Clinical effectiveness and cost-effectiveness of surgical options for the management of anterior and/or posterior vaginal wall prolapse: two randomised controlled trials within a comprehensive cohort study results from the PROSPECT Study

Conservative management for women with prolapse

Although there is only one RCT to inform the use of mechanical devices (pessaries or rings), these are often used for women who are unfit for surgery or who wish to avoid surgery. They can be very efficacious, but questions remain about the best type of device, the long-term adverse effects and the use of supplementary treatment such as oestrogen. Further research is required. 8

Conservative physical treatments such as PFMT are also often recommended as first-line management. A recent update of the relevant Cochrane review9 has found some evidence supporting the use of PFMT to reduce prolapse symptoms and severity, as well as benefits for urinary and bowel symptoms.

In addition, vaginal oestrogen treatment can be used to reduce symptoms for postmenopausal women, before or after surgery. The evidence supporting its use is limited and inconclusive. 10

Surgical management for women with anterior or posterior vaginal wall prolapse

The PROSPECT Study compared surgical operations for vaginal wall pelvic organ prolapse:

• anterior vaginal wall prolapse (urethrocele, cystocele, paravaginal defect)

• posterior vaginal wall prolapse (enterocele, rectocele, perineal deficiency).

A woman may present with prolapse of one or both of these sites, and she may be having a primary or a secondary procedure. She may also have a concomitant uterine or vault prolapse or stress UI that requires a continence procedure. For each of these sites there are several alternative traditional surgical techniques, none of which has been properly evaluated in adequately powered multicentre RCTs. Major potential adverse effects include infection, bleeding, mesh exposure and dyspareunia, as well as failure of repair and failure to cure symptoms.

The techniques for performing anterior or posterior repair or implanting mesh or graft can vary widely between gynaecologists. These include the following.

Principal objectives

To determine the effectiveness (including safety) and cost-effectiveness of surgical treatment, primarily in terms of improvement in prolapse symptoms, in women who were having anterior and/or posterior vaginal wall pelvic organ prolapse surgery, separately in two trials:

1. In women who were having a primary prolapse repair, the effects of:

   1. a standard repair versus a standard repair using a non-absorbable or combined mesh inlay and

   2. a standard repair versus a standard repair using a biological graft inlay.

2. In women who were having a repeat prolapse repair, the effects of:

   1. a standard repair versus a standard repair using a non-absorbable or combined mesh inlay and

   2. a standard repair versus a mesh kit procedure.

The two groups are being considered independently because different surgical options are considered to be appropriate for clinical reasons.

Secondary objectives

1. To determine the differential effects on other outcomes, such as urinary, sexual and bowel function, QoL, general health, need for secondary surgery and adverse effects.

2. To identify possible effect modifiers (e.g. different types of mesh, concomitant procedures, age, complex prolapse types).

3. To establish if the findings of the research, including implications for service delivery, training and introduction of mesh, are generalisable to the UK NHS.

This study assessed which of the most frequently employed techniques for the most common types of prolapse (anterior and posterior vaginal wall prolapse) are most clinically effective and safe. The study also assessed cost-effectiveness. This will guide gynaecologists in their surgical practice and purchasers in their choice of provision of health care. Given the number of prolapse procedures currently performed (28,000 annually in the UK) and the anticipated rise in need for such surgery with an ageing population (a twofold increase in the age group at risk in the next 30 years is predicted), the potential cost implications for the health service are considerable. 6

Objective prolapse measurement

We intended that, at baseline and (for randomised women) at 12 months after surgery, women would have objective measurements of their prolapse compartments. Objective prolapse staging was carried out using the POP-Q system. 27 This measures the maximum descent of each of the three prolapse compartments (anterior, posterior and upper) relative to the hymen (at 0 cm): measurements inside the vagina are negative, whereas those outside are positive. A measure of prolapse (classified from stage 0 to 4) was determined for anterior, posterior and uterine/vault, with the leading edge of the most descended compartment used to define overall stage. An algorithm was used to ensure that POP-Q staging was correctly calculated from the component measurements of the POP-Q [Aa, Ba, C, D, Bp, Ap and total vaginal length (TVL)] in which common recording errors (e.g. Ba measurement less than Aa) were corrected or queried. If data were discrepant, they were corrected by consultation with the local hospital records to obtain additional data. If POP-Q data were missing, we accepted the surgeon’s qualitative record of stage, both overall and in individual compartments (i.e. surgeons could specify the stage without giving the POP-Q measurements).

Usually, using the classic Bump et al. 27 criteria for the POP-Q system, any measurement from –1 cm (inside the hymen) to 1 cm outside counts as stage 2. However, we further subdivided stage 2 into prolapse at the hymen or within (–1 cm to 0 cm; stage 2a or less) compared with prolapse at > 0 cm (stage 2b). 28,29 Thus, women were classified as having objective prolapse if the leading edge was at any point outside the hymen (measured at > 0 cm, stage 2b, 3 or 4).

Urinary, bowel and sexual symptoms

Symptoms related to other aspects of pelvic floor dysfunction were measured using the ICI suite of validated questionnaires. 26

Urinary incontinence was assessed using the International Consultation on Incontinence-Urinary Incontinence Short Form (ICIQ-UI-SF). Other urinary symptoms were recorded by the ICIQ-Female Lower Urinary Tract Symptoms (ICIQ-FLUTS). The latter provides subscales for filling, voiding and incontinence symptoms.

The International Consultation on Incontinence Questionnaire (ICIQ)-Bowel Symptom was not finalised when we began PROSPECT. We therefore adapted draft questions to produce a short summary of relevant bowel symptoms. We used similar questions to map on to the ROME criteria to define constipation (Table 1). 30

We assessed vaginal and sexual symptoms using the International Consultation on Incontinence Questionnaire-Vaginal Symptoms (ICIQ-VS). The ICIQ-VS provides a brief and robust measure to assess the impact of vaginal symptoms and associated sexual matters on QoL and outcome of treatment. It provides subscales for vaginal symptoms, sexual matters and the overall impact of vaginal symptoms on QoL. Women were asked if they were sexually active and, if not, whether or not this was because of their vaginal or prolapse symptoms, or for another reason, including no partner. Women’s responses to this question were post-coded to ensure reliability and consistency. Data were included in the analysis of sexual outcomes for women who were sexually active or for women who were sexually inactive because of prolapse symptoms.

