Paracetamol and Ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 03/09/01. The contractual start date was in December 2004. The draft report began editorial review in January 2008 and was accepted for publication in November 2008. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

None

Copyright statement

© 2009 Queen’s Printer and Controller of HMSO. This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2009 Queen’s Printer and Controller of HMSO

Fever in children

Antipyretics

Temperature reduction can be achieved by physical or pharmacological methods. Physical methods include keeping the child lightly dressed and giving cool drinks. Tepid sponging is not recommended22 because it may cause peripheral vasoconstriction and raise the core temperature higher than that intended by the hypothalamic set point. In this report, we will use the term ‘antipyretic’ to refer to the pharmacological methods.

Cost and frequency of over-the-counter antipyretic use

Table 1 shows that, although European expenditure on over-the-counter purchases of paediatric formulae antipyretics increased overall between 1997 and 2004, sales of paracetamol fell (Boots HealthCare International, Nottingham, UK, personal communication). Anecdotal evidence suggests large differences between nations’ attitudes to the treatment of fever, with for, example, the British using considerably more antipyretics than their Dutch counterparts (Professor Chris Van Weel, University of Nijmegen, the Netherlands, personal communication). Our UK experience is that when children are seen in primary care, they have typically been given one antipyretic, usually paracetamol,10,40 but that ibuprofen is being increasingly used, both with and without paracetamol. While clinical practice varies between institutions, the use of combined therapy in secondary care appears to be widespread.

TABLE 1 - European expenditure (£ millions) on paediatric formulae antipyretics

Year	Paracetamol	Ibuprofen	Total
1997	188	65	253
2004	128	277	405

Figure 1 shows the trends in UK pharmacy purchases of paediatric antipyretic formulae (paracetamol 120 mg/5 ml and ibuprofen 100 mg/5 ml) per 1000 children aged 0–6 years between 1995 and 2005, and suggests that paracetamol use is falling while ibuprofen use appears to be increasing (data source: IMS Health). 41 Average consumption per child aged 0–6 years in 2005 was equivalent to 200 ml of 120 mg/5 ml paracetamol and 100 ml of 100 mg/5 ml ibuprofen. However, these data cannot distinguish analgesic and febrile indications or the extent to which they are used together (alternately or in combination).

FIGURE 1.

UK pharmacy purchases of antipyretics between 1995 and 2005.

Frequency of combined medicine use

Despite the lack of evidence of effectiveness for combined use, which we will summarise below, there is both anecdotal (the authors’ experience) and survey evidence that parents and clinicians are increasingly using both medicines, either simultaneously or alternately. These increases may vary between nations and, although we are not aware of UK-based survey data, data from 1999 show that paracetamol and ibuprofen were used in combination by up to 27% of parents25 in the US and by 8% of parents of children attending an emergency department in the United Arab Emirates. 24 When US paediatricians were surveyed in 1999, 50% said that they routinely advised combined use and 29% thought that this was recommended practice. 39

Antipyretic doses

Two dosing methods are available. ‘Dosing by age’ is probably typically used by parents because the quantities are available on the medicine packaging and this method is easy to use. The more complex but appropriate alternative, typically used in secondary care and to some extent in primary care too, is ‘dosing by weight’. The National Service Framework for children, young people and maternity services79 states that children should receive age-, weight- and development-appropriate medicines and that, in order to reduce medication error and improve dosing, prescribing should be by weight. It also states that, in order to reduce medication error, the intended dose should be prescribed in mg/kg. In common with all paediatric formularies, the BNFC presents all dosing information per kilogram. There is some evidence from a survey of parents attending an American children’s emergency department that dose by weight is more accurate and less likely to lead to dose error. 80 In Israel, 70% of doctors, 70% of nurses and 30% of parents are already dosing by weight. 19 In this section we will describe the differences in total medicine dose a child receives if calculated by weight or age. Figure 2 and Figure 3 show the total medicine doses for paracetamol and ibuprofen, respectively, if calculated by weight (given two extreme and one central weight percentiles) and age. They both show that age calculations produce stepped doses and the differences in total daily doses that are produced between weight and age calculations. They also illustrate that calculations by weight are superior as they are more likely to be consistent with a child’s pharmacokinetics.

FIGURE 2.

Comparison of total daily doses of paracetamol calculated by weight and age.

FIGURE 3.

Comparison of total daily doses of ibuprofen calculated by weight and age.

Summary of the justification for the PITCH study

Aims of the PITCH study

1. To establish the relative clinical effectiveness of both medicines compared with paracetamol and ibuprofen separately for time without fever in the first four hours in children aged between six months and six years presenting to primary care and/or being managed at home.

2. To assess the relative clinical effectiveness of both medicines compared with paracetamol and ibuprofen separately for the relief of fever-associated discomfort at 48 hours post randomisation.

3. To use qualitative methods to optimise the overall trial process and explore parents’ and clinicians’ beliefs about the use, effectiveness and side effects of paracetamol and ibuprofen.

4. To perform an economic evaluation from the perspectives of the NHS and parents comparing the cost and benefits of each treatment.

5. To describe the natural history of fever.

Trial design, funding and approval

The trial was a single-centre (multisite), individually randomised, blinded, three-arm trial comprising paracetamol alone, ibuprofen alone or paracetamol and ibuprofen together. The trial was funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme and started in December 2004 (reference number 03/09/01). The trial was approved by the Bath Research Ethics Committee, UK (reference number 04/Q2001/197), and is registered with the International Standard Randomised Controlled Trial Register (reference number 26362730) and Eudract (number 2004-000160-28).

Participants

According to the original protocol, children were eligible to participate in the study if they were between the ages of 6 months and 5 years and were previously well, but had a fever of between 38°C and 40°C due to any underlying illness that could be managed in the community. Owing to recruitment difficulties, the eligibility criteria were revised and approved seven times during the trial. They expanded to allow the recruitment of previously well children aged between 6 months and 6 years with a nurse-measured temperature of at least 37.8°C and up to 41°C presenting for the first time (for that episode of fever).

Interventions

Study medicines

The intervention was the provision of, and advice to give, the study medicines for up to 48 hours. Consented children were randomised to receive either (a) paracetamol^active and ibuprofen^placebo, (b) paracetamol^placebo and ibuprofen^active or (c) paracetamol^active and ibuprofen^active as Figure 4 demonstrates.

FIGURE 4.

Treatment allocation.

Parents received two medicine bottles and were aware which was nominally paracetamol/placebo and which was ibuprofen/placebo. All liquid suspensions were sugar free and supplied in licensed containers with approved child-resistant caps.

Dose calculation

The dose of study medicines used was calculated by weight, as recommended by the Children’s National Service Framework and the Royal Pharmaceutical Society for Great Britain in the BNFC. These were:

• paracetamol 15 mg/kg repeated every 4–6 hours (maximum of four doses in 24 hours); and

• ibuprofen 10 mg/kg repeated every 6–8 hours (maximum of three doses in 24 hours).

This dosing regimen was chosen because it avoids differential dosing of heavier children compared with lighter children of the same age. The active medicine bottles contained the standard concentrations: 120 mg/5 ml of paracetamol and 100 mg/5 ml of ibuprofen. The volume of suspension per dose was calculated according to the required dose, which the research nurse first calculated to the nearest 0.1 ml, and then confirmed during the process of randomisation.

