Hemiarthroplasty and total hip arthroplasty for treating primary intracapsular fracture of the hip: a systematic review and cost-effectiveness analysis

Identification of studies

A comprehensive search was undertaken in October and December 2010 to identify systematically both clinical effectiveness and cost-effectiveness literature comparing THA and HA in patients with fractures of the femoral neck. The search consisted only of combining terms for THA with terms for HA. The MEDLINE search strategy is reported in Appendix 1. The aim of the strategy was to identify all studies that reported on trials comparing THA with HA. No MeSH (medical subject heading) term was used as the only appropriate term, ‘arthroplasty, replacement, hip’ covers both HA and THA. The strategy using the MeSH term therefore retrieved many studies concerning only one of the procedures, e.g. either THA or HA, but few studies covered both, the study design required for the review. This search was developed by the reviewer (CC) and the information specialist (PE).

The following electronic databases and online conference proceedings were searched from inception for published and unpublished research evidence:

• MEDLINE (Ovid) 1950 to December 2010

• EMBASE 1980 to December 2010

• Cumulative Index to Nursing and Allied Health Literature (EBSCO) 1982 to December 2010

• The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects, Health Technology Assessment and NHS Economic Evaluation Database 1991 to December 2010

• Biological Abstracts [via Institute for Scientific Information (ISI) Web of Science] 1969 to December 2010

• Science Citation Index (via ISI Web of Science) 1900 to December 2010

• Social Science Citation Index (via ISI Web of Science) 1956 to December 2010

• Conference Proceedings Citation Index-Science (via ISI Web of Science) 1990 to December 2010

• UK Clinical Trials Research Network and the National Research Register archive up to December 2010

• Current Controlled Trials up to December 2010

• ClinicalTrials.gov up to December 2010.

All citations were imported into Reference Manager Version 12 (Thomson Reuters, CA, USA) software and duplicates were deleted. Titles and abstracts of all unique citations were then double-screened by two reviewers (CC and AS) using the inclusion criteria outlined below. Any discrepancies were resolved by retrieving the full paper. The full papers of all potentially relevant citations were retrieved so that an in-depth assessment concerning inclusion could be made. The reference lists of all included studies and relevant reviews were also screened to identify additional, relevant studies not retrieved by the search of electronic databases.

Inclusion criteria

Outcomes

Follow-up

There was no minimum duration of follow-up.

Study design

Randomised controlled trials (RCTs) only, as a scoping report for this project (HTA 09/108/01) identified at least seven such trials.

Exclusion criteria

Data extraction strategy

Data were extracted independently from all included studies by one reviewer (CC) using a data extraction form developed for this review and piloted on two studies (see Appendix 2). All data extracted were checked thoroughly by a second reviewer (AS) and any discrepancies were resolved by discussion and reference to the full paper.

Quality assessment strategy

The quality assessment of included RCTs was undertaken using appropriate quality assessment criteria. There is no published surgical RCT checklist, so this review applied surgical-quality assessment criteria outlined in a relevant Cochrane review. 21 These are included in the Appendix 3. Critical appraisal was performed by one reviewer (CC) and checked thoroughly by a second reviewer (AS). Any discrepancies or differences were resolved by discussion and reference to the full paper.

Methods of analysis/synthesis

Meta-analysis of trials was performed using RevMan 5.0 (The Nordic Cochrane Centre, Copenhagen, Denmark). For discrete and numerical outcomes, relative risk (RR; also known as risk ratio) and risk difference (RD) were reported with 95% confidence intervals (CIs). For continuous outcomes, weighted mean differences were calculated using the inverse variance and reported with 95% CIs. The studies were appraised in terms of clinical validity and methodological heterogeneity to determine whether or not statistical pooling of trial data within a meta-analysis was appropriate. Where studies were meta-analysed, the more conservative random-effects model was used to account for clinical and methodological variations between trials. 22 Statistical heterogeneity was described using the I² statistic, and potential reasons for any heterogeneity were discussed. The level of heterogeneity was defined as low (< 25%), moderate (25–50%) or high (≥ 50%). 23 Only randomised participants for whom a valid outcome had been evaluated and reported were included in the analysis. 24 The denominators used were determined based on the intention-to-treat principle, i.e. follow-up denominators included individuals who had died, unless an outcome (e.g. hip score) required the patient to respond at a specific point in time (e.g. 1 year). Otherwise, individuals lost to follow-up and therefore without a possible evaluated outcome, e.g. missing data, were excluded. Forest plots are presented for all the analyses in which there was more than one relevant study and sufficient data to undertake a meta-analysis. Results for all analyses, including those of single studies, are presented in summary tables. One comparison is analysed and presented: THA versus HA. Separate analyses were performed both for early follow-up (≤ 1 year), where these data were available, and for all follow-up periods, for the outcomes of dislocations, revisions, any surgery and mortality. The possibility of a difference in outcome for surgical approach, cementing of the prosthesis and the use of unipolar or bipolar prosthesis in hemiarthroplasty has been suggested, but not conclusively addressed, by previous research using randomised trial evidence. 19,21,25,26 Subgroup analyses were therefore performed using Altman and Bland’s27 test of interaction, comparing treatment effects between independent subgroups, applying a method for estimating the ratio of two relative risks. The aim was to determine whether or not differences in outcomes between THA and HA were sensitive to the following potentially confounding variables: approach (anterolateral vs posterior); the use of cement; the use of unipolar or bipolar HA prostheses; and study quality. The subgroups were defined by these variables.

Quantity of research available

The search of electronic databases identified 532 unique citations. After screening, 13 citations representing seven published RCTs satisfied all of the inclusion criteria: Dorr et al. ,28 Skinner et al. ,29 Ravikumar and Marsh,30 Baker et al. ,19 Keating et al. ,2,31 Blomfeldt et al. ,32,33 Macaulay et al. 34–36 and Mouzopoulos et al. 37 An eighth RCT, van den Bekerom et al. ,38 was identified by the clinical advisor (SB) shortly before completion of the report. This study had not been published and catalogued in the databases at the time at which the searches were performed. One further potentially relevant study was excluded because it was unclear whether or not it satisfied the population inclusion criteria (it was published as an abstract only), and it did not report any of the primary outcomes. 39 Three ongoing trials were also identified (ISRCTN70736853, NCT00556842 and NCT01109862). No additional relevant papers were identified from reference tracking. Details of the screening and inclusion process are provided in the PRISMA flow chart (Figure 1).

FIGURE 1.

PRISMA flow diagram: clinical effectiveness. a: Multiple publications, including abstracts.

Summary of studies

Eight RCTs were identified that provided data on primary outcomes comparing THA with HA for adults with displaced intracapsular or subcapital hip fracture (Table 1). 2,19,28–36,37,38 The mean age of participants in the included trials ranged from 69 to 82 years, with an overall age range of 41–96 years. At least 68% of participants in each of the trials were women. The number of participants in the eight trials ranged from 40 to 252. Five studies compared THA with cemented19,31,32,38 or uncemented HA29,30 or with a mixture of both types of prosthesis fixture. 28,34 Mouzopoulos et al. 37 did not report whether or not the prosthesis was cemented or uncemented. 37 The surgery reported in the trials by Baker et al. 19 and Blomfeldt et al. 32 was undertaken using the direct lateral approach; the trials reported by Dorr et al. ,28 Skinner et al. ,29 and Ravikumar and Marsh30 used the posterior approach; and the trials reported by Keating et al. ,31 Macaulay et al. 35 and van den Bekerom et al. 38 used a mixture of the two approaches, depending on surgeon’s choice. The approach used was not reported by Mouzopoulos et al. 37 The time from fracture to treatment was reported in only three trials and ranged from within 24 hours of admission29 to within up to 48 hours of trial entry. 19,31 Dorr et al. ,28 Skinner et al. ,29 Baker et al. ,19 Blomfeldt et al. ,32 Macaulay et al. ,35 Mouzopoulos et al. 37 and van den Bekerom et al. 38 all reported follow-up data on a primary outcome for up to 1 year, and Dorr et al. ,28 Ravikumar and Marsh,30 Baker et al. ,19 Keating et al. ,31 Mouzopoulos et al. 37 and van den Bekerom et al. 38 all reported data on these outcomes for follow-up points > 1 year. Some trials reported primary and secondary outcome data for a number of different follow-up periods.