Primary trial

Pilot data showed a conservative estimate of the standard deviation (SD) of the primary participant-reported outcome POP-SS at 1 year to be eight units, and we considered a difference in means of two units to be a clinically important difference. The sample size calculation for the Primary trial was, therefore, based on a standardised effect size of 0.25. To detect a difference of 0.25 SDs with 90% power and alpha equal to 0.025 (to maintain the nominal p-value at 0.05 with tests for two comparisons), we planned to follow-up 400 women in each arm of the primary repair RCT (a total of 1200 participants). The sample size was inflated to 1450 participants, which allowed for a dropout rate of 17.5%. A trial of this size is also adequately powered to detect important differences in the economic and secondary outcomes.

Secondary trial

It was estimated that 30% of women requiring anterior and/or posterior repair would receive a secondary or subsequent repair. Therefore, during the proposed time period required for recruiting 1450 women to the primary repair RCT above, it was anticipated that approximately 620 women who were having secondary surgery would be randomised to the secondary repair RCT (assuming the same rate of eligibility and willingness to participate as in the primary repair RCT. The total expected recruitment across both trials was therefore 2070 randomised women.

Pilot data indicated that women who were having secondary repairs have a higher level of symptoms at baseline. Therefore, we considered it to be biologically plausible that these women might show a larger benefit from surgical treatment than women who were having their first repair. We therefore calculated that it would be possible to detect, with 90% power and alpha equal to 0.025, a standardised effect size of 0.38, which equates to three points on the Pelvic Organ Prolapse Symptom scale.

Quality of life (quality-adjusted life-years)

The primary health-economic analysis is based on a cost–utility framework, with results reported as incremental cost per QALY gained. The purpose of a cost–utility analysis is to provide information to health-care decision-makers regarding the scarce allocation of health resources at a health-care level. It allows for a determination of value for money of one treatment approach over another and is used to guide recommendations to UK policy-makers, such as NICE.

The EQ-5D-3L25 generic QoL instrument was administered to all trial participants at baseline and at 6-month, 1-year and 2-year follow-up. The EQ-5D-3L measure divides health status into five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depressions). Each of these dimensions have three levels, so 243 possible health states exist. EQ-5D-3L responses are presented in graphical format, illustrating the percentage of respondents with any or severe problems on each health domain, split by randomised arms of the trial. The results are presented in accordance with EuroQoL guidelines. 25

The responses to the EQ-5D-3L questionnaire were valued using UK general population tariffs, based on the time trade-off technique to generate a utility score for every participant within the trial. 25 QoL data derived from the EQ-5D-3L were combined with mortality data from the trial, using the standard assumption that all participants who have died in the trial will have a utility value of 0 from the date of death to the end of follow-up. QALYs were then calculated on the basis of these assumptions, using an area beneath the curve approach, assuming linear extrapolation of utility between time points.

Resource use and costs

The perspective of the primary economic analysis is that of the NHS. A supplementary analysis presents costs from a wider patient/societal perspective. In all cases, resource use and costs relate to consultations in primary and secondary care which are related to women’s prolapse or prolapse-related symptoms.

Health services costs

The resource-use data were sourced from participant-completed questionnaires and supplemented with data that were post-coded to patient records for secondary care resource use. Post-coding was conducted by checking all reported cases of secondary care resource use against patient notes to verify reported length of stay, category of care use (so, outpatient or inpatient) and to verify that the reported use of care was for issues related to prolapse and not for some other unrelated reason. Data were obtained from the clinical centres for the price of mesh and clinical expert opinion was sought to bridge any data gaps relating to staff requirements for surgery. National average unit costs were applied to resource-use data to generate total costs to the health services. The sources of unit costs were the British National Formulary (BNF) and the NHS Business Services Authority electronic drug tariff online catalogue33 for medications resource use;34 Information Services Division (ISD) Scotland35 and NHS reference costs36 for secondary care resource-use data; and Personal and Social Services Research Unit (PSSRU) unit costs of health and social care for primary care resource-use data. 37 The costs were reported in 2013–14 UK pound sterling (£). The costs incurred in the second year of follow-up were discounted at a rate of 3.5% per annum. The sensitivity analysis explored the impact of varying the discount rate in accordance with NICE recommendations. 38

The resource-use data and costs for the health-economic analysis were broken into the following categories of NHS resource use:

• intervention costs (including costs of completing the surgery, preparation costs and hospital resource-use costs in theatre, based on operation time, staff time and other additional treatments)

• postoperative costs (from surgery to discharge) including time on ward, return to theatre and cost of treating any infections or complications

• inpatient costs (cost of any follow-up operations and length of stay in hospital related to prolapse symptoms, including overnight and day-case admissions)

• outpatient costs (including all outpatient contacts over the trial follow-up)

• primary care costs (including GP contacts, occupational therapist, physiotherapist and nurse contacts)

• medications and other treatments related to treating prolapse and UI symptoms.

Unit costs

Costs to the health services are estimated by combining resource-use data with unit costs of resource use. Table 2 includes a list of all unit costs used in the within-trial economic analysis, together with their source and any assumptions used to develop the unit cost used for analysis. Further details regarding calculations underpinning the unit costs presented in Table 2 are outlined in more detail in Appendix 6. Unit costs applied to the Primary and Secondary trial analyses were similar with the exception of the unit cost of mesh materials to complete the operative procedure.