At the baseline visit and before randomisation, the research nurse weighed the child, undressed to one layer, without nappy or shoes, using scales approved for paediatric use (SECA, UK). The child’s weight was recorded in the CRF to one decimal point. A standard operating procedure (SOP) was developed to estimate the child’s weight if a child could not be weighed (see Appendix 14). The research nurses would abandon randomisation if the child’s weight could not be established and they deemed administration of the study medicines to be unsafe. At the point of randomisation, the research nurse entered the child’s weight (amongst other variables) and the telephone randomisation system used an algorithm to calculate the medicine volumes, rounded down to the nearest 0.5 ml (see Appendix 15). The research nurse checked that this dose corresponded to her calculation and noted this on the child’s CRF. The dose for each medicine was also noted on the medicine bottles and on the patient participation card (Appendix 16).

Administration and timings

The research nurses handled, dispensed and administered the study medicines according to an SOP (see Appendix 17). After randomisation, and in the presence of the nurse, both study medicines (either paracetamol/placebo and ibuprofen/placebo) were given to the child. The first doses were timed to coincide with the child’s next due dose of antipyretic, respectively 4–6 or 6–8 hours after paracetamol or ibuprofen. Suspensions were administered to the nearest 0.5 ml using 10-ml syringes marked at 0.5-ml increments. Parents were given detailed dosing advice to take account of intervention medicines received in the 24 hours prior to randomisation, in order to prevent the maximum 24-hour recommended dose being exceeded.

The order in which the first medicine was administered was determined randomly (see below for details). The time that the medicines were swallowed was recorded using a personalised digital assistant (PDA; Palm, UK), was designated as time zero (t₀). This was used to determine all subsequent data collection times. The details of the administration (which medicine first, dose, volume, indication that the medicines were successfully swallowed/taken) were logged on the symptom diary by the research nurses. For the first 4 hours after administration of the study medicines, termed the ‘efficacy period’, no further medicine should have been given. From 4 to 24 hours, parents were asked to administer the medicines regularly (‘proactive period’), i.e. paracetamol repeated every 4–6 hours and ibuprofen repeated every 6–8 hours. From 24 to 48 hours parents were asked to give the medicines as required (‘reactive period’) in response to the child’s symptoms. Table 2 describes the intervention period. The light and dark grey squares represent the times when paracetamol or ibuprofen were to be administered respectively.

TABLE 2 - Use of the interventions during the first 24 hours

Drug	Hours following randomisation
	0	2	4	6	8	10	12	14	16	18	20 to 24
Paracetamol
Ibuprofen
	⟵‘Efficacy period’⟶			⟵‘Proactive period’⟶

The medicine volumes to be given and the child’s initials, enrolment number and date dispensed were written on the medicine bottles and storage box. At 48 hours, the study medicines were retrieved from the family and weighed. From 48 hours to the day 5 final follow-up, the parents were advised to use over-the-counter medications if needed. The research nurses also offered guidance to the parents regarding what to do in the event of medicine spillage or subsequent vomiting. In addition, all parents were given a standardised advice sheet (Appendix 18) regarding other cooling measures, such as appropriate clothing, ambient temperature and avoiding tepid sponging.

Outcomes

Sample size

In the original protocol the target difference for the time spent without fever in the first 4 hours was 30 minutes (with an assumed standard deviation of 80 minutes82), and that for the binary outcome of scoring ‘normal’ on the discomfort scale at 48 hours was 60% versus 75% [equivalent to an odds ratio (OR) of 2.0]. To detect the latter comparison with 90% power at a two-sided alpha of 0.027 (allowing for multiple comparisons between the combined therapy and each of the two single-therapy groups88) required a total sample size of 747. Recruitment difficulties led to the alternative recruitment methods, namely the ‘remote’ and ‘community’ approaches, and a reduced achievable target sample size. Using a revised standard deviation of 50 minutes based on an analysis of the first 50 outcome measures obtained irrespective of randomisation group, a sample size of 180 conferred 80% power to maintain the original target difference for time without fever with the same two-sided alpha of 0.027. Moreover, attrition and missing thermometry data were at that point both known to be minimal. However, sensitivity to differences in the binary discomfort outcome was reduced considerably, with ORs of just over 4 now detectable with 80% power. The trial was therefore not adequately powered to detect either the original target OR for binary outcomes or, indeed, ORs considered to be plausible.

Randomisation

Blinding

The parents, principal investigator, trial co-ordinator, research nurses and project administrator were all blinded to the study medicines allocated to randomised children throughout the recruitment and analysis periods. All external members (TSC, DMSC) of the trial were also blinded. The trial statistician was aware of group identity but remained blinded to the treatment allocation.

Statistical methods

Economic evaluation

Qualitative process study

Study objective 3 was to use qualitative methods to optimise the trial process and explore parents’ beliefs about the use of antipyretic medicines. It was our original intention that the trial co-ordinator would conduct these interviews once the trial was successfully recruiting. However, recruitment remained problematic, requiring the addition of the remote and community methods, and diverting resources away from the qualitative studies.

To address the qualitative aspect of the trial’s objectives, at least in part, the PITCH team collaborated with a Medical Research Council (MRC)-funded study called QUARTET (Qualitative Research to Improve Recruitment to Randomised Controlled Trials) run at the University of Bristol. The aim of this study was to investigate whether qualitative research methods could be used to increase trial recruitment rates and simultaneously ensure that children receive a well-balanced explanation of the trial, thereby improving the trial process. Specifically, QUARTET focused on how recruiters provided verbal information about the trial to potential children and, from their collaboration with multiple trials, developed general guidelines for good practice. In relation to the PITCH trial, the QUARTET team focused on how the research nurses provided information to the children’s parents.

The data collected from the QUARTET team included information collected during face-to-face interviews with some members of the trial team, namely the principal investigator, the trial co-ordinator and four research nurses. Ten research nurse–parent telephone calls about trial participation, involving three research nurses, were recorded, with parental consent. Finally, observations of local recruitment at two GP practices with two research nurses were also recorded. The QUARTET team analysed these data using qualitative methods in conjunction with up-to-date recruitment CONSORT figures. At two points during the recruitment period, the QUARTET team provided feedback based on these analyses to inform the trial team.

Feedback to the trial team first occurred in November 2006, 22 months into the recruitment period, and overall the feedback was highly positive. The investigators found that the team members were competent, hard-working and strongly committed to seeing that the trial completed successfully, and that they believed that the trial aims were important both clinically and socially. The investigators recognised that, within the team, low recruitment rates were a cause for concern and that proactive strategies to address this had occurred. Analysis of the recruitment figures found that in a large proportion of cases the children of parents approached for possible inclusion were ineligible from the outset because of the absence of fever. It was noted that this difficulty was being countered by employing multiple recruitment strategies. The rate of refusal to participate among parents whose children had a fever and were assumed to be eligible on other criteria was lower. The report concluded that it was encouraging to note that only a minority of ‘remote’ parents decided against participating after being contacted by a study nurse about the trial, possibly due to the endorsement of the trial participation by the child’s clinician. Within the trial team, the QUARTET investigators found that the research nurses reflected regularly on their experiences in an effort to communicate the trial information to parents effectively. It was clear from the recordings of recruiter–parent telephone conversations that they implemented good practice; they provided a balanced explanation of the trial, checks to see how parents felt about the trial, addressed concerns and possible refusals and were approachable and friendly. The QUARTET team recommended that recruiters approach all possible parents, irrespective of previous disappointing experiences with certain groups. It was also observed that asking parents directly to participate was within the rights of the team but, similarly, it was within the parents’ rights to decline if asked. These recommendations were welcomed by the trial team, discussed and implemented.