Quality assessment

Randomisation and allocation concealment were considered adequate in the studies by Baker et al. ,19 Blomfeldt et al. ,32 Macaulay et al. ,35 Keating et al. 31 and van den Bekerom et al. 38 (e.g. use of sealed envelopes or a computer-generated randomisation sequence). In the studies by Dorr et al. ,28 Skinner et al. ,29 and Ravikumar and Marsh,30 randomisation was by hospital number only and allocation concealment was not reported. Mouzopoulos et al. 37 reported randomisation to intervention based on selection of every third admission; details of allocation concealment were unreported. All eight RCTs defined inclusion criteria for the study and reported follow-up of at least 1 year (Table 2). Only Dorr et al. 28 did not describe fully or compare intervention groups. van den Bekerom et al. 38 described both groups fully, but did not perform any tests to determine whether or not the differences in terms of cardiovascular, neurological and locomotive comorbidities, the taking of analgesics and pre-operation mobility were statistically significant. Four studies19,31,32,35 clearly conducted intention-to-treat analyses, but this was unclear in the remaining four studies. Baker et al. ,19 Blomfeldt et al. ,32 Mouzopoulos et al. 37 and van den Bekerom et al. 38 also clearly reported comparable care for both intervention groups; this was unclear in the remaining four trials.

Only Blomfeldt et al. 32 reported that the surgeons involved were experienced in both procedures; Baker et al. 19 reported that the surgery in each trial arm was performed by surgeons with similar levels of training; and Keating et al. 31 reported that more patients were treated by consultants/senior surgeons in the THA group than in the HA group. The relative expertise of the surgeons conducting the two procedures was only reported in two studies. 19,38 Only in one study was it clear that the outcome assessors were blind to the intervention. 37 Keating et al. 31 and Macaulay et al. 35 both reported ≤ 5% loss to follow-up, and Blomfeldt et al. 32 reported a loss to follow-up of 6–8% across arms. The remaining studies all had an attrition rate of ≥ 10% or did not report whether or not any loss to follow-up had occurred.

Summary of effectiveness

Numbers of patients experiencing dislocations

Six studies19,28,29,32,35,38 (762 analysed participants) compared numbers of patients with dislocations within or up to 1 year post operation. A meta-analysis demonstrated a borderline statistically significant increased risk of dislocation for those receiving THA compared with HA (RR 3.98, 95% CI 0.98 to 16.12, p = 0.05), with a moderate level of statistical heterogeneity (I² = 46%) (Figure 2 and Table 3). There was a 4% increase in the absolute risk of dislocation for those receiving THA compared with HA (meta-analysed RD 0.04, 95% CI 0.00 to 0.09, p = 0.05, with a high level of statistical heterogeneity (I² = 59%) (see Table 3). The presence of such heterogeneity may be because of the absence, or very small number, of events in some of the trial arms.

FIGURE 2.

Risk of dislocations within and up to 1 year.

TABLE 3 - Relative risks and RD for THA versus HA

Included studies	Number of studies	Follow-up	THA vs HA	RR (95% CI)	I2 (%)	RD (95% CI)	I2 (%)
Dislocations
Dorr et al.,28 Skinner et al.,29 Baker et al.,19 Blomfeldt et al.,32 Macaulay et al.,35 van den Bekerom et al.38	6	≤ 1 year	26/360 vs 10/402	3.98 (0.98 to 16.12), p = 0.05	46	0.04 (0.00 to 0.09), p = 0.05	59
Dorr et al.,28 Ravikumar and Marsh,30 Baker et al.,19 Keating et al.,31 Blomfeldt et al.,32 Macaulay et al.,35 van den Bekerom et al.38	7	Up to 13 years	40/429 vs 16/471	2.40 (1.41 to 2.76), p = 0.01	13	0.05 (0.00 to 0.09), p = 0.03	64
Revisions
Skinner et al.,29 Blomfeldt et al.,32 Macaulay et al.,35 Mouzopoulos et al.,37 van den Bekerom et al.38	5	≤ 1 year	5/320 vs 15/349	0.41 (0.16 to 1.03), p = 0.06	0	–0.02 (–0.06 to 0.02), p = 0.35	64
Dorr et al.,28 Ravikumar and Marsh,30 Baker et al.,19 Blomfeldt et al.,32 Macaulay et al.,35 Mouzopoulos et al.,37 van den Bekerom et al.38	7	Up to 13 years	12/399 vs 42/440	0.31 (0.17 to 0.59), p = 0.0003	0	–0.05 (–0.12 to 0.01), p = 0.09	80
Any surgery
Skinner et al.,29 Blomfeldt et al.,32 Macaulay et al.,35 Mouzopoulos et al.,37 van den Bekerom et al.38	5	≤ 1 year	24/320 vs 22/349	1.72 (0.41 to 7.21), p = 0.46	56	0.01 (–0.04 to 0.07), p = 0.61	57
Dorr et al.,28 Ravikumar and Marsh,30 Baker et al.,19 Keating et al.,31 Blomfeldt et al.,32 Macaulay et al.,35 Mouzopoulos et al.,37 van den Bekerom et al.38	8	Up to 13 years	50/468 vs 54/509	1.09 (0.65 to 1.83), p = 0.75	33	0.01 (–0.04 to 0.05), p = 0.74	40
Mortality
Skinner et al.,29 Blomfeldt et al.,32 Keating et al.,31 Mouzopoulos et al.,37 van den Bekerom et al.38	5	≤ 1 year	50/376 vs 58/400	0.91 (0.65 to 1.29), p = 0.60	0	–0.01 (–0.05 to 0.04), p = 0.75	0
Ravikumar and Marsh,30 Baker et al.,19 Keating et al.,31 Blomfeldt et al.,32 Macaulay et al.,35 Mouzopoulos et al.,37 van den Bekerom et al.38	7	Up to 13 years	176/433 vs 180/464	1.03 (0.80 to 1.32), p = 0.81	48	0.00 (–0.07 to 0.07), p = 1.00	52

Seven studies19,28,30–32,35,38 (900 analysed participants) compared the number of patients with dislocations for all follow-up periods post operation, up to 13 years. A meta-analysis demonstrated a statistically significant increased risk of dislocation for those receiving THA compared with HA (RR 2.40, 95% CI 1.41 to 2.76, p = 0.01), with a low level of statistical heterogeneity (I² = 13%) (see Figure 3 and Table 3). The 1-year follow-up data may have also generated a statistically significant difference had the sample been larger. There was a 5% increase in the absolute risk of dislocation for those treated with THA compared with HA (meta-analysed RD 0.05, 95% CI 0.00 to 0.09, p = 0.03), with a high level of statistical heterogeneity (I² = 64%) (see Table 3).

FIGURE 3.

Risk of dislocations up to 13 years.

Number of patients experiencing revision surgery or any surgery

Revisions included revisions because of all causes, including dislocations. Five studies29,32,35,38,39 (669 analysed participants) compared the number of patients who experienced revision surgery within or up to 1 year post operation. A meta-analysis demonstrated a statistically non-significant 59% reduced risk of revision for those receiving THA compared with HA (RR 0.41, 95% CI 0.16 to 1.03, p = 0.06), with no statistical heterogeneity (I² = 0%) (see Figure 4 and Table 3). There was a 2% reduction in the absolute risk of revision for those receiving THA compared with HA (meta-analysed RD –0.02, 95% CI –0.06 to 0.02, p = 0.35), with a high level of statistical heterogeneity (I² = 64%) (see Table 3).

FIGURE 4.

Risk of revision surgery within and up to 1 year.

Seven studies19,28,30,32,35,38,39 (839 analysed participants) compared the numbers of patients who experienced revision surgery for all follow-up periods post operation, up to 13 years. A meta-analysis demonstrated a statistically significant 69% reduced risk of revision for those receiving THA compared with HA (RR 0.31, 95% CI 0.17 to 0.59, p = 0.0003), with no statistical heterogeneity (I² = 0%) (see Figure 5 and Table 3). There was a 5% reduction in the absolute risk of revision for those exposed to THA compared with HA (meta-analysed RD –0.05, 95% CI –0.12 to 0.01, p = 0.09), with a high level of statistical heterogeneity (I² = 80%) (see Table 3).

FIGURE 5.

Risk of revision surgery up to 13 years.