Intervention costs

The resource-use data required to deliver each intervention were collected prospectively for every participant in the study. The operative details were recorded at the time of surgery (e.g. time in theatre, grade of operating gynaecologist, grade of anaesthetist and grade of surgical supervision if present). The details of concomitant surgery and catheterisation were recorded and incorporated into the costing analysis. The details were sourced from data recorded on the CRFs (see Appendix 3). The data from the CRFs were supplemented with centre-specific data for the costs of mesh products. Each centre was asked to provide information on the mesh products used by each surgeon at their site for each trial intervention. The surgeon-specific data on mesh use were costed using NHS list prices, sourced from participating centres financial departments.

For some cases, we were not able to identify mesh costs directly from the participating surgeons. This resulted in some missing data for mesh costs. In such cases, we imputed mean costs of mesh calculated from those surgeons/centres that provided data. It is possible that there is heterogeneity across surgeons in terms of the size of mesh product used, or within individual surgeons, who may use different mesh sizes on a case-by-case basis. Where possible, we have costed the same (or similar) mesh sizes across different mesh products so as to avoid any bias against individual mesh products. It should be noted that the analysis does not seek to make statements about the effectiveness or cost-effectiveness of individual mesh products, but rather seeks to develop an average cost for each arm of the trial, which is relevant and generalisable to clinical practice in the UK.

When data regarding surgical resource use (particularly regarding the number of supplementary staff present during a typical surgical procedure, such as nurses and theatre assistants) were unavailable from formal records, we have made assumptions based on the clinical opinion of experts working on the trial team. When there was uncertainty in the resource-use estimates to complete the intervention, and when any assumptions were required, sensitivity analysis explored the impact of these assumptions on the total intervention cost and on the estimates of cost-effectiveness.

The purpose of the intervention costing analysis was to find an average procedure cost, based on typically used meshes at participating centres. Data on mesh usage were available from the 35 participating centres. Unit costs of mesh usage were also sourced through a separate costing exercise directly from centres, which were asked to provide NHS list prices. When data were missing for individual mesh products at centres, the average of all mesh products within that category (e.g. synthetic mesh) was assumed and applied as the unit cost. A similar approach was taken for biological graft repair.

Inpatient costs over follow-up

As length of stay is one of the secondary outcomes of the trial, we collected detailed data on inpatient length of stay in relation to both the participant’s prolapse surgery and their UI. The hospital-based costs in the immediate aftermath of the surgery (up until date of discharge of the patient) were recorded on the RO CRF (see Appendix 3), eliciting information on whether or not the patient returned to theatre for a procedure-related event within 72 hours of having their operation and if catheterisation was required in the first 10 days postoperatively. Longer-term inpatient resource-use data were collected from the participant-completed questionnaires issued at 6-month, 1-year and 2-year follow-up. When participants reported having a hospital readmission, these were checked against patient records to determine the reason for admission. Furthermore, this post-coding exercise identified any participant reporting errors (e.g. patient confused follow-up surgery with index operation; participant double-counted single admissions on both 1-year and 2-year questionnaires; participant misidentified reason for readmission). The costs of additional surgery related to prolapse and/or urinary leakage were estimated using national tariffs, as well as any other inpatient costs. The data collected from both the 1-year and the 2-year follow-ups were used to inform the economic model extrapolating resource use over the patient’s lifetime.

Outpatient costs

The participant-completed questionnaires were used to determine outpatient contacts related to the women’s prolapse symptoms over follow-up. Again, these were post-coded against patient records to check the accuracy of the data and resolve any discrepancies.

Owing to the post-coding exercises undertaken, we have a high degree of confidence in the estimates of secondary care resource use across the trial for each individual woman returning a questionnaire. Therefore, if a woman did not report a secondary care event, it was assumed that no resource use was incurred. If a woman did not return a questionnaire then data were treated as missing.

Primary care costs

Participants were asked to provide detailed information on contacts with primary care health professionals in relation to their prolapse symptoms and UI (see Appendix 4). This included visits to the GP, practice nurse, occupational therapist and physiotherapist at each follow-up time point.

For primary care resource-use questions that are left blank on a returned participant questionnaire, resource use is assumed to be zero. The reason for this is to ensure the best possible use of the available data to generate a reasonably sized complete case data set for the economic analysis. Sensitivity analysis explored the effect of multiply imputed data. As with the secondary care data, if a participant questionnaire is not returned then data are treated as missing.

Total NHS costs

The total costs from the health services perspective were calculated by summing all intervention treatment and follow-up costs related to the respective prolapse repairs for each participant in the data set. If one of the component costs was missing because of a non-returned questionnaire then that participant was dropped from the complete case analysis. If a component cost was missing for primary care consultations then these data were treated according to the assumptions outlined above. The total NHS costs and individual component costs incurred within the second year were discounted by 3.5%.

Participant- and companion-incurred costs and indirect costs, including opportunity costs of time and travel

Participant resource utilisation comprised three main elements: self-purchased health care; travel costs for making return visit(s) to NHS health care (such as petrol, public transport and parking); and time costs of travelling and attending NHS health care (such as time involved away from usual activities or work). All self-purchased health care relate to treatment purchased for the management or treatment of prolapse-related symptoms. Likewise, time and travel costs relate to time spent travelling to and attending hospital or primary care for prolapse symptoms. Estimation of travel costs required information from participants about the number of visits to, for example, their GP or physiotherapist (estimated from the health-care utilisation questions) and the unit cost of making a return journey to each type of health-care provider (from the participant time and travel cost questionnaire; see Appendix 4).

The cost of participant time was estimated in a similar manner. The participant was asked, in the participant time and travel cost questionnaire, how long they spent travelling to, and attending, their last visit to each type of health-care provider. Participants were also asked what activity they would have been undertaking (e.g. paid work, leisure, housework) had they not attended the health-care provider. They were further asked if they were accompanied by a friend or a relative. If so, their time and travel costs were also incorporated into the analysis. These data are presented in their natural units, for example hours, and also costed using standard economic conventions, using the Department of Transport estimates for the value of work and leisure time. 41 These unit time costs were then combined with the number of health-care contacts derived from the health-care utilisation questions to elicit a total time and travel cost from a patient perspective.