The QUARTET team organised a feedback workshop in April 2007 to suggest ways in which the research nurses could fine-tune their practice for the last month of recruitment. The final feedback to the trial occurred in May 2007, detailing the feedback from the workshop and an update on the interim report. Finally, the research nurses’ perspectives on involvement with QUARTET was also reported. Again, overall the investigators found that the research nurses were dedicated, hard-working and committed to the success of the trial. They commented that all the research nurses were effective communicators and no substantive problems with information provision to parents were found. The workshop addressed the minor issues previously identified, namely making decisions about parents’ willingness to participate and the issue of not directly asking parents to participate. Further minor issues were identified, for example sympathising with parents and judging whether to make a home visit to potentially eligible children. Examples of good practice were also identified, as was implementation of the previous report’s recommendations. Finally, it was reported that the research nurses and other trial members felt that their interaction with the QUARTET study had made a difference and that the reflection process, feedback, analysis and discussions generated from hearing their parent–recruiter recordings during the workshop had helped.

Natural history of fever

As with the qualitative studies, it had been our intention to recruit febrile children whose parents did not want to use the PITCH study medicines into an observational study to investigate symptom duration and complications. Full research governance and ethics approvals were received for this study, but, due to the trial recruitment challenges, we prioritised resources to the trial.

Nonetheless, we will present the data from all children in the study to provide information regarding symptom duration, treatments and complications. Symptom definitions such as ‘fever’ or ‘cough’ are preferred to disease definitions in the research of acute conditions in primary care,100 because of the inconsistency with which disease labels are used. 101 For consistency, we used the same definition of the ‘recovered child’ as with the economic analyses (see above), i.e. parents reporting that the child was ‘normal’ with respect to discomfort, activity, appetite and sleep and having a temperature less than 37.2°C or ‘returned to normal for that child’. In addition, we recorded the number of children treated with antibiotics subsequent to randomisation and the number admitted to hospital.

Data management

Participants

Letters were sent from the PITCH study office to 68 primary care sites in the Bristol area inviting them to participate in local and/or remote recruitment. Replies were received from 44 sites and those that expressed were sent an information pack was sent. A total of 35 sites agreed to take part in local or remote recruitment. These sites consisted of one WIC, one children’s emergency department, the Avon, Gloucester and Wiltshire NHS Direct, two GP out-of-hours co-operatives and 30 general practices. The first participant was recruited on 17 January 2005 and the last participant completed the study on the 22 May 2007. Early recruitment analysis showed that recruiting children locally yielded a low randomisation rate. Therefore, the remote and community strategies were started in May 2005 and May 2006 respectively. All children randomised to the study were within the correct age range, pyrexial and met all other inclusion criteria. No children withdrew from the study.

The flow of children through the study is shown in Figure 5. It shows the three recruitment methods, the overall numbers ineligible, the numbers for whom eligibility was unknown and that 156 children were randomised. It also shows the very low data attrition rates with respect to the two primary outcomes, time without fever and discomfort.

FIGURE 5.

Overall flow of children through the study.

Local recruitment

Figure 6 shows that total of 3746 research nurse invitations were issued during local recruitment. Of these, 3042 children were known to be ineligible (I), mainly because they were not sufficiently pyrexial (2669). Forty-one potentially eligible children were admitted to hospital, 30 children had parents who did not have a sufficient understanding of English to give informed consent and seven children were living outside the Bristol area. Other potential children were missed because their parents were called through to visit their GP while research nurses were giving information to other parents in the waiting room or because they left the site before the research nurse could make contact. In these cases eligibility was unknown (U). Of the 1288 potential children who were pyrexial, 417 potential children declined. The principal reasons for decline were the commitment required being too great (163) and concerns about the study medicines (79), usually because the parent wanted to use both medicines. Forty-six children had an eligibility status of unknown (U) as they were missed at the site. The total number of children randomised to the trial via local recruitment was 46.

FIGURE 6.

Flow of children through local recruitment. U, eligibility unknown; I, ineligible.

Remote recruitment

Figure 7 shows that a total of 641 children were referred from sites by fax during the course of the study. Of these, 259 children were excluded on the basis that they were not sufficiently pyrexial and 83 children were excluded as they failed to meet other inclusion criteria, including 17 children who were outside the age range of the study, 11 children who were admitted to hospital, five children who had cardiac disease and three children who had renal disease. The study team was unable to make contact with 77 children, and parents of 136 children declined to take part in the study when contacted. The main reason cited for declining to take part was the study time/commitment involved in taking part in the trial and that parents wanted to administer both medicines to children. A total of 83 children were randomised via remote recruitment.

FIGURE 7.

Flow of children through remote recruitment. U, eligibility unknown; I, ineligible.

Community recruitment

Figure 8 shows that a total of 128 calls were received via the community hotline. Of children referred in this way, 37 were excluded because they were apyrexial or were missed due to the study team being unable to make contact. Following the triage process and a home visit, a further 36 children were excluded on the basis of not being sufficiently pyrexial. Seven children declined due to bad timing/study commitment (4) or because of concerns about the study medicines (3). In the case of the last three children, the parents declined to participate because they wanted to use both paracetamol and ibuprofen. Overall, 27 children were randomised via community recruitment.

FIGURE 8.

Flow of children through community recruitment. U, eligibility unknown; I, ineligible.

Numbers analysed – sample size

A total of 156 children were recruited to the trial. Numbers analysed in each group for the time without fever outcome were 52, 51 and 50 in the paracetamol, ibuprofen and combined medicine groups respectively. The number analysed in each group for the discomfort primary outcome was 52. Thus, children were omitted from analyses only if none of the data required were available, and as these were so few in number the influence of missing data on the intention-to-treat analyses was negligible. For example, where the logger was faulty, or the temperature probe had dislodged from the child’s underarm and had recorded implausibly high or low temperatures (as discussed in Chapter 4), the readings were excluded from the analysis.

Baseline data

The three treatment groups had similar baseline characteristics, as shown in Table 4. The majority of the children included in the study were of white ethnicity. Children taking part in the study were of average weight for their age, and there were similar numbers of children in each age category. The majority of children were not on antibiotic treatment at the baseline visit, had not received ibuprofen in the 8 hours prior to randomisation, had been pyrexial for over 24 hours and had not had a previous febrile convulsion. Around one-third of children (equally distributed across treatment arms) had received paracetamol in the 4–6 hours prior to randomisation. Most children were recorded as having some discomfort, or disruption to their activity, sleep or appetite. At baseline, the proportion of children with a discomfort level of ‘not quite normal’ was 60%, 52% and 58% in the paracetamol, ibuprofen and paracetamol and ibuprofen groups respectively. Similarly, 34%, 35% and 27% of children in the paracetamol, ibuprofen and combined treatment group, respectively, reported discomfort levels of ‘some pain/distress’. The potentially influential between-group differences were gender, recruitment method and baseline activity. Although we thought it unlikely they would greatly influence the primary comparisons, we controlled for them in secondary analyses.