Five studies29,32,35,38,39 (669 analysed participants) compared the number of patients who experienced any form of surgery (including open or closed reduction of a dislocation, revision or surgery for any other cause) within or up to 1 year post operation. A meta-analysis demonstrated a statistically non-significant increased risk of any surgery for those receiving THA compared with HA (RR 1.72, 95% CI 0.41 to 7.21, p = 0.46), with a high level of statistical heterogeneity (I² = 56%) (see Figure 6 and Table 3). There was a 2% increase in the absolute risk of surgery for those receiving THA compared with HA (meta-analysed RD 0.01, 95% CI –0.04 to 0.07, p = 0.61), with a high level of statistical heterogeneity (I² = 57%) (see Table 3).

FIGURE 6.

Risk of any surgery within and up to 1 year.

Eight studies19,28,30–32,35,38,39 (977 analysed participants) compared the number of patients who experienced any surgery for all follow-up periods post operation, up to 13 years. A meta-analysis demonstrated a statistically non-significant increased risk of any surgery for those receiving THA compared with HA (RR 1.09, 95% CI 0.65 to 1.83, p = 0.75), with a moderate level of statistical heterogeneity (I² = 33%) (see Figure 7 and Table 3). There was a 1% increase in the absolute risk of surgery for those receiving THA compared with HA (meta-analysed RD –0.01, 95% CI –0.04 to 0.05, p = 0.74), with a moderate level of statistical heterogeneity (I² = 40%) (see Table 3).

FIGURE 7.

Risk of any surgery up to 13 years.

This analysis combined outcome data on patients with dislocations, revisions (not including dislocated revisions) and, where reported, other non-revision or dislocation surgery. Baker et al. ,19 Macaulay et al. ,35 Mouzopoulos et al. 37 and van den Bekerom et al. 38 reported only dislocation and/or revision event data, and no data on any other surgery. However, the exclusion of these four studies from the analysis, so that only studies reporting data on all three types of possible surgery were included, does not affect the result: RR 1.14, 95% CI 0.57 to 1.26, p = 0.72.

Mortality

Five studies29,31,32,38,39 (767 analysed participants) compared the number of patients who died within and up to 1 year post operation. A meta-analysis demonstrated a non-statistically significant 9% reduced risk of mortality for those treated with THA compared with HA (RR 0.91, 95% CI 0.65 to 1.29, p = 0.60), with no statistical heterogeneity (I² = 0%) (see Figure 8 and Table 3). There was a 1% reduction in the absolute risk difference (meta-analysed RD –0.01, 95% CI –0.05 to 0.04, p = 0.75), with no statistical heterogeneity (I² = 0%) (see Table 3).

FIGURE 8.

Risk of mortality up to 1 year.

Seven studies19,30–32,35,38,39 (888 analysed participants) compared the number of patients who died for all follow-up periods post operation, up to 13 years. A meta-analysis demonstrated a statistically non-significant 4% increased risk of death for those treated with THA compared with HA (RR 1.03, 95% CI 0.80 to 1.32, p = 0.81), with a moderate level of statistical heterogeneity (I² = 48%) (see Figure 9 and Table 3). There was no reduction in the absolute risk difference (meta-analysed RD 0.00, 95% CI –0.07 to –0.07, p = 1.00), with a high level of statistical heterogeneity (I² = 52%) (see Table 3). It is commented that as the time period increases it is expected that the RR of mortality would become nearer to 1 as the patients are elderly and at risk of dying from causes other than those associated with either THA or HA.

FIGURE 9.

Risk of mortality up to 13 years.

Quantity of research available

The search of electronic databases identified 532 unique citations. Seven full papers were retrieved to determine whether or not they were relevant to this review. After screening, four studies satisfied the inclusion criteria. 31,44–46 Details of the screening and inclusion process are provided in the PRISMA flow chart (Figure 10). Three studies used mathematical models to perform an economic evaluation,44–46 and one paper31 reported the costs and utilities collected alongside an RCT.

FIGURE 10.

PRISMA flow diagram – cost-effectiveness.

A review of the cost-effectiveness literature

Four papers were identified as having an economic element, although only one took the form of a cost–utility analysis. This paper46 evaluated a patient population with a displaced femoral neck fracture who were elderly and active and treated in an American setting. All costs associated with the surgical procedure and future revisions were included in a Markov model. The conclusion from the model was that THA was the more cost-effective treatment in the patient population with an expected 1.53 quality-adjusted life-years (QALYs) being provided at a cost of US$3000. The cost per QALY ratio of US$1960 would be viewed as extremely cost-effective using standard UK cost-effectiveness thresholds. 47 It was seen that the key driver of this result was the increased utility associated with patients who had undergone THA compared with those that had HA. These data were taken from Keating et al. ,31 with the difference in utility shown to be significant at 24 months (p = 0.008).

The study by Aleem et al. 45 did not include the costs associated with either surgical procedure and focused on the procedure that produced the greatest patient benefit, which implicitly assumes that costs are equal for THA and HA. The derivation of the utilities used within the model was far from ideal as these were derived from asking surgeons and hypothetical patients to rate model outcomes in terms of 0 (death) to 100 (perfect health), rather than using utilities reported directly from patients and with the derived utilities based on public preferences, using a choice-based method, as recommended by the National Institute for Health and Clinical Excellence (NICE). 47 Additionally, median values were used rather than mean values, which is incorrect in economic evaluations. The authors concluded that arthroplasty produces better patient outcomes than internal fixation and that THA had slightly better outcomes than HA.

The analysis of Iorio et al. 44 reported outcomes in terms of the cost per ambulatory patient at 2 years for four procedures (reduction with internal fixation, unipolar HA, bipolar HA and THA). As such, differences in the quality and length of life of patients during this period were ignored and the paper in essence reports a cost minimisation analysis. The authors concluded that THA was the most cost-effective of the four procedures.

Keating et al. 31 reported the costs and utility consequences from an RCT which compared THA and HA. The authors claim that THA is more cost-effective, but do not provide incremental cost-effectiveness ratios. The data contained within this manuscript could be used to calculate an estimate of the likely cost-effectiveness of THA compared with HA at the duration of follow-up (2 years) and at extrapolated time horizons. The authors of this report undertook this using a simple mathematical model that is detailed later (see Chapter 4, The economic evaluation undertaken within this report).

An assessment of Slover et al. ,46 using the Drummond et al. 48 checklist, is contained in Appendix 4. The remaining three papers with economic elements were not assessed as they were considered less appropriate owing to undertaking either a cost minimisation44 or a benefit maximisation45 approach or simply reported data from an RCT. 31

The economic evaluation undertaken within this report

It was deemed that the Iorio et al. 44 and Aleem et al. 45 studies were too limited to inform the decision problem fully. The paper by Slover et al. 46 was a mathematical model of reasonable quality, but was based on a US setting rather than a UK one. The authors of this report decided to perform an economic evaluation based on the Keating et al. 31 RCT as this had high internal validity and was directly applicable to the study population. If the results from this analysis concurred with those from Slover et al. ,46 and to a lesser extent those of Iorio et al. 44 and Aleem et al. ,45 then this would support the conclusions that THA was more cost-effective than HA. The proposed modelling methodology was discussed with the clinical expert, who deemed that this was an acceptable conceptual model. Given the resource constraints, a decision to employ a simplistic model was undertaken.

The Keating et al. 31 RCT is directly relevant to the decision problem as it was conducted in Scotland and compared the two interventions of interest. The data reported contained the utility of patients at 4, 12 and 24 months using the EQ-5D questionnaire and the mean costs associated with each intervention over the 2-year period. The EQ-5D is the utility measure preferred by NICE. 47 Costs were presented in five categories: initial inpatient episode; hip-related admissions; non-hip-related admissions; total hip-related costs; and total costs. Data concerning the characteristics of the Keating et al. 31 RCT are presented in Table 1. Owing to the direct relevance and high internal validity, the authors believed that these data were more appropriate to populate the economic model than the results produced by the meta-analyses undertaken earlier in this report.

An estimate of the cost-effectiveness of THA compared with HA was calculated assuming that the increased costs associated with THA were normally distributed with a mean of £3010 with a standard error (SE) of £2250. This cost differential is given some support by data from the American 2003 National Inpatient Survey reported in Slover et al. 46 that stated that the average hospital charges for THA compared with HA were US$4409 higher. The costs from Keating et al. 31 were inflated from the 2000–1 price year to a 2007–8 price year,49 resulting in a mean increase in costs associated with THA compared with HA of £3937; the SE of this increase was assumed to increase to £2943. It was assumed that all costs were incurred in the first year and that costs would remain constant for both arms for the remainder of the model. This approach has support in research undertaken by Haentjens et al. ,50 which indicated that the type of surgical procedure (THA or HA) was not associated with differential costs in the year following hospital discharge. Given this methodology, costs were not discounted.