The data collected through the health services resource-use questionnaire were used to estimate the costs of self-purchased health care, including pads bought by the participant, prescription costs and over-the-counter medications. The cost to the participant of any self-purchased health care was collected directly within the questionnaire.

Indirect costs were defined as the production losses resulting from treatment when the participant was unable to return to work or was required to take sick leave due to her prolapse problems. The cost of days lost was estimated using the average UK gross hourly wage in the economy. When a participant’s own reported costs associated with a specific type of health service visit were missing, the mean cost for that type of visit was imputed. Participants completing the annual health resource utilisation questionnaire were asked how many days they were off work in the last 12 months as a result of prolapse symptoms or problems. Questions were asked at both 1-year and 2-year follow-up. The data were recorded as natural units and multiplied by standard economic costings as reported below (see Table 3). The total production losses due to time away from work for non-retirees as a result of prolapse symptoms were estimated and compared across treatment groups.

The unit costs applied to the participant (and companion) time, travel and indirect economic costs data are outlined in Table 3. The unit costs were based on standard economic sources and were inflated, where appropriate, to 2014 values. For the purposes of inflation, we utilised the Cochrane economics group inflation calculator application, using International Monetary Fund-reported inflation data. 44

The data on time and travel costs, participant-incurred medical costs and time away from work or usual activities (to attend medical appointments and as a result of recovery from surgery) were all summed together to generate a total participant cost. The incremental cost differences between groups from a participant perspective were estimated using the same methods outlined in the statistical analysis of economic data detailed in the following section.

Statistical analysis of economic data

The economic analysis was conducted following the intention-to-treat principle. The perspective was predominantly that of the NHS, with a supplementary wider economic and patient perspective conducted. The period of follow-up was 2 years and costs and QALYs in the second year were discounted at a rate of 3.5%. All components of costs were described with the appropriate descriptive statistics where relevant: mean and SD for continuous and count outcomes; numbers and percentages for dichotomous and categorical outcomes (e.g. numbers reporting problems on EQ-5D-3L). All analyses were conducted using Stata^® version 14.1 software (StataCorp LP, College Station, TX, USA).

To investigate the potential for skewed cost data (i.e. a small proportion of participants incurring very high costs), we used GLMs, testing alternative model specifications for appropriate fit to the data. The GLM models allow for heteroscedasticity by selecting and specifying an appropriate distributional family for the data. This family offers alternative specifications to reflect the relationship between the mean and variance of the estimates under consideration. 49,50 Two diagnostic actions were performed to select the most appropriate distributional family: (1) a modified Park test, which identified two potentially viable distributional families for costs, namely Gaussian or gamma, and (2) as a check on the most appropriate model, the Akaike information criterion (AIC) was consulted, which identified a Gaussian model with an identity link as having the lowest AIC score and the most appropriate model fit. This suggests a standard ordinary least squares (OLS) model should be fitted for cost data. The next-best model fit according to the AIC criteria was a gamma regression with log link, and this was explored in sensitivity analysis. Regression models applied to cost components (such as ‘other treatments’ and ‘hospital costs’) in the analyses above are also assumed to follow the same distributional assumptions as the total cost data. A standard OLS model was also identified as the most appropriate model and applied to the analysis of incremental QALY gains. All analyses were conducted using heteroscedastic robust standard errors (SEs).

Analysis models were run to estimate the incremental effect of treatment group on costs and QALYs. Models were adjusted using minimisation covariates (age group, type of prolapse, concomitant continence procedure and concomitant upper compartment prolapse surgery), as well as surgeon and baseline EQ-5D-3L score. 51 For the Secondary trial, using all available data, analyses were further adjusted for randomised stratum. The coefficient on treatment in the respective linear OLS models is taken as the estimate of incremental costs for use in the economic evaluation. 49,50

Overall results of the cost–utility analysis are reported as incremental cost per QALY gained for different treatment arms (relative to standard repair). The cost per QALY is presented using the ICER, calculated as the coefficient of treatment effect on costs divided by the coefficient of treatment effect on QALYs from the respective linear regression models. Estimates of the ICER are then compared with the recommended willingness-to-pay (WTP) decision-making threshold in the UK, currently between £20,000 and £30,000 per QALY gained. 38

We used non-parametric bootstrapping methods to estimate 95% CIs for treatment effects on costs and QALYs, using 1000 repetitions. 52 These were further used to summarise the uncertainty surrounding the estimated ICERs, which was illustrated using:

1. Incremental scatterplots of bootstrapped repetitions for incremental costs and incremental QALY pairs for the respective mesh treatments compared with standard repair. 53,54 Presentation of the bootstrapped iterations of costs and outcomes on the cost-effectiveness plane allows the reader to see the probability of one intervention outperforming another in terms of cost-effectiveness, illustrating the probability of that said intervention falling into each quadrant of the cost-effectiveness plane being (1) less costly and more effective; (2) more costly and less effective; (3) less costly and less effective; or (4) more costly and more effective.

2. The bootstrapped estimates of treatment effect were further used to generate cost-effectiveness acceptability curves (CEACs). 54 CEACs were generated using estimates of net monetary benefit (NMB), generated using the bootstrapped replications, in accordance with the net benefit statistic given in Equation 1:

where ‘QALYs’ and ‘cost’ are the estimated total QALYs and total costs for a treatment strategy and lambda (λ) represents the ceiling ratio of a decision-maker’s WTP for a QALY gained. For the purposes of the base-case analysis, λ is set to £30,000, the upper end of the commonly accepted range of ICERs considered to offer good value for money at NICE. However, for the base-case analyses, a number of alternative threshold values presented at £0, £10,000, £20,000, £30,000 and £50,000 are explored, presented numerically within the tables and visually represented on the CEACs presented. 53,54

The study initially planned to present results as cost per woman cured for the trial-based analyses. However, it is not clear how ‘cure’ should be defined. For example, it may be subjective improvement, anatomical improvement or a change in QoL: these are not always in accord with each other. Although many women experienced improvements in their prolapse symptoms, few achieved a state of being completely symptom free. As we are unable to explicitly define cure for the clinical effectiveness analysis, it would be misleading, therefore, to do so for the economic evaluation. The greatest value to decision-makers in the UK NHS relates to an assessment of cost per QALY gained, which is the primary economic outcome and has been used as the basis of all the economic analyses.