Primary outcomes

Secondary outcomes

Planned subgroup analyses

We conducted a pre-planned subgroup analysis employing appropriate interaction terms in the regression models to ascertain any differential effects of the combined compared with single therapies across the following baseline categories: temperature, discomfort, fever duration,antibiotic use, age and a diagnosis of otitis media. The subgroup analyses were carried out on fewer patients than expected and lacked statistical power. Table 10 presents p-values from subgroup analyses for the primary outcomes, which were mostly > 0.2. However, in relation to time without fever in the first 4 hours, these exploratory analyses suggest greater effects for combined therapy in children aged over 18 months (p = 0.14) and those with fever duration of at least 24 hours (p = 0.19). Insufficient numbers of children were diagnosed with otitis media to ascertain any differential effects of the combined compared with single therapies.

Mean temperature by treatment group over 24 hours

Figure 9 shows the mean temperature every 15 minutes by treatment group. The graph is consistent with the tabulated results in demonstrating that ibuprofen and both medicines reduced children’s temperatures faster and for longer than paracetamol in the first 4 hours, and that both medicines were superior to either monotherapy in reducing mean temperatures over 24 hours. The mean temperatures seen in Figure 9 are lower than expected. To counter the possibility that for the combined group this may be due to a liberal range of valid temperatures, allowing inclusion of implausibly low temperatures (for example, if the axillary probe had become partially detached), we carried out a sensitivity analysis excluding temperatures below 33.5°C, 34°C, 34.5°C and 35°C (see Figure 10 and Figure 11). These analyses raised the lowest mean temperatures between 4 and 24 hours, but not the relative positions of the treatment means, showing that these low temperature recordings were equally distributed across the treatment arms. We looked in detail at the small number of children who were reported to be ‘cold to touch’ during the course of the study. Parents of three children in the ibuprofen group and two children in the combined treatment group reported ‘cold’ as an adverse event (see Table 11). One (with pneumonia) had a temperature of 37.5°C at the time and the others had parent-measured temperatures of 36.1°C, 33.5°C, 35.9°C and 35.3°C. These events were all recorded within the first 4 hours of the study, and within 2 hours all temperatures had risen to over 36°C.

FIGURE 9.

Mean temperatures over 24 hours measured by treatment group. aAll children recorded temperatures of > 37.2°C at baseline eligibility assessment, as measured by standard digital axillary thermometry. Delays between this measure and medicine dosing (the median number of minutes between randomisation and giving the first dose of study drug was 8 for paracetamol plus ibuprofen and 9 for paracetamol and for ibuprofen) and differences between digital and data logger thermometry methods mean that, for some children (n = 19), the data logger temperature measured < 37.2°C.

FIGURE 10.

Mean temperatures over 24 hours discarding temperatures below different levels. (a) Temperatures below 35.5°C disregarded. (b) Temperatures below 34.0°C disregarded. (c) Temperarures below 34.5°C disregarded. (d) Temperatures below 35.0°C disregarded.

FIGURE 11.

Treatment group mean temperatures disregarding temperatures below different levels. (a) Paracetamol treatment group. (b) Ibuprofen treatment group. (c) Paracetamol and ibuprofen treatment group.

Adverse events

Adverse events were recorded at 24 hours, 48 hours and at day 5. An adverse event was defined in accordance with the European Clinical Trials Directive 2001/20/EC as a new symptom or a worsening of a pre-existing symptom. Overall, 62% of children experienced one or more adverse events. Table 11 shows that the most common adverse events recorded were diarrhoea and vomiting, and that these were equally distributed across treatment groups.

Serious adverse events

Five children were admitted to hospital because of serious adverse events (SAEs) during the course of their study involvement: one in the paracetamol group, three in the ibuprofen group and one in the combined treatment group.

Economic evaluation

Cost-effectiveness analysis at 48 hours

In Table 14 we show the incremental costs and benefits at 48 hours. Cost is expressed as incremental mean cost per child by group; benefits are expressed as the proportion of children in each group returning to ‘normal for that child’ (based on combining temperature, discomfort, activity, appetite and sleep). The incremental cost-effectiveness ratios (ICERs), comparing each treatment group with each of the other two, are expressed as cost per extra child returning to ‘normal for that child’. From the perspective of the NHS, the dual therapy is cheaper but less effective than either of the two monotherapies, and paracetamol alone is more expensive but more effective than ibuprofen alone. The ICERs all fall in the south-west quadrant of the cost-effectiveness plane. From the parent perspective, paracetamol and ibuprofen together is more expensive and less effective than either of the single treatments. Ibuprofen alone is cheaper but less effective than paracetamol alone. The level of uncertainty around the ICERs is shown by the bootstrapped replications shown on the cost-effectiveness planes in Figure 12. All replications fall in all four quadrants for all comparisons, suggesting that there is little evidence that any treatment choice is more cost-effective than any other. This is reinforced by the cost-effectiveness acceptability curves in Figure 13, in which the probability of one treatment being more cost-effective than another is shown. None of these probabilities reaches 50%.

TABLE 14 - Cost-effectiveness at 48 hours: incremental mean costs and benefits

CI, confidence interval; SD, standard deviation.

Based on complete cases: proportions vary by perspective due to missing data.

	Paracetamol alone	Ibuprofen alone	Paracetamol plus ibuprofen	Paracetamol plus ibuprofen vs paracetamol alone	Paracetamol plus ibuprofen vs ibuprofen alone	Ibuprofen alone vs paracetamol alone
NHS perspective (n = 154)
Mean (SD) total cost (£)	11.33 (23.18)	8.49 (29.13)	8.16 (16.36)
Incremental cost (95% CI) (£)				–3.16 (–11.05 to 4.72)	–0.33 (–9.59 to 8.93)	–2.84 (–13.14 to 7.46)
Proportion (SD) of children returning to ‘normal for that child’a	0.275 (0.451)	0.269 (0.448)	0.235 (0.428)
Incremental benefit (95% CI)				–0.039 (–0.212 to 0.134)	–0.034 (–0.205 to 0.137)	–0.005 (–0.181 to 0.170)
Cost per extra child returning to ‘normal for that child’				£80.70	£9.62	£537.65
Parent perspective (n = 143)
Mean (SD) total cost (£)	23.86 (62.20)	20.60 (58.52)	25.07 (51.60)
Incremental cost (95% CI) (£)				1.20 (–22.20 to 24.60)	4.47 (–17.90 to 26.90)	–3.27 (–27.70 to 21.20)
Proportion (SD) of children returning to ‘normal for that child’a	0.298 (0.462)	0.286 (0.456)	0.234 (0.428)
Incremental benefit (95% CI)				–0.064 (–0.246, 0.119)	–0.052 (–0.231, 0.128)	–0.012 (–0.198, 0.174)
Cost per extra child returning to ‘normal for that child’				£–18.87	£–86.55	£268.78

FIGURE 12.

Cost-effectiveness planes comparing cost with proportion children ‘normal’ at 48 hours.

FIGURE 13.