Based on distributions presented in Keating et al. ,31 it was assumed that the EQ-5D increase was 0.09 (SE 0.05), 0.05 (SE 0.05) and 0.16 (SE 0.06) at 4, 12 and 24 months, respectively. It was assumed that there was a linear change from zero to the sampled difference in utility at 4 months, a linear change between the sampled differences at 4 and 12 months and a linear change between the sampled differences at 12 and 24 months. The difference at 24 months was assumed to persist until the end of the modelling horizon. Utilities were discounted at 3.5% per annum as recommended by NICE. 47 In the analyses undertaken, time horizons of 2, 3 and 5 years were assessed as it was believed that the vast majority of patients who were alive at 2 years would survival an additional 3 years.

The incremental cost per QALY of THA was calculated as the incremental cost of THA divided by the incremental QALY. A plot of the modelled utilities is provided in Figure 11 assuming that the midpoint estimates for both THA and HA are correct.

The mortality rates observed within the trial were considered. In the Keating et al. 31 RCT there was a greater proportion of deaths in the HA arm (13%) than in the THA arm (9%), although this was not statistically significant (p = 0.36). These data were pooled to form a risk of mortality in both arms of 11%, and it was assumed that the incremental QALY gain estimated for THA would be reduced by 11% to account for mortality.

FIGURE 11.

The assumed gain in utility associated with THA compared with HA.

In order to preserve consistency between the sampled utility differences when conducting the probabilistic sensitivity analyses, the same random number was used to select from the cumulative distribution function for each time point. This would ensure that if the value sampled for the difference at 4 months was higher than the median; the differences at 12 and 24 months would also be higher than the median value.

For clarity, the parameter values used in the probabilistic sensitivity analyses are given in Table 10.

The results from this model are provided in Table 11 and used 1000 Monte Carlo simulations. It is seen that even when the utility benefits are constrained to the 2-year horizon the cost per QALY is < £30,000. When the time horizon is extrapolated to more realistic values, the cost per QALY decreases, reaching a value < £10,000 with a horizon of only 5 years. This value would be seen as cost-effective under current cost-effectiveness thresholds. 47 It is seen that the results produced within our analyses concur with previous authors44–46 in that THA is likely to be more cost-effective than HA.

The likelihood of THA being more cost-effective than HA can be displayed on a cost-effectiveness acceptability curve; this is shown in Figure 12. All time horizons are shown simultaneously on this figure for brevity; these are different modelling scenarios rather than competing strategies within one decision problem.

FIGURE 12.

Cost-effectiveness acceptability curves depicting the likelihood that THA is more cost-effective than HA.

Limitations of the analyses

It is commented that longer-term consequences, such as the rates of revision and dislocation, have not been considered in this analysis. Data from studies with a follow-up to 13 years indicate that THA is associated with significantly fewer revisions (RR 0.31, 95% CI 0.17 to 0.59; see Table 3), whereas HA is associated with significantly fewer dislocations (RR 2.40, 95% CI 1.21 to 4.76; see Table 3). The impact of these omissions is likely to be unfavourable to THA as clinical advice indicates that the costs and disutility associated with revisions are far greater than those associated with dislocations. As such, this strengthens the conclusions that THA is more cost-effective than HA.

The effect of ageing on the incremental gain in utility has not been considered. There are no data to indicate whether or not the gain would increase, decrease or remain static as patients age; however, it is expected that the results may be more uncertain than presented.

Exploratory sensitivity analyses

Exploratory sensitivity analyses were undertaken assuming that the increased utility associated with THA compared with HA was equal to the midpoint reported by Blomfeldt et al. ,32 which was 0.05 (0.68 for THA and 0.63 for HA). Although this difference was statistically non-significant, the indication from Keating et al. 31 is that there is a real difference in utility. In this sensitivity analysis, the cost per QALY was £44,997, £30,511 and £18,932 at 2, 3 and 5 years, respectively. These values were was not as favourable to THA as the analyses based on Keating et al. ,31 but they still indicate that THA is likely to be more cost-effective than HA assuming a time horizon of ≥ 5 years using standard UK thresholds. 48

However, the authors prefer the data from Keating et al. 31 as this study has a UK setting, has a slightly larger sample size, has a greater follow-up period and is consistent with the values used for increased costs associated with THA.

The cost data from Keating et al. 31 were inflated to 2007–8 prices, and it is uncertain whether or not the costs originally reported would have risen equally for both THA and HA, although it is likely there would have been some correlation regarding costs, such as inpatient costs that would be incurred in each operation.

Additionally, although there is some support for equal costs after the 2-year period,50 it may be that the different rates of revisions and dislocations have a cost implication.

In order to explore the possibility that these incremental costs may differ from that used in the base case, sensitivity analyses were conducted varying the incremental cost of THA compared with HA (Table 12).

These sensitivity analyses indicate that even if the incremental cost of THA compared with HA increased to £8000 then it is likely that THA would still be cost-effective provided that the time horizon was ≥ 5 years, given current cost-effectiveness thresholds. 47

The expected value of perfect information.

The expected value of perfect information (EVPI)51 was calculated for the base-case model, assuming that the funders were prepared to pay a cost of £20,000 per QALY gained. 47 Population EVPI provides the maximum that a funder would be prepared to pay to eliminate all uncertainty in the decision problem and thus know with certainty which option was more cost-effective. If the cost of the research required to provide further information is greater than the population EVPI then the research should not be funded.

The estimated EVPI per patient is given in Table 13 using time horizons of 3 and 5 years. At these time points the adoption decision would be THA. Population EVPI is calculated by the number of patients who are assumed to benefit owing to the greater certainty of which procedure is the more cost-effective.

As previously discussed, the omission of the costs and disutilities associated with revisions and dislocations is likely to strengthen the conclusion that THA is more cost-effective than HA. This would reduce the uncertainty in the decision and therefore it is likely that the EVPI is overestimated.

It is seen that the EVPI decreases as the modelling horizon increases. This is due to the greater certainty that THA is more cost-effective than HA when the time horizon is of larger duration. These values, however, are likely to change when trials currently under way report their findings and the evidence base expands.

Strengths

• This review developed a sensitive search strategy combining only terms for THA and HA, rather than limiting the search further by using terms for population, outcomes or study design. This search identified studies satisfying the inclusion criteria for both clinical effectiveness and cost-effectiveness.

• The search was comprehensive. There were no limitations of language or date (e.g. non-English-language studies have been included), reference tracking was applied to all included studies and an expert was consulted on other potentially relevant studies. Unpublished studies and ongoing trials were also identified. This suggests that the likelihood of publication bias in this review is relatively small.

• The review process: all titles and abstracts of citations retrieved by the search of electronic databases were screened independently for inclusion and exclusion by two reviewers; and all data extraction and quality assessment of included studies were checked thoroughly by two reviewers and any discrepancies identified and resolved.

• The impact of possible confounding variables, such as study quality, surgical approach, the use of cement and unipolar of bipolar prostheses, have been tested for.

• Exploratory modelling has been undertaken that shows that THA is highly likely to be cost-effective compared with HA even when the limitations of the data and methodology are considered. This concurs with previously published economic analyses.

Weaknesses

• Despite efforts to identify all published and unpublished research satisfying the inclusion criteria, publication bias as a result of the non-publication of trials demonstrating no effect cannot be entirely discounted.

• The costs and disutilities associated with revisions and dislocations were not included in the economic evaluation undertaken by the authors. However, this omission strengthens the conclusion that THA is more cost-effective than HA.

4.1 Purpose of the decision to be made

The assessment will address the question: What is the clinical and cost effectiveness of total hip-arthroplasty compared to hemi hip-arthroplasty?

4.2 Clear definition of the intervention

Total hip arthroplasty (THA). THA involves replacing both the femoral head and acetabular articular surface. These prostheses may or may not be cemented into place. 2

4.3 Place of the intervention in the treatment pathway(s)

This review will focus on the use of interventions in the treatment of intracapsular hip fractures.

4.4 Relevant comparators

Hemiarthroplasty (HA). HA involves replacing the femoral head and may be unipolar (generally used for patients with lower functional demands2), or, more recently, the more mobile bipolar, which aims to reduce acetabular erosion. 6 These prostheses may or may not be cemented into place. 2

4.5 Population and relevant sub-groups

Patients eligible for hip replacement due to intracapsular fracture, who are able to give consent and are independently mobile prior to fracture.