Deterministic sensitivity analyses

Although the presentation of CEACs and scatterplots addresses the issue of sampling uncertainty in the data, other assumptions surrounding the most appropriate discount rate and analysis models undertaken may create additional uncertainty, which are not captured in the presented CEACs. Furthermore, the impact of missing data on cost-effectiveness outcomes is explored. All sensitivity analyses (other than the use of imputed data sets) were conducted using complete case 2-year follow-up data for total cost and QALY pairs.

Missing data

We have used a combination of pragmatic and statistical approaches to deal with missing data. Pragmatic approaches have been outlined through this chapter where relevant and were applied to all base-case analyses. As base analyses were conducted using complete case data for cost and QALY pairs, there was a substantial proportion of missing data. This can pose significant problems for data analysis, especially surrounding data reported using participant-completed questionnaires. Therefore, we have undertaken statistical MI of missing data as a sensitivity analysis. The imputation analysis was undertaken using Stata’s multiple imputation (MI) procedure. 55 Missing component costs (e.g. cost of primary care, outpatient care) and utility values were imputed at each questionnaire time point (6 months, 1 year and 2 years).

Components of cost data were imputed, based on linear regression models that were adjusted for minimisation variables, baseline utility and treatment allocation group. Missing utility values were imputed using predictive mean matching, accounting for the five closest estimates. Chained equations were used for the imputations. The imputation procedure predicted 10 plausible alternative imputed data sets, which was found to be sufficient to provide stable estimates. An analysis of incremental costs and outcomes was undertaken across the 10 imputed data sets and combined to generate one imputed estimate of incremental costs and QALYs.

We also explore the impact of changing the discount rate used for second-year costs and QALYs in accordance with NICE best practice recommendations, ranging the discount rate from 0% to 6% per annum. Furthermore, to ensure comparability of our economic analysis with the clinical effectiveness analyses presented in following chapters, we have conducted a secondary analysis for trial-based cost-effectiveness using data from all of the women randomised to the Primary trial arm.

All of the analysis methods for base case, uncertainty and sensitivity analyses were conducted similarly for both the Primary trial analyses (see Chapter 5) and Secondary trial analyses (see Chapter 7) unless otherwise stated. As noted at the outset, the main difference between the economic analyses across the two chapters pertains to the data considered for the base-case analysis. For the base-case Primary trial analysis, we consider RCT1A (women randomised only across the three-way comparison), whereas for the base-case Secondary trial analysis we consider all women who were having a secondary prolapse surgical repair (RCT2).

The study office team

The study office was based at CHaRT in Aberdeen and provided day-to-day support for the clinical centres. It was responsible for all data collection (such as mailing questionnaires), follow-up, data processing and analysis. It was also responsible for randomisation and communicating with the centres about PROSPECT-specific issues. PROSPECT newsletters were developed for participants and collaborators to inform everyone of progress and maintain enthusiasm.

The PROSPECT Study office team (Aberdeen-based grant-holders and study office members) met formally at least monthly during the course of the study to ensure smooth running and trouble-shooting.

Project Management Group

The study was supervised by the Project Management Group (PMG), which consisted of the grant-holders and representatives from the study office. The PMG met, in person or by teleconference every 3 months on average.

Trial Steering Committee

The study was overseen by an independent TSC. The membership comprised four independent members (see Acknowledgements for membership details), the Chief Investigator and grant-holders. Observers or members of the host university (Aberdeen) and the funders (the NIHR HTA) were invited to attend, as were other members of the PROSPECT Study office. The committee met 11 times between August 2009 and July 2015 at approximately 6-monthly intervals, as decided by the Committee.

Data Monitoring Committee

A separate and independent DMC was convened (see Acknowledgements for membership details) and comprised four members: an academic clinician (as the independent chairperson); a gynaecologist, who was not involved in the trial; a statistician with experience of monitoring accumulating RCT data; and a consumer representative.

The members met once to agree terms of reference (August 2009) and a further five times between September 2011 and September 2014 to monitor accumulating data and oversee safety issues. During the period of recruitment to the study, interim analyses were supplied, in strict confidence, to the DMC, together with any other analyses that the committee requested. In the light of these interim analyses, the DMC would have advised the TSC if, in its view:

1. one of the methods of prolapse surgery had been proven, beyond reasonable doubt, to be different from the control (standard management) for all or some types of women (with respect to either effectiveness or unacceptable safety concerns), and

2. the evidence from the economic data was sufficient to guide a decision from health-care providers about choosing operations.

On each occasion, the DMC recommended continuation of the trial with no change of protocol. All other groups, the TSC, PMG, clinical collaborators and study office team (except the trial statistician, who supplied the confidential analyses) remained ignorant of the interim results considered by the committee.

Prolapse symptoms at baseline

The overall prolapse symptom score (POP-SS) was around 13.5 in the women who were having their first repair [with no difference between the randomised and cohort women (13.7 vs. 13.3; Table 8)] but significantly higher in those having a repeat procedure [with no difference between the randomised and cohort women (14.4 vs. 14.9)]. Using a POP-SS of 0 to indicate absence of symptoms, > 99% of women had at least one symptom. The women who were having a uterine or vault repair only (CC3) had an intermediate score, with a mean POP-SS of 14.5 (see Table 8). The latter group will be further described separately in Chapter 8.