Cost-effectiveness acceptability curves for NHS and parent perspectives at 48 hours. (a) NHS perspective. (b) Parent perspective

Natural history of fever

Table 4 shows that 37% of children were diagnosed with a ‘non-specific viral infection’, 28% with a respiratory tract infection, 16% with otitis media and 20% with ‘other’ diagnoses. As expected, Table 5 and Table 17 show that fever and associated symptoms resolve in increasing numbers of children with time. Overall, 26% of children ‘recovered’ (or were back to ‘normal for that child’) by 48 hours and 36% by day 5. Discomfort and activity levels normalised before sleep or appetite. Table 17 also shows that increasing numbers of children were being treated with antibiotics as the study progressed, with the highest proportion (45%) being seen at day 5. By this time only a few (8%) were being treated with over-the-counter antipyretics.

As described, there were five children (3%) admitted to hospital, two with pneumonia, two bronchiolitis and one with a severe but unidentified ‘viral illness’. No child was admitted with meningitis and none died.

Other results

Protocol deviations

Data quality

Data quality was assessed by double data entry according to the data quality SOP (see Appendix 28). There was a 2% overall disagreement error rate on all symptom diary data entries and a 1% error rate for CRF data entries. Disagreement for selected baseline and all primary outcome data was overcome by referring to the CRF.

Clinical effectiveness

Cost-effectiveness

Qualitative studies

Natural history of fever

Our data show that by 48 hours one-quarter, and by day 5 around one-third, of children with fever, the majority of whom were seen in primary care, were symptom free. Nearly half were taking antibiotics by day 5, and most were no longer using antipyretics. Three per cent required hospital admission. There are no other UK-based studies investigating the natural history of fever in children presenting to primary care with which to compare our data. One US cohort of children with fever aged up to 3 months recruited by office-based paediatricians found that 36% were admitted to hospital. 105 The higher rates of more severe illness compared with our study are likely to be due to a different illness spectrum presenting to paediatricians as opposed to primary care clinicians and the younger age group. A large study of children aged up to 16 years presenting with any acute, non-trauma-related illness to primary care in Belgium106 found that 0.8% were admitted to hospital. In a study of pre-school children with acute cough presenting to UK primary care, we found that 2% required hospital admission. 107 The proportion of children recovered at day 5 from the same cohort was around 20%. 108 Parents and clinicians should be aware that, overall, fever is a relatively short-lived symptom, but may have more serious prognostic implications than other common symptom presentations. Specific information regarding symptom duration and the potential for hospitalisation may help set realistic parental expectations.

Recruitment challenges

Conclusions

Contribution of authors

A.D.H. had the original idea for the study. A.D.H., A.A.M., S.H., M.F. and T.J.P. designed the trial, drafted the protocol and were responsible for its ongoing conduct. N.M.R. and C.C. were responsible for day-to-day trial management. C.C., A.A.M., S.H. and T.J.P. analysed the data. All authors were involved in data interpretation, drafting the report and have approved the final version.

Publications

Hollinghurst S, Redmond, N Costelloe C, Montgomary A, Fletcher M, Peters TJ, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): economic evaluation of a randomised controlled trial. BMJ 2008;337:a1490.

Hay AD, Costerlloe C, Redmond NM, Montgomery AA, Fletcher M, Hollinghurst, S, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial BMJ 2008; 337:a1302.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Health Technology Assessment reports published to date

1. Home parenteral nutrition: a systematic review.

   By Richards DM, Deeks JJ, Sheldon TA, Shaffer JL.

2. Diagnosis, management and screening of early localised prostate cancer.

   A review by Selley S, Donovan J, Faulkner A, Coast J, Gillatt D.

3. The diagnosis, management, treatment and costs of prostate cancer in England and Wales.

   A review by Chamberlain J, Melia J, Moss S, Brown J.

4. Screening for fragile X syndrome.

   A review by Murray J, Cuckle H, Taylor G, Hewison J.

5. A review of near patient testing in primary care.

   By Hobbs FDR, Delaney BC, Fitzmaurice DA, Wilson S, Hyde CJ, Thorpe GH, et al.

6. Systematic review of outpatient services for chronic pain control.

   By McQuay HJ, Moore RA, Eccleston C, Morley S, de C Williams AC.

7. Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

   A review by Pollitt RJ, Green A, McCabe CJ, Booth A, Cooper NJ, Leonard JV, et al.

8. Preschool vision screening.

   A review by Snowdon SK, Stewart-Brown SL.

9. Implications of socio-cultural contexts for the ethics of clinical trials.

   A review by Ashcroft RE, Chadwick DW, Clark SRL, Edwards RHT, Frith L, Hutton JL.

10. A critical review of the role of neonatal hearing screening in the detection of congenital hearing impairment.

    By Davis A, Bamford J, Wilson I, Ramkalawan T, Forshaw M, Wright S.

11. Newborn screening for inborn errors of metabolism: a systematic review.

    By Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, Cockburn F, et al.

12. Routine preoperative testing: a systematic review of the evidence.

    By Munro J, Booth A, Nicholl J.

13. Systematic review of the effectiveness of laxatives in the elderly.

    By Petticrew M, Watt I, Sheldon T.

14. When and how to assess fast-changing technologies: a comparative study of medical applications of four generic technologies.

    A review by Mowatt G, Bower DJ, Brebner JA, Cairns JA, Grant AM, McKee L.

1. Antenatal screening for Down’s syndrome.

   A review by Wald NJ, Kennard A, Hackshaw A, McGuire A.

2. Screening for ovarian cancer: a systematic review.

   By Bell R, Petticrew M, Luengo S, Sheldon TA.

3. Consensus development methods, and their use in clinical guideline development.

   A review by Murphy MK, Black NA, Lamping DL, McKee CM, Sanderson CFB, Askham J, et al.

4. A cost–utility analysis of interferon beta for multiple sclerosis.

   By Parkin D, McNamee P, Jacoby A, Miller P, Thomas S, Bates D.

5. Effectiveness and efficiency of methods of dialysis therapy for end-stage renal disease: systematic reviews.

   By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M, Daly C, et al.

6. Effectiveness of hip prostheses in primary total hip replacement: a critical review of evidence and an economic model.

   By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M, Bevan G.

7. Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomised controlled trials.

   By Song F, Glenny AM.

8. Bone marrow and peripheral blood stem cell transplantation for malignancy.

   A review by Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA.

9. Screening for speech and language delay: a systematic review of the literature.

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10. Resource allocation for chronic stable angina: a systematic review of effectiveness, costs and cost-effectiveness of alternative interventions.

    By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR, Buxton MJ.

11. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review.

    By Ebrahim S.

12. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review.

    By McQuay HJ, Moore RA.

13. Choosing between randomised and nonrandomised studies: a systematic review.

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14. Evaluating patient-based outcome measures for use in clinical trials.

    A review by Fitzpatrick R, Davey C, Buxton MJ, Jones DR.

15. Ethical issues in the design and conduct of randomised controlled trials.

    A review by Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J.

16. Qualitative research methods in health technology assessment: a review of the literature.

    By Murphy E, Dingwall R, Greatbatch D, Parker S, Watson P.

17. The costs and benefits of paramedic skills in pre-hospital trauma care.

    By Nicholl J, Hughes S, Dixon S, Turner J, Yates D.

18. Systematic review of endoscopic ultrasound in gastro-oesophageal cancer.

    By Harris KM, Kelly S, Berry E, Hutton J, Roderick P, Cullingworth J, et al.