4.6 Key factors to be addressed

1. Evaluate the clinical and cost-effectiveness of THA versus HA.

2. Evaluate the safety of THA versus HA.

3. Identify any key areas for further research.

5.1 Population

Adult patients eligible for hip replacement due to intracapsular fracture, who are able to give consent and are independently mobile prior to fracture.

5.2 Intervention

THA.

5.3 Comparator

HA.

5.4 Settings

Secondary care.

5.5 Outcomes

5.6 Follow-up

There is to be no minimum duration of follow-up.

5.7 Study design

Randomised Controlled Trials (RCTs) only, as a scoping report for this project identified seven such trials (09/108/01).

5.8 Search strategy

The search strategy will comprise the following main elements:

• Searching of electronic databases

• Contact with experts in the field

• Scrutiny of bibliographies of retrieved papers.

5.9 Inclusion criteria

The inclusion criteria are as reported in 5.1-5.7 above. Titles and abstracts of all unique citations will be screened independently by two reviewers using the inclusion criteria outlined below. Disagreement will be resolved by consensus, or with reference to a third reviewer when necessary. The full papers of all potentially relevant citations will be retrieved so that an in-depth assessment concerning inclusion could be made. Reference-tracking of all included studies and relevant reviews will also be performed to identify additional, relevant studies not retrieved by the search of electronic databases.

5.10 Exclusion criteria

Reviews of primary studies, and non-RCT evidence which otherwise satisfies the criteria, will not be included in the analysis, but will be retained for discussion and identification of additional trials.

5.11 Data extraction strategy

Data will be extracted independently from all studies by two reviewers using a standardised data extraction form (see Appendix 10.2). Discrepancies will be resolved by discussion, and with reference to a third reviewer if necessary. Authors will also be contacted for relevant missing data, as far as time allows.

5.12 Quality assessment strategy

The quality assessment of included RCTs will be undertaken using an appropriate quality assessment criteria. This is no published surgical RCT checklist, so this review will apply surgical quality assessment criteria outlined in a relevant Cochrane review. 21 These are included in Appendix 10.3. Critical appraisal will be performed by two reviewers independently. Discrepancies will be resolved by discussion, with involvement of a third reviewer when necessary.

5.13 Methods of analysis/synthesis

Data will be tabulated and relative risks (RRs) using both fixed and random effects models will be calculated where possible (if they were not published). 19 Included studies will be combined in a meta-analysis if clinical advice suggests that the included trials are sufficiently, clinically homogenous. Two previous reviews comparing THA with HA have clearly applied different criteria when choosing to combine or not combine included trials, but the rationale behind the approaches taken was not reported in either review. 20,21 Clinical advice will therefore dictate whether trials of unipolar and bipolar, or cemented and uncemented HA can be justifiably combined, and whether trials employing different surgical approaches (anterior or posterior) may be meaningfully combined. Statistical heterogeneity between trials will also be tested using the I² statistic. 19 If clinical advice dictates that the combining of all studies is not appropriate, then sub-group and sensitivity analyses will be performed based on type of prostheses or surgical approach.

6.1 Identifying and systematically reviewing published cost effectiveness studies

The search strategy and sources detailed in Section 5 will be used to identify studies of cost effectiveness. The approach described is very sensitive as no study design filters are being used and will retrieve any relevant cost-effectiveness studies. Identified economic literature will be critically appraised and assessed using the Drummond checklist. 22 Existing cost effectiveness analyses will also be used to identify sources of evidence to inform structural modelling assumptions and parameter values for the economic model.

6.2 Development of a health economic model

A de novo economic evaluation will be constructed, with the primary outcome from the model being an estimate of the incremental cost per additional quality adjusted life year (QALY) gained associated with use of echocardiography for newly diagnosed AF patient. The time horizon of our analysis will be a patient’s lifetime in order to reflect the chronic nature of the disease and potential mortality. The perspective will be that of the National Health Services and Personal Social Services. Both costs and QALYs will be discounted at 3.5%. 23

The model structure will be determined in consultation with clinical experts. It will incorporate the costs of each intervention and that of subsequent events that are dependent on the rates of adverse events associated with intervention. The health impacts of these events will also be simulated, which will allow an analysis of whether THA is more cost effective than HA for selected patient groups. Modelling assumptions will be taken from the literature, supplemented by clinical expert opinion where necessary.

Ideally, health related quality of life estimates will be available from the reviewed literature. In the absence of such evidence, the economic model may use indirect evidence on quality of life from alternative sources. Quality of life data will be reviewed and used to generate the quality adjustment weights required for the model. National sources (e.g. NHS reference costs,24 national unit costs25) as well as the reviewed literature will be used to estimate resource use and costs for use in the economic model.

It is anticipated that there may be limited evidence for some of parameters that will be included in the economic model. Therefore the uncertainty around the parameter estimates will be modelled to take account of this. The uncertainty in the central value for each required parameter will be represented by a distribution, enabling probabilistic sensitivity analysis to be undertaken on the model results. This will allow an assessment of the uncertainty to be made, and the results will be interpreted accordingly. Through expected value of perfect information analysis26 and, if resources allow, expected value of partial perfect information analyses27 we will identify whether further research is valuable, and in which areas further research is likely to be particularly valuable.

TAR Centre

The ScHARR Technology Assessment Group (ScHARR-TAG) undertakes reviews of the effectiveness and cost effectiveness of healthcare interventions for the NHS R&D Health Technology Assessment Programme on behalf of a range of policy makers in a short timescale, including the National Institute for Health and Clinical Excellence. A list of our publications can be found at: http://www.sheffield.ac.uk/scharr/sections/heds/collaborations/scharr-tag/reports.

Much of this work, together with our reviews for the international Cochrane Collaboration, underpins excellence in healthcare worldwide.

Team members’ contributions

Christopher Carroll, Research Fellow, ScHARR: has extensive experience in systematic reviews of health technologies. CC will lead the project and undertake the review of effectiveness. He will co-ordinate the review process, protocol development, abstract assessment for eligibility, quality assessment of trials, data extraction, data entry, data analysis and review development of background information and clinical effectiveness.

Matt Stevenson, Reader in Health Technology Assessment, ScHARR: has extensive experience in performing health technology assessments and has been the lead, or co-author on over ten full Health Technology reports. MS is also a NICE committee member and is the technical director of ScHARR-TAG. MS will construct, operate and interpret the results from the mathematical model.

Alison Scope, Research Associate, ScHARR: has experience in systematic reviews of health technologies. AS will assist CC with the abstract assessment for eligibility, quality assessment of trials, data extraction, data entry and data analysis for the clinical effectiveness review.

Philippa Evans, Systematic Reviews Information Officer, ScHARR: has experience of undertaking literature searches for the ScHARR Technology Assessment Group systematic reviews and other external projects. PE will be involved in developing the search strategy and undertake the electronic literature searches.

Gill Rooney, Project Administrator: will assist in the retrieval of papers and in preparing and formatting the report.

Clinical and expert advisors

Simon Buckley, Consultant, Northern General Hospital, Sheffield: Simon is a consultant surgeon in primary and revision hip and knee arthroplasty. He gained the FRCS (Tr & Orth) qualification in 2000, was previously the Cavendish Hip Fellow in Sheffield, and President of the British Orthopaedic Trainees Association (2001-2002). He is the audit lead for the Orthopaedic department at Sheffield Teaching Hospitals.