The most common individual prolapse symptom was ‘a feeling of something coming down from or in your vagina’, which was reported in > 90% of women, with two-thirds of women reporting this most or all of the time (Table 9). The QoL score (‘overall, how much do your prolapse symptoms interfere with your everyday life?’) ranged from 6.6 to 7.0 of 10 (see Table 8). About half of the women found the prolapse to pose hygiene problems, and about one in five needed to relieve pressure or discomfort from the prolapse using their fingers (see Table 9). Women had been symptomatic for ≥ 3 years and bothered by their symptoms for about a year less.

Among women having a recent repair, there was a significant difference in duration of symptoms in the cohort women (CC2, 3.8 years) compared with the randomised women (RCT2, 3.8 vs. 2.8 years; p = 0.034).

There were no other differences between any of the groups with respect to:

• duration of prolapse symptoms (the mean duration ranged from 2.8 to 4.3 years)

• duration of bothersome symptoms (the mean ranged from 2.4 to 3.2 years of bother)

• mean prolapse symptom score (the mean ranged from 13.3 to 14.9 out of a maximum score of 28 on the Pelvic Organ Prolapse Symptom scale.

Urinary symptoms at baseline

Using the ICIQ-UI-SF,26 up to 80% of women reported at least some UI; however, 20–23% had more severe leakage based on a higher score (Table 10). The most common type of UI was stress UI: women were counted as symptomatic if they had the symptom ‘most or all of the time’. There were no systematic differences between the groups of women.

Bowel symptoms at baseline

Using ROME58 criteria to define bowel symptoms, around one-quarter or more of the women reported constipation (Table 11). Over one-third had FI, defined as loss of solid or liquid stool, but not including loss of flatus (wind). Three-quarters of the FI was ‘passive,’ defined as ‘not accompanied by bowel urgency’. There were no systematic differences between the groups of women at baseline.

Vaginal and sexual symptoms at baseline

We used the ICI-validated instruments to measure a variety of vaginal and sexual symptoms. These were common, and had important effects on QoL. Although the majority of women were not sexually active, in about 40% of women this was most often attributable to their prolapse symptoms (Table 12). Among the women who were sexually active, or whose reason for no sex life was ‘due to prolapse symptoms’, around 10% had dyspareunia at baseline. There were no systematic differences between the groups of women.

Comparison between women who were having a first repair and those who were having a repeat repair

From Table 5, it might seem that around 11% of women in the primary repair groups (RCT1, CC1) had had previous prolapse surgery, but the compartment that required surgery was the opposite to that which had previously been repaired. The compartment of previous surgery was unknown in 60 women, who were therefore classified as having a first repair.

We identified a number of important demographic and clinical differences between women who were having a primary and a secondary repair. Those having a primary repair were, on average, 2.7 years older than those having a secondary procedure (59.4 years vs. 62.1; p < 0.001; see Table 5).

Among women who were having a primary repair, fewer had had a previous hysterectomy than those having a repeat repair (28% vs. 69%; p < 0.001; see Table 5), and in the repeat repair group, the previous hysterectomy was more likely to have been via the vaginal, rather than abdominal, route. Very few women who were having a primary repair had experienced a previous vault repair (2%), whereas this was more common for women who were having a second repair (13%; p < 0.001; see Table 5). Only 7% of women who were having their first repair had previously had continence surgery, whereas 15% of those having a second procedure had done so (p < 0.001; see Table 5).

Women who were having their first prolapse repair had a slightly lower (better) level of symptoms measured on the Pelvic Organ Prolapse Symptom scale (13.5) compared with those having repeat surgery (14.7; p < 0.001; see Table 8). This was reflected in a higher (better) score for the primary group on the generic QoL scale [EuroQol-5 Dimensions (EQ-5D) 0.71 vs. 0.67; p = 0.001; see Table 5]. Significantly more women who were having their first prolapse operation (64%) had a prolapse beyond the hymen (> 0 cm) than those (55%) having a repeat repair (p = 0.001; see Table 7).

Finally, more than three times as many women who were having a first repair were expected to require a concomitant vaginal hysterectomy (34% vs. 9%), and twice as many were expected to have concomitant continence surgery (12% vs. 6%), compared with those having a repeat repair, whereas women who were having a repeat repair were more likely to require a concomitant vault repair (25% vs. 18% for the primary group; see Table 6).

Summary of findings

The average age for a first prolapse repair was just < 60 years, with women who were having repeat (secondary) surgery being around 2.5 years older (see Table 5). Most women’s babies had been delivered vaginally. Although the mean BMI was < 30 kg/m², 43 morbidly obese women with a BMI of ≥ 40 kg/m² did receive surgery.

Women who were having a repeat repair were more likely to have had a previous vaginal hysterectomy, vault repair or continence surgery. This difference in clinical characteristics justified our initial decision to conduct two separate trials among women who were having a first repair (primary) and a repeat repair (secondary).

Prolapse symptoms and measurements

Most women were expected to have surgery for an anterior vaginal wall prolapse (see Table 6). The majority of women had stage 2 prolapse, whereas around one-third had stage 3 or 4 (see Table 7). When prolapse was redefined as the leading edge beyond the hymen (> 0 cm on POP-Q), around 63% of women had a protruding prolapse: this was most common among women who were randomised in the Primary trial (67% compared with both the Primary CC (61%) and the Secondary women [52% (RCT2), 58% (CC2)].

Women had a high level of prolapse symptomatology, as shown by their POP-SSs, of around 14 out of a maximum score of 28 (see Table 8). The most common symptom was a feeling of something coming down (over 90%; see Table 9). Women who were having repeat surgery were less likely to have prolapse beyond the hymen (see Table 7) but their symptom score was, on average, one point higher (worse) than those having their first repair, and their prolapse-related QoL score was significantly worse (see Table 8).

Other clinical symptoms

Over three-quarters of women had UI, and this was slight or moderate in most cases (see Table 10). Nevertheless, at least one in five women had severe urine leakage, defined using the ICI-UI SF score of ≥ 13, and most of them had stress UI (‘most or all of the time’). However, only around 10% of those with UI having a first repair, and 5% having a repeat repair, were expected to undergo continence surgery (see Table 6); on the other hand, 1 in 20, and 1 in 8, respectively, had already had previous continence surgery (see Table 5).