19. Systematic reviews of trials and other studies.

    By Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F.

20. Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses.

    A review by Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, et al.

1. Informed decision making: an annotated bibliography and systematic review.

   By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J, Robinson MB, et al.

2. Handling uncertainty when performing economic evaluation of healthcare interventions.

   A review by Briggs AH, Gray AM.

3. The role of expectancies in the placebo effect and their use in the delivery of health care: a systematic review.

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4. A randomised controlled trial of different approaches to universal antenatal HIV testing: uptake and acceptability. Annex: Antenatal HIV testing – assessment of a routine voluntary approach.

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   A review by Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J.

9. A review of the use of health status measures in economic evaluation.

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10. Methods for the analysis of quality-of-life and survival data in health technology assessment.

    A review by Billingham LJ, Abrams KR, Jones DR.

11. Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis.

    By Zeuner D, Ades AE, Karnon J, Brown J, Dezateux C, Anionwu EN.

12. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses.

    A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, Jones A, et al.

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    A review by Robert G, Milne R.

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    By Bradley M, Cullum N, Sheldon T.

18. Systematic reviews of wound care management: (2) Dressings and topical agents used in the healing of chronic wounds.

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    A review by Prescott RJ, Counsell CE, Gillespie WJ, Grant AM, Russell IT, Kiauka S, et al.

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    A review by Lord J, Victor C, Littlejohns P, Ross FM, Axford JS.

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   A review by Cairns JA, van der Pol MM.

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   A review by White SJ, Ashby D, Brown PJ.

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   By Clegg A, Bryant J, Milne R.

10. Publication and related biases.

    A review by Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ.

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    A rapid review by Song F, O’Meara S, Wilson P, Golder S, Kleijnen J.

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    By Lister-Sharp D, McDonagh MS, Khan KS, Kleijnen J.

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    By Payne N, Chilcott J, McGoogan E.

19. Randomised controlled trial of non-directive counselling, cognitive–behaviour therapy and usual general practitioner care in the management of depression as well as mixed anxiety and depression in primary care.

    By King M, Sibbald B, Ward E, Bower P, Lloyd M, Gabbay M, et al.

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    By Kerry S, Hilton S, Patel S, Dundas D, Rink E, Lord J.

21. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration.

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    By Parkes J, Bryant J, Milne R.

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    By Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HAW.

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    By McDonagh MS, Bachmann LM, Golder S, Kleijnen J, ter Riet G.

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    By Turner J, Nicholl J, Webber L, Cox H, Dixon S, Yates D.

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    By Williams JE, Louw G, Towlerton G.

33. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review.

    By Shepherd J, Waugh N, Hewitson P.

34. A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

    By MacLehose RR, Reeves BC, Harvey IM, Sheldon TA, Russell IT, Black AMS.

35. Intravascular ultrasound-guided interventions in coronary artery disease: a systematic literature review, with decision-analytic modelling, of outcomes and cost-effectiveness.

    By Berry E, Kelly S, Hutton J, Lindsay HSJ, Blaxill JM, Evans JA, et al.

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    By Simpson S, Corney R, Fitzgerald P, Beecham J.

37. Systematic review of treatments for atopic eczema.

    By Hoare C, Li Wan Po A, Williams H.

38. Bayesian methods in health technology assessment: a review.

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40. A systematic review of treatments for severe psoriasis.

    By Griffiths CEM, Clark CM, Chalmers RJG, Li Wan Po A, Williams HC.

1. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease: a rapid and systematic review.

   By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al.

2. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review.

   By Stewart A, Sandercock J, Bryan S, Hyde C, Barton PM, Fry-Smith A, et al.

3. Equity and the economic evaluation of healthcare.

   By Sassi F, Archard L, Le Grand J.

4. Quality-of-life measures in chronic diseases of childhood.

   By Eiser C, Morse R.

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   By Ryan M, Scott DA, Reeves C, Bate A, van Teijlingen ER, Russell EM, et al.

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   By Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G.

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    By De Broe S, Christopher F, Waugh N.

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19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

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    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

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    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

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    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

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   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

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   By Carroll B, Ali N, Azam N.

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    By Scott DA, Loveman E, McIntyre L, Waugh N.

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20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Reimsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda^®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera^®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris^®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.

1. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease.

   By Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al.

2. FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke.

   By Dennis M, Lewis S, Cranswick G, Forbes J.

3. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews.

   By Black C, Bagust A, Boland A, Walker S, McLeod C, De Verteuil R, et al.

4. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

   By Whiting P, Gupta R, Burch J, Mujica Mota RE, Wright K, Marson A, et al.

5. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

   By Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR.

6. Systematic review and evaluation of methods of assessing urinary incontinence.

   By Martin JL, Williams KS, Abrams KR, Turner DA, Sutton AJ, Chapple C, et al.

7. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

   By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

8. Surveillance of Barrett’s oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

   By Garside R, Pitt M, Somerville M, Stein K, Price A, Gilbert N.

9. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

   By Main C, Bojke L, Griffin S, Norman G, Barbieri M, Mather L, et al.

10. Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

    By Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M.

11. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

    By Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, et al.

12. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.

    By Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al.

13. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

    By Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

14. The cost-effectiveness of screening for oral cancer in primary care.

    By Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, et al.

15. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

    By Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton A, Thomas S, et al.

16. Systematic review of the effectiveness and cost-effectiveness of HealOzone^® for the treatment of occlusal pit/fissure caries and root caries.

    By Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al.

17. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

    By Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Kerwin R, et al.

18. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation.

    By Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, et al.

19. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

    By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

20. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1.

    By Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al.

21. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

    By Wright M, Grieve R, Roberts J, Main J, Thomas HC, on behalf of the UK Mild Hepatitis C Trial Investigators.

22. Pressure relieving support surfaces: a randomised evaluation.

    By Nixon J, Nelson EA, Cranny G, Iglesias CP, Hawkins K, Cullum NA, et al.

23. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

    By King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al.

24. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.

    By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

25. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

    By Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, et al.

26. A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

    By Robinson L, Hutchings D, Corner L, Beyer F, Dickinson H, Vanoli A, et al.

27. A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost–utility for these groups in a UK context.

    By Buxton M, Caine N, Chase D, Connelly D, Grace A, Jackson C, et al.

28. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Takeda A, Davidson P, Price A.

29. An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

    By Harvey S, Stevens K, Harrison D, Young D, Brampton W, McCabe C, et al.

30. Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

    By Wardlaw JM, Chappell FM, Stevenson M, De Nigris E, Thomas S, Gillard J, et al.

31. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

    By Woolacott N, Bravo Vergel Y, Hawkins N, Kainth A, Khadjesari Z, Misso K, et al.

32. The cost-effectiveness of testing for hepatitis C in former injecting drug users.

    By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al.

33. Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation.

    By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M, Beverley C, et al.

34. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

    By Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, et al.

35. Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

    By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al.

36. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

    By Whiting P, Westwood M, Bojke L, Palmer S, Richardson G, Cooper J, et al.

37. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

    By O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A.

38. A comparison of the cost-effectiveness of five strategies for the prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

    By Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al.

39. The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease: systematic review.

    By Waugh N, Black C, Walker S, McIntyre L, Cummins E, Hillis G.

40. What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).

    By Williams J, Russell I, Durai D, Cheung W-Y, Farrin A, Bloor K, et al.