10.1 Draft Medline search strategy

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) < 1950 to Present >

Search Strategy:

1. ((femoral adj head) or total hip replacement).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier] (5092)

2. hemiarthroplasty.mp. (1129)

3. (hemi adj5 arthroplasty).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier] (103)

4. hemi hip arthroplasty.mp. (1)

5. 2 or 3 or 4 (1217)

6. 1 and 5 (90)

Prioritisation Group

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Professor Imti Choonara, Professor in Child Health, Academic Division of Child Health, University of Nottingham

   Chair – Pharmaceuticals Panel

3. Dr Bob Coates, Consultant Advisor – Disease Prevention Panel

4. Dr Andrew Cook, Consultant Advisor – Intervention Procedures Panel

5. Dr Peter Davidson, Director of NETSCC, Health Technology Assessment

6. Dr Nick Hicks, Consultant Adviser – Diagnostic Technologies and Screening Panel, Consultant Advisor–Psychological and Community Therapies Panel

7. Ms Susan Hird, Consultant Advisor, External Devices and Physical Therapies Panel

8. Professor Sallie Lamb, Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick

   Chair – HTA Clinical Evaluation and Trials Board

9. Professor Jonathan Michaels, Professor of Vascular Surgery, Sheffield Vascular Institute, University of Sheffield

   Chair – Interventional Procedures Panel

10. Professor Ruairidh Milne, Director – External Relations

11. Dr John Pounsford, Consultant Physician, Directorate of Medical Services, North Bristol NHS Trust

    Chair – External Devices and Physical Therapies Panel

12. Dr Vaughan Thomas, Consultant Advisor – Pharmaceuticals Panel, Clinical

    Lead – Clinical Evaluation Trials Prioritisation Group

13. Professor Margaret Thorogood, Professor of Epidemiology, Health Sciences Research Institute, University of Warwick

    Chair – Disease Prevention Panel

14. Professor Lindsay Turnbull, Professor of Radiology, Centre for the MR Investigations, University of Hull

    Chair – Diagnostic Technologies and Screening Panel

15. Professor Scott Weich, Professor of Psychiatry, Health Sciences Research Institute, University of Warwick

    Chair – Psychological and Community Therapies Panel

16. Professor Hywel Williams, Director of Nottingham Clinical Trials Unit, Centre of Evidence-Based Dermatology, University of Nottingham

    Chair – HTA Commissioning Board

    Deputy HTA Programme Director

HTA Commissioning Board

1. Professor of Dermato-Epidemiology, Centre of Evidence-Based Dermatology, University of Nottingham

2. Department of Public Health and Epidemiology, University of Birmingham

3. Professor of Clinical Pharmacology, Director, NIHR HTA programme, University of Liverpool

1. Professor Ann Ashburn, Professor of Rehabilitation and Head of Research, Southampton General Hospital

2. Professor Peter Brocklehurst, Professor of Women’s Health, Institute for Women’s Health, University College London

3. Professor Jenny Donovan, Professor of Social Medicine, University of Bristol

4. Professor Jonathan Green, Professor and Acting Head of Department, Child and Adolescent Psychiatry, University of Manchester Medical School

5. Professor John W Gregory, Professor in Paediatric Endocrinology, Department of Child Health, Wales School of Medicine, Cardiff University

6. Professor Steve Halligan, Professor of Gastrointestinal Radiology, University College Hospital, London

7. Professor Freddie Hamdy, Professor of Urology, Head of Nuffield Department of Surgery, University of Oxford

8. Professor Allan House, Professor of Liaison Psychiatry, University of Leeds

9. Dr Martin J Landray, Reader in Epidemiology, Honorary Consultant Physician, Clinical Trial Service Unit, University of Oxford

10. Professor Stephen Morris, Professor of Health Economics, University College London, Research Department of Epidemiology and Public Health, University College London

11. Professor Irwin Nazareth, Professor of Primary Care and Head of Department, Department of Primary Care and Population Sciences, University College London

12. Professor E Andrea Nelson, Professor of Wound Healing and Director of Research, School of Healthcare, University of Leeds

13. Professor John David Norrie, Chair in Clinical Trials and Biostatistics, Robertson Centre for Biostatistics, University of Glasgow

14. Dr Rafael Perera, Lecturer in Medical Statisitics, Department of Primary Health Care, University of Oxford

15. Professor Barney Reeves, Professorial Research Fellow in Health Services Research, Department of Clinical Science, University of Bristol

16. Professor Martin Underwood, Professor of Primary Care Research, Warwick Medical School, University of Warwick

17. Professor Marion Walker, Professor in Stroke Rehabilitation, Associate Director UK Stroke Research Network, University of Nottingham

18. Dr Duncan Young, Senior Clinical Lecturer and Consultant, Nuffield Department of Anaesthetics, University of Oxford

1. Dr Tom Foulks, Medical Research Council

2. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

HTA Clinical Evaluation and Trials Board

1. Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick and Professor of Rehabilitation, Nuffield Department of Orthopaedic, Rheumatology and Musculoskeletal Sciences, University of Oxford

2. Professor of the Psychology of Health Care, Leeds Institute of Health Sciences, University of Leeds

3. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

1. Professor Keith Abrams, Professor of Medical Statistics, Department of Health Sciences, University of Leicester

2. Professor Martin Bland, Professor of Health Statistics, Department of Health Sciences, University of York

3. Professor Jane Blazeby, Professor of Surgery and Consultant Upper GI Surgeon, Department of Social Medicine, University of Bristol

4. Professor Julia M Brown, Director, Clinical Trials Research Unit, University of Leeds

5. Professor Alistair Burns, Professor of Old Age Psychiatry, Psychiatry Research Group, School of Community-Based Medicine, The University of Manchester & National Clinical Director for Dementia, Department of Health

6. Dr Jennifer Burr, Director, Centre for Healthcare Randomised trials (CHART), University of Aberdeen

7. Professor Linda Davies, Professor of Health Economics, Health Sciences Research Group, University of Manchester

8. Professor Simon Gilbody, Prof of Psych Medicine and Health Services Research, Department of Health Sciences, University of York

9. Professor Steven Goodacre, Professor and Consultant in Emergency Medicine, School of Health and Related Research, University of Sheffield

10. Professor Dyfrig Hughes, Professor of Pharmacoeconomics, Centre for Economics and Policy in Health, Institute of Medical and Social Care Research, Bangor University

11. Professor Paul Jones, Professor of Respiratory Medicine, Department of Cardiac and Vascular Science, St George‘s Hospital Medical School, University of London

12. Professor Khalid Khan, Professor of Women’s Health and Clinical Epidemiology, Barts and the London School of Medicine, Queen Mary, University of London

13. Professor Richard J McManus, Professor of Primary Care Cardiovascular Research, Primary Care Clinical Sciences Building, University of Birmingham

14. Professor Helen Rodgers, Professor of Stroke Care, Institute for Ageing and Health, Newcastle University

15. Professor Ken Stein, Professor of Public Health, Peninsula Technology Assessment Group, Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth

16. Professor Jonathan Sterne, Professor of Medical Statistics and Epidemiology, Department of Social Medicine, University of Bristol

17. Mr Andy Vail, Senior Lecturer, Health Sciences Research Group, University of Manchester

18. Professor Clare Wilkinson, Professor of General Practice and Director of Research North Wales Clinical School, Department of Primary Care and Public Health, Cardiff University

19. Dr Ian B Wilkinson, Senior Lecturer and Honorary Consultant, Clinical Pharmacology Unit, Department of Medicine, University of Cambridge

1. Ms Kate Law, Director of Clinical Trials, Cancer Research UK

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

Diagnostic Technologies and Screening Panel

1. Scientific Director of the Centre for Magnetic Resonance Investigations and YCR Professor of Radiology, Hull Royal Infirmary

2. Professor Judith E Adams, Consultant Radiologist, Manchester Royal Infirmary, Central Manchester & Manchester Children’s University Hospitals NHS Trust, and Professor of Diagnostic Radiology, University of Manchester

3. Mr Angus S Arunkalaivanan, Honorary Senior Lecturer, University of Birmingham and Consultant Urogynaecologist and Obstetrician, City Hospital, Birmingham

4. Dr Diana Baralle, Consultant and Senior Lecturer in Clinical Genetics, University of Southampton

5. Dr Stephanie Dancer, Consultant Microbiologist, Hairmyres Hospital, East Kilbride

6. Dr Diane Eccles, Professor of Cancer Genetics, Wessex Clinical Genetics Service, Princess Anne Hospital

7. Dr Trevor Friedman, Consultant Liason Psychiatrist, Brandon Unit, Leicester General Hospital

8. Dr Ron Gray, Consultant, National Perinatal Epidemiology Unit, Institute of Health Sciences, University of Oxford

9. Professor Paul D Griffiths, Professor of Radiology, Academic Unit of Radiology, University of Sheffield

10. Mr Martin Hooper, Public contributor

11. Professor Anthony Robert Kendrick, Associate Dean for Clinical Research and Professor of Primary Medical Care, University of Southampton

12. Dr Nicola Lennard, Senior Medical Officer, MHRA

13. Dr Anne Mackie, Director of Programmes, UK National Screening Committee, London

14. Mr David Mathew, Public contributor

15. Dr Michael Millar, Consultant Senior Lecturer in Microbiology, Department of Pathology & Microbiology, Barts and The London NHS Trust, Royal London Hospital