Around 1 in 10 women had bowel urgency or severe FI, and over one-third of women reported at least occasional faecal leakage, mostly passive (see Table 11). The pattern of bowel problems was remarkably similar in women who were having first or repeat prolapse surgery, and within these groups.

Just over one-third of the women were sexually active at baseline (see Table 12). Around 10% of them reported dyspareunia before surgery: as more women answered this question than the number professing to be sexually active, it can be inferred that some women may have refrained from intercourse because of dyspareunia or other prolapse symptoms. We allowed for this by including the women who were sexually inactive because of prolapse symptoms in the denominator for this analysis. Interestingly, the proportion with dyspareunia was similar in women who were having first or repeat prolapse surgery, around 10–15%.

In summary, there were no important clinical differences between women randomised in PROSPECT, and the comparable CC populations who were not randomised.

Strengths and weaknesses

PROSPECT is the most comprehensive study of women who were having prolapse surgery in the UK. The large number of women (over 3000), centres (35) and recruiting gynaecologists (70), and recruitment of 80% of their patients who had prolapse surgery, ensured that the findings are representative of the majority of general gynaecological practice within the NHS in the UK. The centres were a mix of secondary and tertiary referral hospitals.

We used a tightly defined classification of primary and secondary repair using international recommendations to separate our population of women. Within each group, there were few systematic differences between women who were randomised, and those who were not. On the other hand, there were clear clinical and demographic differences between women who were having a first or a repeat procedure, thus justifying our decision to analyse these groups of women in separate trials.

Our definition of secondary surgery was prespecified to refer to ‘repeat surgery in the same compartment’. This resulted in some women who had a previous repair in another compartment being classified as ‘primary’. Although we do not know the original denominator, we can calculate an approximation of the total number of women who were having any further prolapse surgery: dividing the number of women who were having any repeat repair (n = 674) by the number presenting for a first operation (2474 – 276 = 2198) suggests that the population rate of further surgery is 30.7%, very similar to that published by Olsen et al. 4 for further prolapse surgery in any compartment.

Conflict of interest

The study was not at risk of bias because it was publicly funded, and the investigators did not have personal or professional links with industry. The commercial companies which manufactured the mesh and mesh kits did not provide any funding or material in kind (such as the supply of free materials) to the centres, the surgeons or the investigators.

Choice of validated outcome measures

We chose outcome measures for PROSPECT to reflect international standards57 of reporting and ensure that the findings would be relevant to the needs of all groups that were likely to be affected by the findings, including patients, clinical staff and policy-makers. These outcomes were measured at baseline to provide values for later statistical adjustments. Our primary measure of prolapse symptoms was the subjective woman-reported prolapse symptom scale (Pelvic Organ Prolapse Symptom scale), developed and validated in a variety of populations for both research and in clinical practice. 27 This tool is relevant to women and, arguably, focused on the symptoms that led them to seek treatment.

We used validated instruments to measure secondary urinary and vaginal symptoms. 26 Similar short validated measures for bowel function were not available in the ICI suite of outcome measures when we started our study. We therefore adapted the questions used in the long ICIQ-Bowel Symptom instrument. We are currently validating them. In addition, we adapted some of these bowel function questions to approximate those advocated in the ROME consultation (see Table 1).

The objective assessment of prolapse stage was carried out using the standardised and internationally recognised POP-Q system. 27 Although the majority of women were classed as stage 2, based on the leading edge of the prolapse, some researchers have called into question whether or not this is an appropriate cut-off point for the diagnosis of prolapse. The mismatch between symptoms and objective findings is well recognised. 3,59,60 Based on this argument, Nygaard et al. 28 chose to define objective prolapse as leading edge beyond the hymen (> 0 cm) in a prolapse surgery trial. We have therefore used this cut-off point to dichotomise the ordinal POP-Q findings in the women who had individual measurements recorded at baseline (83% of all women).

Blinding of participants

Clinical baseline data were reported by women before randomisation using self-completed questionnaires. The objective assessment of prolapse stage before surgery was also carried out, as far as possible, by observers who did not have knowledge of the randomised operations, normally before a decision for surgery had been made.

Objective outcome measures

We were able to ascribe a prolapse stage to 93% of women at baseline, although only 83% had at least one recorded measurement on the POP-Q examination. It is difficult to explain why a small minority of women appeared not to have significant prolapse (stage 0 or 1). We can offer a number of suggestions. These measurements may have been recorded:

• without the use of provocation, such as Valsalva manoeuvre or coughing, or

• without the use of position and gravity to demonstrate the maximum descent, or

• at a time when the prolapse was not evident (e.g. in the morning), or

• in theatre under anaesthetic, or

• with a pessary in place, or

• incorrectly.

We did check that the patients’ symptoms were bothersome (according to the Pelvic Organ Prolapse Symptom scale). These women clearly requested surgery, with which their gynaecologists concurred.

During the study we placed emphasis on the importance of accurate recording of stage and compartment using the POP-Q guideline. 27 We hope that demonstration of these few apparently anomalous women will improve clinical practice with respect to selection of women for prolapse surgery, and/or their better assessment.

Women’s characteristics at baseline

There were no important epidemiological or clinical differences between the randomised groups of women, including the EQ-5D-3L (trial 1, trial 2; Table 13) or between the randomised women in RCT1 and the non-randomised in CC1 (see Table 13). In this chapter, the data for the cohort women are provided in the outcome tables for comparison with the randomised groups but they have not been formally statistically compared.

The ages of the recruited women ranged from 24 to 90 years. The mean BMI was < 30 kg/m² for all groups of women but 10% had a BMI of > 35 kg/m². The majority of women were parous: only 1% had not had any deliveries. Most babies had been born by spontaneous vaginal delivery. All of the groups were comparable at baseline.

