy with steroid injection.
-While our specifically designed non-surgical pathway of early structured physiotherapy was the least costly intervention, MUA was the most cost-effective option to the NHS. ACR was not cost-effective.

Supplementary material
Additional information about how we handled missing data in the analysis and the impact on cost-effectiveness results.