16. Mrs Una Rennard, Public contributor

17. Dr Stuart Smellie, Consultant in Clinical Pathology, Bishop Auckland General Hospital

18. Ms Jane Smith, Consultant Ultrasound Practitioner, Leeds Teaching Hospital NHS Trust, Leeds

19. Dr Allison Streetly, Programme Director, NHS Sickle Cell and Thalassaemia Screening Programme, King’s College School of Medicine

20. Dr Matthew Thompson, Senior Clinical Scientist and GP, Department of Primary Health Care, University of Oxford

21. Dr Alan J Williams, Consultant Physician, General and Respiratory Medicine, The Royal Bournemouth Hospital

1. Dr Tim Elliott, Team Leader, Cancer Screening, Department of Health

2. Dr Joanna Jenkinson, Board Secretary, Neurosciences and Mental Health Board (NMHB), Medical Research Council

3. Professor Julietta Patrick, Director, NHS Cancer Screening Programme, Sheffield

4. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

5. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

6. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Disease Prevention Panel

1. Professor of Epidemiology, University of Warwick Medical School, Coventry

2. Dr Robert Cook, Clinical Programmes Director, Bazian Ltd, London

3. Dr Colin Greaves, Senior Research Fellow, Peninsula Medical School (Primary Care)

4. Mr Michael Head, Public contributor

5. Professor Cathy Jackson, Professor of Primary Care Medicine, Bute Medical School, University of St Andrews

6. Dr Russell Jago, Senior Lecturer in Exercise, Nutrition and Health, Centre for Sport, Exercise and Health, University of Bristol

7. Dr Julie Mytton, Consultant in Child Public Health, NHS Bristol

8. Professor Irwin Nazareth, Professor of Primary Care and Director, Department of Primary Care and Population Sciences, University College London

9. Dr Richard Richards, Assistant Director of Public Health, Derbyshire County Primary Care Trust

10. Professor Ian Roberts, Professor of Epidemiology and Public Health, London School of Hygiene & Tropical Medicine

11. Dr Kenneth Robertson, Consultant Paediatrician, Royal Hospital for Sick Children, Glasgow

12. Dr Catherine Swann, Associate Director, Centre for Public Health Excellence, NICE

13. Mrs Jean Thurston, Public contributor

14. Professor David Weller, Head, School of Clinical Science and Community Health, University of Edinburgh

1. Ms Christine McGuire, Research & Development, Department of Health

2. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

External Devices and Physical Therapies Panel

1. Consultant Physician North Bristol NHS Trust

2. Reader in Wound Healing and Director of Research, University of Leeds

3. Professor Bipin Bhakta, Charterhouse Professor in Rehabilitation Medicine, University of Leeds

4. Mrs Penny Calder, Public contributor

5. Dr Dawn Carnes, Senior Research Fellow, Barts and the London School of Medicine and Dentistry

6. Dr Emma Clark, Clinician Scientist Fellow & Cons. Rheumatologist, University of Bristol

7. Mrs Anthea De Barton-Watson, Public contributor

8. Professor Nadine Foster, Professor of Musculoskeletal Health in Primary Care Arthritis Research, Keele University

9. Dr Shaheen Hamdy, Clinical Senior Lecturer and Consultant Physician, University of Manchester

10. Professor Christine Norton, Professor of Clinical Nursing Innovation, Bucks New University and Imperial College Healthcare NHS Trust

11. Dr Lorraine Pinnigton, Associate Professor in Rehabilitation, University of Nottingham

12. Dr Kate Radford, Senior Lecturer (Research), University of Central Lancashire

13. Mr Jim Reece, Public contributor

14. Professor Maria Stokes, Professor of Neuromusculoskeletal Rehabilitation, University of Southampton

15. Dr Pippa Tyrrell, Senior Lecturer/Consultant, Salford Royal Foundation Hospitals’ Trust and University of Manchester

16. Dr Nefyn Williams, Clinical Senior Lecturer, Cardiff University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Interventional Procedures Panel

1. Professor of Vascular Surgery, University of Sheffield

2. Consultant Colorectal Surgeon, Bristol Royal Infirmary

3. Mrs Isabel Boyer, Public contributor

4. Mr Sankaran Chandra Sekharan, Consultant Surgeon, Breast Surgery, Colchester Hospital University NHS Foundation Trust

5. Professor Nicholas Clarke, Consultant Orthopaedic Surgeon, Southampton University Hospitals NHS Trust

6. Ms Leonie Cooke, Public contributor

7. Mr Seumas Eckford, Consultant in Obstetrics & Gynaecology, North Devon District Hospital

8. Professor Sam Eljamel, Consultant Neurosurgeon, Ninewells Hospital and Medical School, Dundee

9. Dr Adele Fielding, Senior Lecturer and Honorary Consultant in Haematology, University College London Medical School

10. Dr Matthew Hatton, Consultant in Clinical Oncology, Sheffield Teaching Hospital Foundation Trust

11. Dr John Holden, General Practitioner, Garswood Surgery, Wigan

12. Dr Fiona Lecky, Senior Lecturer/Honorary Consultant in Emergency Medicine, University of Manchester/Salford Royal Hospitals NHS Foundation Trust

13. Dr Nadim Malik, Consultant Cardiologist/Honorary Lecturer, University of Manchester

14. Mr Hisham Mehanna, Consultant & Honorary Associate Professor, University Hospitals Coventry & Warwickshire NHS Trust

15. Dr Jane Montgomery, Consultant in Anaesthetics and Critical Care, South Devon Healthcare NHS Foundation Trust

16. Professor Jon Moss, Consultant Interventional Radiologist, North Glasgow Hospitals University NHS Trust

17. Dr Simon Padley, Consultant Radiologist, Chelsea & Westminster Hospital

18. Dr Ashish Paul, Medical Director, Bedfordshire PCT

19. Dr Sarah Purdy, Consultant Senior Lecturer, University of Bristol

20. Dr Matthew Wilson, Consultant Anaesthetist, Sheffield Teaching Hospitals NHS Foundation Trust

21. Professor Yit Chiun Yang, Consultant Ophthalmologist, Royal Wolverhampton Hospitals NHS Trust

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Pharmaceuticals Panel

1. Professor in Child Health, University of Nottingham

2. Senior Lecturer in Clinical Pharmacology, University of East Anglia

3. Dr Martin Ashton-Key, Medical Advisor, National Commissioning Group, NHS London

4. Dr Peter Elton, Director of Public Health, Bury Primary Care Trust

5. Dr Ben Goldacre, Research Fellow, Division of Psychological Medicine and Psychiatry, King’s College London

6. Dr James Gray, Consultant Microbiologist, Department of Microbiology, Birmingham Children’s Hospital NHS Foundation Trust

7. Dr Jurjees Hasan, Consultant in Medical Oncology, The Christie, Manchester

8. Dr Carl Heneghan, Deputy Director Centre for Evidence-Based Medicine and Clinical Lecturer, Department of Primary Health Care, University of Oxford

9. Dr Dyfrig Hughes, Reader in Pharmacoeconomics and Deputy Director, Centre for Economics and Policy in Health, IMSCaR, Bangor University

10. Dr Maria Kouimtzi, Pharmacy and Informatics Director, Global Clinical Solutions, Wiley-Blackwell

11. Professor Femi Oyebode, Consultant Psychiatrist and Head of Department, University of Birmingham

12. Dr Andrew Prentice, Senior Lecturer and Consultant Obstetrician and Gynaecologist, The Rosie Hospital, University of Cambridge

13. Ms Amanda Roberts, Public contributor

14. Dr Gillian Shepherd, Director, Health and Clinical Excellence, Merck Serono Ltd

15. Mrs Katrina Simister, Assistant Director New Medicines, National Prescribing Centre, Liverpool

16. Professor Donald Singer, Professor of Clinical Pharmacology and Therapeutics, Clinical Sciences Research Institute, CSB, University of Warwick Medical School

17. Mr David Symes, Public contributor

18. Dr Arnold Zermansky, General Practitioner, Senior Research Fellow, Pharmacy Practice and Medicines Management Group, Leeds University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Mr Simon Reeve, Head of Clinical and Cost-Effectiveness, Medicines, Pharmacy and Industry Group, Department of Health

3. Dr Heike Weber, Programme Manager, Medical Research Council

4. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

5. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Psychological and Community Therapies Panel

1. Professor of Psychiatry, University of Warwick, Coventry

2. Consultant & University Lecturer in Psychiatry, University of Cambridge

3. Professor Jane Barlow, Professor of Public Health in the Early Years, Health Sciences Research Institute, Warwick Medical School