41. The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

    By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P.

42. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

    By Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al.

43. Telemedicine in dermatology: a randomised controlled trial.

    By Bowns IR, Collins K, Walters SJ, McDonagh AJG.

44. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

    By Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C.

45. Clinical effectiveness and cost-effectiveness of laparoscopic surgery for colorectal cancer: systematic reviews and economic evaluation.

    By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C, McKinley A, et al.

46. Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

    By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

47. Systematic reviews of clinical decision tools for acute abdominal pain.

    By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al.

48. Evaluation of the ventricular assist device programme in the UK.

    By Sharples L, Buxton M, Caine N, Cafferty F, Demiris N, Dyer M, et al.

49. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

    By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al.

50. Amniocentesis results: investigation of anxiety. The ARIA trial.

    By Hewison J, Nixon J, Fountain J, Cocks K, Jones C, Mason G, et al.

1. Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

   By Dundar Y, Bagust A, Dickson R, Dodd S, Green J, Haycox A, et al.

2. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.

   By Collins R, Fenwick E, Trowman R, Perard R, Norman G, Light K, et al.

3. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

   By Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al.

4. The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women.

   By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.

5. A systematic review of quantitative and qualitative research on the role and effectiveness of written information available to patients about individual medicines.

   By Raynor DK, Blenkinsopp A, Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

6. Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.

   By Adi Y, Juarez-Garcia A, Wang D, Jowett S, Frew E, Day E, et al.

7. Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

   By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

8. Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection.

   By Low N, McCarthy A, Macleod J, Salisbury C, Campbell R, Roberts TE, et al.

9. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

   By Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al.

10. Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.

    By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D, Harridge SDR, et al.

11. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N.

12. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

    By Tappenden P, Jones R, Paisley S, Carroll C.

13. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.

    By Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, et al.

14. A systematic review and economic evaluation of statins for the prevention of coronary events.

    By Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan A, et al.

15. A systematic review of the effectiveness and cost-effectiveness of different models of community-based respite care for frail older people and their carers.

    By Mason A, Weatherly H, Spilsbury K, Arksey H, Golder S, Adamson J, et al.

16. Additional therapy for young children with spastic cerebral palsy: a randomised controlled trial.

    By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ.

17. Screening for type 2 diabetes: literature review and economic modelling.

    By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A, Goyder E, et al.

18. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Mealing S, Roome C, Snaith A, et al.

19. The clinical effectiveness and cost-effectiveness of gemcitabine for metastatic breast cancer: a systematic review and economic evaluation.

    By Takeda AL, Jones J, Loveman E, Tan SC, Clegg AJ.

20. A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease.

    By Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, et al.

21. The clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review.

    By Colquitt JL, Kirby J, Green C, Cooper K, Trompeter RS.

22. A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.

    By Fayter D, Nixon J, Hartley S, Rithalia A, Butler G, Rudolf M, et al.

23. Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

    By McCormack K, Rabindranath K, Kilonzo M, Vale L, Fraser C, McIntyre L, et al.

24. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis.

    By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D, et al.

25. A randomised controlled trial and economic evaluation of direct versus indirect and individual versus group modes of speech and language therapy for children with primary language impairment.

    By Boyle J, McCartney E, Forbes J, O’Hare A.

26. Hormonal therapies for early breast cancer: systematic review and economic evaluation.

    By Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L.

27. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

    By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

28. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.

    By McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, et al.

29. Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses.

    By Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et al.

30. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review.

    By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al.

31. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

    By Prescott RJ, Kunkler IH, Williams LJ, King CC, Jack W, van der Pol M, et al.

32. Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.

    By Bamford J, Fortnum H, Bristow K, Smith J, Vamvakas G, Davies L, et al.

33. The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

    By Black C, Cummins E, Royle P, Philip S, Waugh N.

34. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis.

    By Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, et al.

35. The Birmingham Rehabilitation Uptake Maximisation Study (BRUM). Homebased compared with hospital-based cardiac rehabilitation in a multi-ethnic population: cost-effectiveness and patient adherence.

    By Jolly K, Taylor R, Lip GYH, Greenfield S, Raftery J, Mant J, et al.

36. A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.

    By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

37. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

    By Marson AG, Appleton R, Baker GA, Chadwick DW, Doughty J, Eaton B, et al.

38. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anti-coagulation therapy: a systematic review and economic modelling.

    By Connock M, Stevens C, Fry-Smith A, Jowett S, Fitzmaurice D, Moore D, et al.

39. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

    By Soares-Weiser K, Bravo Vergel Y, Beynon S, Dunn G, Barbieri M, Duffy S, et al.

40. Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

    By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

41. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

    By Burr JM, Mowatt G, Hernández R, Siddiqui MAR, Cook J, Lourenco T, et al.

42. Acceptability, benefit and costs of early screening for hearing disability: a study of potential screening tests and models.

    By Davis A, Smith P, Ferguson M, Stephens D, Gianopoulos I.

43. Contamination in trials of educational interventions.

    By Keogh-Brown MR, Bachmann MO, Shepstone L, Hewitt C, Howe A, Ramsay CR, et al.

44. Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

    By Facey K, Bradbury I, Laking G, Payne E.

45. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Rogers G, Dyer M, Mealing S, et al.

46. Drug-eluting stents: a systematic review and economic evaluation.

    By Hill RA, Boland A, Dickson R, Dündar Y, Haycox A, McLeod C, et al.

47. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model.

    By Fox M, Mealing S, Anderson R, Dean J, Stein K, Price A, et al.

48. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study.

    By Campbell MK, Snowdon C, Francis D, Elbourne D, McDonald AM, Knight R, et al.

49. Cost-effectiveness of functional cardiac testing in the diagnosis and management of coronary artery disease: a randomised controlled trial. The CECaT trial.

    By Sharples L, Hughes V, Crean A, Dyer M, Buxton M, Goldsmith K, et al.

50. Evaluation of diagnostic tests when there is no gold standard. A review of methods.

    By Rutjes AWS, Reitsma JB, Coomarasamy A, Khan KS, Bossuyt PMM.

51. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding.

    By Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al.

52. A review and critique of modelling in prioritising and designing screening programmes.

    By Karnon J, Goyder E, Tappenden P, McPhie S, Towers I, Brazier J, et al.

53. An assessment of the impact of the NHS Health Technology Assessment Programme.

    By Hanney S, Buxton M, Green C, Coulson D, Raftery J.

1. A systematic review and economic model of switching from nonglycopeptide to glycopeptide antibiotic prophylaxis for surgery.

   By Cranny G, Elliott R, Weatherly H, Chambers D, Hawkins N, Myers L, et al.

2. ‘Cut down to quit’ with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.

   By Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D.

3. A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management.

   By Thornton J, Ashcroft D, O’Neill T, Elliott R, Adams J, Roberts C, et al.

4. Does befriending by trained lay workers improve psychological well-being and quality of life for carers of people with dementia, and at what cost? A randomised controlled trial.

   By Charlesworth G, Shepstone L, Wilson E, Thalanany M, Mugford M, Poland F.

5. A multi-centre retrospective cohort study comparing the efficacy, safety and cost-effectiveness of hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids. The HOPEFUL study.

   By Hirst A, Dutton S, Wu O, Briggs A, Edwards C, Waldenmaier L, et al.

6. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

   By Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, et al.