Regarding previous treatment, 13.1–17.5% were using a vaginal pessary, and 25.8–30.1% had seen a physiotherapist for prolapse symptoms, but rather fewer for UI; and around 1 in 10 had used drugs for UI. Regarding previous prolapse surgery, 8.2–12.9% had prior treatment, but these were all in the compartment opposite to the one now requiring repair. In terms of upper compartment procedures, 23.3–28.8% of women had a prior hysterectomy (more than half of those were via the abdominal route); and 5.4–7.2% had already had continence surgery.

Preoperative prolapse measurements

Women in the randomised groups in each trial were comparable in terms of the maximum descent of the three different prolapse compartments. Using qualitative descriptions of prolapse stage to supplement missing POP-Q data, > 98% of the women had prolapse stage 2 or greater before surgery. For the women who had a quantitative score measured using the POP-Q system, about two-thirds were found to have the leading edge of the prolapse outside the hymen (> 0 cm). Table 14 shows the level of prolapse in the individual compartments.

Prolapse symptoms at baseline

Women had noticed symptoms of prolapse for a mean of 3.3–3.8 years, and had been bothered for 2.4–2.8 years before surgery (Table 15). The Pelvic Organ Prolapse Symptom scale is composed of seven individual prolapse symptoms (each scored from 0 to 4, where 0 is ‘never’ and 4 is ‘all the time’; see Chapter 2). The mean POP-SS ranged from 13.7 to 13.8 out of a maximum score of 28. Almost all women (over 99%) were deemed to be symptomatic using the criterion of scoring at least 1 on the Pelvic Organ Prolapse Symptom scale (see Table 15). The most common symptom was ‘a feeling of something coming down from or in the vagina’, and over 90% of women reported this symptom at least occasionally, whereas about two-thirds had a visible prolapse outside the hymen (see Table 14).

As well as the women in each trial being comparable at baseline for the overall score, there were no systematic differences in any individual prolapse symptoms or other measures of the effect of prolapse on QoL or in modifying women’s behaviour to ameliorate the effects of prolapse.

Urinary symptoms at baseline

The urinary symptoms reported by women were captured using a variety of validated questionnaires and scales from the ICI Modular Questionnaire suite26 (Table 16). Around four in five women had at least some urinary leakage, and this was severe for one in five.

There were no systematic differences between the women in either trial but urinary symptoms were common in women with prolapse.

Bowel symptoms at baseline

We captured a variety of bowel symptoms (Table 17). There were no systematic differences between the randomised groups in terms of frequency of bowel movements, constipation, bowel urgency or FI, or in the effect bowel symptoms had on QoL. Around 30% of the women had constipation (using the ROME30 criteria) and over one-third reported FI at least occasionally.

Vaginal and sexual symptoms at baseline

We used the validated ICIQ-VS and the ICI Sexual Matters instruments to capture aspects of vaginal and sexual function. 26 Between 59.9% and 64.9% of women were not sexually active (Table 18); around one-quarter of these women did not have sexually active partners, and the most common reason in the remainder was ‘due to their prolapse symptoms’. Around 6.6–11.4% of women who answered the question reported pain with intercourse (dyspareunia). There were no systematic differences between the randomised groups in terms of these clinical measures at baseline.

Planned operations

The most common operation (anticipated for three-quarters of women) was anterior repair, with just over half of the women planning to have a posterior repair: of these women, around 30% were having a joint procedure (Table 19). Concomitant surgery included about one-third of the women who were thought to need a vaginal hysterectomy, and a further 12.6–18.2% requiring a vault repair. Finally, 9.5–11.7% were thought to require a continence procedure. There were no differences between the women in different arms of the study (see Table 19).

Surgeons could use any mesh, graft or mesh kit, providing that any synthetic mesh was monofilament macroporous polypropylene and mesh inlays were secured with peripheral sutures.

In line with expectations, most women received the surgery planned. Twenty-three women did not receive surgery at all; reasons were being unfit for surgery, change of patient’s mind, surgeon finding that the prolapse surgery was unnecessary, etc. (see Figure 4). Forty-three women did not have either an anterior or a posterior repair once anaesthetised because the surgeon did not deem it necessary for clinical reasons, and therefore they were unable to receive their randomised allocation (see Figure 4).

Surgery actually received

In both trials, more women had a vaginal hysterectomy in the standard arms than in the intervention arms, but this was not significant. It is possible that knowledge of the allocated intervention influenced the surgery actually performed. However, overall there were no substantial differences between the groups in the panel of operations carried out.

Compliance with randomised allocation

In addition to women who did not have any prolapse surgery (N = 23; see Figure 4) or did not require either an anterior or posterior repair (N = 43), and therefore could not receive their randomised allocation, six women who were randomised to standard repair received mesh (N = 2), graft (N = 2) or mesh kit (N = 2); 66 women who were randomised to synthetic mesh did not receive any (N = 60) or received a biological graft (N = 5) or mesh kit (N = 1); and 63 women who were randomised to biological graft did not receive it (N = 57) or received synthetic mesh (N = 6). In some cases, the reason for these protocol deviations were as a result of the appropriate mesh not being available in theatre or failure to inform the theatre staff in good time.

In trial 1, more women failed to receive their allocated (randomised) intervention in the synthetic mesh arm than in the control standard arm because of a clinical decision by the surgeon that mesh was not required, or because of morbidity or complications. Similarly in trial 2, more women did not receive their allocated biological graft than a standard repair because the surgeon decided that graft was or was not indicated and due to morbidity (see Figure 4).

Serious and related adverse effects in first and second years

The diagnoses in Table 22 are confined to those that met our definition of ‘serious’ (see Chapter 2). An adverse effect (AE) was defined as ‘serious’ (SAE) if it was related to prolapse surgery and resulted in death; was life-threatening; required hospitalisation or prolongation of an existing admission; resulted in significant disability/incapacity; or was otherwise considered medically significant by the investigator. If it did not meet the requirement for ‘serious’ then it was classed as ‘other’.