4. Dr Sabyasachi Bhaumik, Consultant Psychiatrist, Leicestershire Partnership NHS Trust

5. Mrs Val Carlill, Public contributor

6. Dr Steve Cunningham, Consultant Respiratory Paediatrician, Lothian Health Board

7. Dr Anne Hesketh, Senior Clinical Lecturer in Speech and Language Therapy, University of Manchester

8. Dr Peter Langdon, Senior Clinical Lecturer, School of Medicine, Health Policy and Practice, University of East Anglia

9. Dr Yann Lefeuvre, GP Partner, Burrage Road Surgery, London

10. Dr Jeremy J Murphy, Consultant Physician and Cardiologist, County Durham and Darlington Foundation Trust

11. Dr Richard Neal, Clinical Senior Lecturer in General Practice, Cardiff University

12. Mr John Needham, Public contributor

13. Ms Mary Nettle, Mental Health User Consultant

14. Professor John Potter, Professor of Ageing and Stroke Medicine, University of East Anglia

15. Dr Greta Rait, Senior Clinical Lecturer and General Practitioner, University College London

16. Dr Paul Ramchandani, Senior Research Fellow/Cons. Child Psychiatrist, University of Oxford

17. Dr Karen Roberts, Nurse/Consultant, Dunston Hill Hospital, Tyne and Wear

18. Dr Karim Saad, Consultant in Old Age Psychiatry, Coventry and Warwickshire Partnership Trust

19. Dr Lesley Stockton, Lecturer, School of Health Sciences, University of Liverpool

20. Dr Simon Wright, GP Partner, Walkden Medical Centre, Manchester

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Expert Advisory Network

1. Professor Douglas Altman, Professor of Statistics in Medicine, Centre for Statistics in Medicine, University of Oxford

2. Professor John Bond, Professor of Social Gerontology & Health Services Research, University of Newcastle upon Tyne

3. Professor Andrew Bradbury, Professor of Vascular Surgery, Solihull Hospital, Birmingham

4. Mr Shaun Brogan, Chief Executive, Ridgeway Primary Care Group, Aylesbury

5. Mrs Stella Burnside OBE, Chief Executive, Regulation and Improvement Authority, Belfast

6. Ms Tracy Bury, Project Manager, World Confederation of Physical Therapy, London

7. Professor Iain T Cameron, Professor of Obstetrics and Gynaecology and Head of the School of Medicine, University of Southampton

8. Professor Bruce Campbell, Consultant Vascular & General Surgeon, Royal Devon & Exeter Hospital, Wonford

9. Dr Christine Clark, Medical Writer and Consultant Pharmacist, Rossendale

10. Professor Collette Clifford, Professor of Nursing and Head of Research, The Medical School, University of Birmingham

11. Professor Barry Cookson, Director, Laboratory of Hospital Infection, Public Health Laboratory Service, London

12. Dr Carl Counsell, Clinical Senior Lecturer in Neurology, University of Aberdeen

13. Professor Howard Cuckle, Professor of Reproductive Epidemiology, Department of Paediatrics, Obstetrics & Gynaecology, University of Leeds

14. Professor Carol Dezateux, Professor of Paediatric Epidemiology, Institute of Child Health, London

15. Mr John Dunning, Consultant Cardiothoracic Surgeon, Papworth Hospital NHS Trust, Cambridge

16. Mr Jonothan Earnshaw, Consultant Vascular Surgeon, Gloucestershire Royal Hospital, Gloucester

17. Professor Martin Eccles, Professor of Clinical Effectiveness, Centre for Health Services Research, University of Newcastle upon Tyne

18. Professor Pam Enderby, Dean of Faculty of Medicine, Institute of General Practice and Primary Care, University of Sheffield

19. Professor Gene Feder, Professor of Primary Care Research & Development, Centre for Health Sciences, Barts and The London School of Medicine and Dentistry

20. Mr Leonard R Fenwick, Chief Executive, Freeman Hospital, Newcastle upon Tyne

21. Mrs Gillian Fletcher, Antenatal Teacher and Tutor and President, National Childbirth Trust, Henfield

22. Professor Jayne Franklyn, Professor of Medicine, University of Birmingham

23. Mr Tam Fry, Honorary Chairman, Child Growth Foundation, London

24. Professor Fiona Gilbert, Consultant Radiologist and NCRN Member, University of Aberdeen

25. Professor Paul Gregg, Professor of Orthopaedic Surgical Science, South Tees Hospital NHS Trust

26. Bec Hanley, Co-director, TwoCan Associates, West Sussex

27. Dr Maryann L Hardy, Senior Lecturer, University of Bradford

28. Mrs Sharon Hart, Healthcare Management Consultant, Reading

29. Professor Robert E Hawkins, CRC Professor and Director of Medical Oncology, Christie CRC Research Centre, Christie Hospital NHS Trust, Manchester

30. Professor Richard Hobbs, Head of Department of Primary Care & General Practice, University of Birmingham

31. Professor Alan Horwich, Dean and Section Chairman, The Institute of Cancer Research, London

32. Professor Allen Hutchinson, Director of Public Health and Deputy Dean of ScHARR, University of Sheffield

33. Professor Peter Jones, Professor of Psychiatry, University of Cambridge, Cambridge

34. Professor Stan Kaye, Cancer Research UK Professor of Medical Oncology, Royal Marsden Hospital and Institute of Cancer Research, Surrey

35. Dr Duncan Keeley, General Practitioner (Dr Burch & Ptnrs), The Health Centre, Thame

36. Dr Donna Lamping, Research Degrees Programme Director and Reader in Psychology, Health Services Research Unit, London School of Hygiene and Tropical Medicine, London

37. Professor James Lindesay, Professor of Psychiatry for the Elderly, University of Leicester

38. Professor Julian Little, Professor of Human Genome Epidemiology, University of Ottawa

39. Professor Alistaire McGuire, Professor of Health Economics, London School of Economics

40. Professor Neill McIntosh, Edward Clark Professor of Child Life and Health, University of Edinburgh

41. Professor Rajan Madhok, Consultant in Public Health, South Manchester Primary Care Trust

42. Professor Sir Alexander Markham, Director, Molecular Medicine Unit, St James’s University Hospital, Leeds

43. Dr Peter Moore, Freelance Science Writer, Ashtead

44. Dr Andrew Mortimore, Public Health Director, Southampton City Primary Care Trust

45. Dr Sue Moss, Associate Director, Cancer Screening Evaluation Unit, Institute of Cancer Research, Sutton

46. Professor Miranda Mugford, Professor of Health Economics and Group Co-ordinator, University of East Anglia

47. Professor Jim Neilson, Head of School of Reproductive & Developmental Medicine and Professor of Obstetrics and Gynaecology, University of Liverpool

48. Mrs Julietta Patnick, Director, NHS Cancer Screening Programmes, Sheffield

49. Professor Robert Peveler, Professor of Liaison Psychiatry, Royal South Hants Hospital, Southampton

50. Professor Chris Price, Director of Clinical Research, Bayer Diagnostics Europe, Stoke Poges

51. Professor William Rosenberg, Professor of Hepatology and Consultant Physician, University of Southampton

52. Professor Peter Sandercock, Professor of Medical Neurology, Department of Clinical Neurosciences, University of Edinburgh

53. Dr Philip Shackley, Senior Lecturer in Health Economics, Sheffield Vascular Institute, University of Sheffield

54. Dr Eamonn Sheridan, Consultant in Clinical Genetics, St James’s University Hospital, Leeds

55. Dr Margaret Somerville, Director of Public Health Learning, Peninsula Medical School, University of Plymouth

56. Professor Sarah Stewart-Brown, Professor of Public Health, Division of Health in the Community, University of Warwick, Coventry

57. Dr Nick Summerton, GP Appraiser and Codirector, Research Network, Yorkshire Clinical Consultant, Primary Care and Public Health, University of Oxford

58. Professor Ala Szczepura, Professor of Health Service Research, Centre for Health Services Studies, University of Warwick, Coventry

59. Dr Ross Taylor, Senior Lecturer, University of Aberdeen

60. Dr Richard Tiner, Medical Director, Medical Department, Association of the British Pharmaceutical Industry

61. Mrs Joan Webster, Consumer Member, Southern Derbyshire Community Health Council

62. Professor Martin Whittle, Clinical Co-director, National Co-ordinating Centre for Women’s and Children’s Health, Lymington