7. The use of economic evaluations in NHS decision-making: a review and empirical investigation.

   By Williams I, McIver S, Moore D, Bryan S.

8. Stapled haemorrhoidectomy (haemorrhoidopexy) for the treatment of haemorrhoids: a systematic review and economic evaluation.

   By Burch J, Epstein D, Baba-Akbari A, Weatherly H, Fox D, Golder S, et al.

9. The clinical effectiveness of diabetes education models for Type 2 diabetes: a systematic review.

   By Loveman E, Frampton GK, Clegg AJ.

10. Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

    By Raftery J, Bryant J, Powell J, Kerr C, Hawker S.

11. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation.

    By Chen Y-F, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al.

12. The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation.

    By Hockenhull JC, Dwan K, Boland A, Smith G, Bagust A, Dundar Y, et al.

13. Stepped treatment of older adults on laxatives. The STOOL trial.

    By Mihaylov S, Stark C, McColl E, Steen N, Vanoli A, Rubin G, et al.

14. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

    By Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al.

15. The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation.

    By Hind D, Tappenden P, Tumur I, Eggington E, Sutcliffe P, Ryan A.

16. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: a systematic review and economic evaluation.

    By Colquitt JL, Jones J, Tan SC, Takeda A, Clegg AJ, Price A.

17. Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease.

    By Mowatt G, Cummins E, Waugh N, Walker S, Cook J, Jia X, et al.

18. Structural neuroimaging in psychosis: a systematic review and economic evaluation.

    By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al.

19. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in adults and children aged 12 years and over.

    By Shepherd J, Rogers G, Anderson R, Main C, Thompson-Coon J, Hartwell D, et al.

20. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in children under the age of 12 years.

    By Main C, Shepherd J, Anderson R, Rogers G, Thompson-Coon J, Liu Z, et al.

21. Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

    By Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al.

22. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

    By Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross P, Harding G, et al.

23. A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial.

    By George S, Pockney P, Primrose J, Smith H, Little P, Kinley H, et al.

24. A review and critical appraisal of measures of therapist–patient interactions in mental health settings.

    By Cahill J, Barkham M, Hardy G, Gilbody S, Richards D, Bower P, et al.

25. The clinical effectiveness and cost-effectiveness of screening programmes for amblyopia and strabismus in children up to the age of 4–5 years: a systematic review and economic evaluation.

    By Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J.

26. A systematic review of the clinical effectiveness and cost-effectiveness and economic modelling of minimal incision total hip replacement approaches in the management of arthritic disease of the hip.

    By de Verteuil R, Imamura M, Zhu S, Glazener C, Fraser C, Munro N, et al.

27. A preliminary model-based assessment of the cost–utility of a screening programme for early age-related macular degeneration.

    By Karnon J, Czoski-Murray C, Smith K, Brand C, Chakravarthy U, Davis S, et al.

28. Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A.

29. Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product categories.

    By Fader M, Cottenden A, Getliffe K, Gage H, Clarke-O’Neill S, Jamieson K, et al.

30. A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.

    By French B, Leathley M, Sutton C, McAdam J, Thomas L, Forster A, et al.

31. The effectiveness and cost-effectivness of minimal access surgery amongst people with gastro-oesophageal reflux disease – a UK collaborative study. The reflux trial.

    By Grant A, Wileman S, Ramsay C, Bojke L, Epstein D, Sculpher M, et al.

32. Time to full publication of studies of anti-cancer medicines for breast cancer and the potential for publication bias: a short systematic review.

    By Takeda A, Loveman E, Harris P, Hartwell D, Welch K.

33. Performance of screening tests for child physical abuse in accident and emergency departments.

    By Woodman J, Pitt M, Wentz R, Taylor B, Hodes D, Gilbert RE.

34. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

    By Rodgers M, McKenna C, Palmer S, Chambers D, Van Hout S, Golder S, et al.

35. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

    By Lourenco T, Armstrong N, N’Dow J, Nabi G, Deverill M, Pickard R, et al.

36. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

    By Wang D, Cummins C, Bayliss S, Sandercock J, Burls A.

1. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation.

   By McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al.

2. Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis.

   By Simpson EL, Stevenson MD, Rawdin A, Papaioannou D.

3. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs.

   By Main C, Liu Z, Welch K, Weiner G, Quentin Jones S, Stein K.

4. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis.

   By McDaid C, Griffin S, Weatherly H, Durée K, van der Burgt M, van Hout S, Akers J, et al.

5. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.

   By Sutcliffe P, Hummel S, Simpson E, Young T, Rees A, Wilkinson A, et al.

6. The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

   By Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, et al.

7. Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients.

   By Mowatt G, Houston G, Hernández R, de Verteuil R, Fraser C, Cuthbertson B, et al.

8. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.

   By Taylor RS, Elston J.

9. Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) – a randomised controlled trial.

   By Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al.

10. Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

    By Pilgrim H, Lloyd-Jones M, Rees A.

11. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

    By Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al.

12. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods.

    By Hobart J, Cano S.

13. Treatment of severe ankle sprain: a pragmatic randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of three types of mechanical ankle support with tubular bandage. The CAST trial.

    By Cooke MW, Marsh JL, Clark M, Nakash R, Jarvis RM, Hutton JL, et al. , on behalf of the CAST trial group.

14. Non-occupational postexposure prophylaxis for HIV: a systematic review.

    By Bryant J, Baxter L, Hird S.

15. Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial.

    By Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, et al.

16. How far does screening women for domestic (partner) violence in different health-care settings meet criteria for a screening programme? Systematic reviews of nine UK National Screening Committee criteria.

    By Feder G, Ramsay J, Dunne D, Rose M, Arsene C, Norman R, et al.

17. Spinal cord stimulation for chronic pain of neuropathic or ischaemic origin: systematic review and economic evaluation.

    By Simpson, EL, Duenas A, Holmes MW, Papaioannou D, Chilcott J.

18. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and costeffectiveness and natural history.

    By Fortnum H, O’Neill C, Taylor R, Lenthall R, Nikolopoulos T, Lightfoot G, et al.

19. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study.

    By Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, et al.

20. Systematic review of respite care in the frail elderly.

    By Shaw C, McNamara R, Abrams K, Cannings-John R, Hood K, Longo M, et al.

21. Neuroleptics in the treatment of aggressive challenging behaviour for people with intellectual disabilities: a randomised controlled trial (NACHBID).

    By Tyrer P, Oliver-Africano P, Romeo R, Knapp M, Dickens S, Bouras N, et al.

22. Randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care: the THREAD (THREshold for AntiDepressant response) study.

    By Kendrick T, Chatwin J, Dowrick C, Tylee A, Morriss R, Peveler R, et al.

23. Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation.

    By Bryant J, Cooper K, Picot J, Clegg A, Roderick P, Rosenberg W, et al.

24. Enhanced external counterpulsation for the treatment of stable angina and heart failure: a systematic review and economic analysis.

    By McKenna C, McDaid C, Suekarran S, Hawkins N, Claxton K, Light K, et al.

25. Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).

    By Donnan PT, McLernon D, Dillon JF, Ryder S, Roderick P, Sullivan F, et al.

26. A systematic review of presumed consent systems for deceased organ donation.

    By Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A.

Health Technology Assessment programme

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

2. Director, Medical Care Research Unit, University of Sheffield