Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR)

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 99/01/01. The contractual start date was in July 2000. The draft report began editorial review in May 2008 and was accepted for publication in June 2009. 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

GJP, RT, RF and HK and are all clinicians involved in providing ECMO services.

Copyright statement

© 2010 Queen’s Printer and Controller of HMSO. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal 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.

2010 Queen’s Printer and Controller of HMSO

Previous studies

A review of the literature was carried out to identify all studies relevant to adult ECMO. MEDLINE was searched using ‘adult’, extracorporeal life support (ECLS) and ‘ECMO’ as keywords. In addition the investigators are closely aware of the ECMO literature, as they are leading members of the international ECMO community. Only two RCTs have been reported,1,12 both from the USA, but they used such different approaches that they have not been combined as a formal meta-analysis. Neither of these studies investigated high flow venovenous (VV) ECMO, which is the current technique of choice for adult respiratory failure. Each study is detailed below, followed by the recent non-experimental evidence.

The first study was an RCT of adult ECMO, conducted by the US National Institutes of Health (NIH),1 in the early days of extracorporeal support in the 1970s. Survival in both groups was very poor (around 10%), and no difference was shown in survival between the conventional and ECMO treated groups. Only very small numbers of patients were treated in each centre (fewer than five). There were a number of important differences in the perfusion and ventilation techniques used during this trial compared with those used today. Firstly, veno-arterial (VA) rather than VV perfusion was used, and this was thought to be responsible for the high incidence of pulmonary micro-thrombosis and fibrosis seen in the lungs of the ECMO patients (due to reduced pulmonary blood flow). Secondly, patients were anticoagulated to such a degree that severe bleeding occurred. Thirdly, high pressure ventilation was continued during ECMO, resulting in continued ventilator lung injury with barotrauma and volutrauma. 13,14 Finally, the mean duration of ventilation prior to ECMO in the NIH ECMO trial was more than 9 days, whereas it is now well recognised that after 7 days of high pressure ventilation with high fraction of inspired oxygen (FiO₂), the lungs have limited powers of recovery. 15

The second RCT was more recent, and concerned the related technique of extracorporeal carbon dioxide removal (ECCO₂R). 12 This showed no difference between ECCO₂R and conventional treatment. Again there were numerous differences in the clinical and perfusion protocols between this trial and those in widespread use in the majority of centres currently. 16,17 Firstly, the experimental arm of the trial used low flow ECCO₂R in a group of patients who had severe lung disease, which warranted higher flow ECMO with full support of oxygenation and carbon dioxide removal. This was demonstrated by the need to increase the airway pressure in the ECCO₂R group halfway through the study. The reliance on the patient’s lungs to provide oxygenation, especially at such high airway pressures, also eliminated any possibility of lung rest. Also, despite the involvement of one of the team in the 1970s NIH ECMO trial, the ECCO₂R programme in this trial was not well developed prior to the study (as the team had only provided ECCO₂R to sheep and one patient before starting the trial). The high incidence of bleeding and thrombotic complications reported in this study may attest to this inexperience. In addition, the conventional treatment used in the trial was pressure controlled inverse ratio ventilation (PCIRV) using a computer-controlled algorithm. The results of this treatment showed a 44% survival rate compared with expected survival rates of less than 20% in other similar series of patients. 2 Despite this, the survival rate in the ECCO₂R group was the same as in the ‘conventional’ group. The success of the PCIRV protocol in this study has led to the wide adoption of the technique within ‘conventional’ ventilatory management with a survival rate of 66% for patients with moderate to severe respiratory failure [mean Murray lung injury score 2.8, mean ratio between the oxygen tension in the arterial blood and the fraction of inspired oxygen (PaO₂/FiO₂) 88 mmHg]. 18 Unfortunately no other authors have been able to duplicate the PCIRV results of Morris et al. 12 for patients with severe progressive respiratory failure.

Because the two trials described above have little relevance to the high flow VV ECMO regimens used in the majority of centres worldwide, the only relevant evidence consists of observational studies. By the nature of their design, the information they provide is potentially biased, and must therefore be viewed with caution.

Recent case series of patients with similar degrees of respiratory failure to the eligibility criteria for the second trial suggest survival rates with conventional ventilation of 33–44%19,20 compared with rates of up to 66% with high flow ECMO (including full support of oxygenation and lung rest), provided by experienced teams principally in the USA, UK and Germany. 11,15–17

In a cohort study of the first 50 adult patients to receive ECMO for respiratory support at Glenfield Hospital, Leicester, UK, patients had severe respiratory failure as shown by the mean pre-ECMO Murray score of 3.4 [standard deviation (SD) 0.5] and PaO₂/FiO₂ ratio of 65 mmHg (SD 36.9). They were referred for ECMO with severe respiratory failure caused by either the acute respiratory distress syndrome (ARDS) or pneumonia. The overall survival rate was 66%. 11

For the reasons outlined above, it was impossible to reach firm conclusions from the above experimental and observational data regarding the clinical effectiveness or cost-effectiveness of VV high flow ECMO for respiratory failure in adults without an RCT.

ECMO received a Cii categorisation (safety and/or efficacy not yet fully established; procedure requires a fully controlled evaluation) from the UK Safety and Efficacy Register of the New Interventional Procedures of the Medical Royal Colleges (SERNIP). During the study SERNIP was superseded by the National Institute for Clinical Excellence (NICE; now known as the National Institute for Health and Clinical Excellence) which issued the following guidance in January 2004: ‘ECMO in adults is under evaluation in the Health Technology Assessment Programme’s CESAR (Conventional Ventilation or Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure) trial. Clinicians wishing to undertake this procedure are strongly advised to enter eligible patients into this trial.’

Economics of ECMO

Given the high cost of treatment, ECMO is considered an expensive technology for many funding systems. However, conventional treatment for severe respiratory failure is also one of the more costly forms of care in any health system. 21 Differences in lengths of stay and types of care received by patients following either clinical pathway may result in different statistical distributions of cost for inpatient care. Also, because appropriate care is provided in relatively few centres, the location of care and need for specialist transport for patients also affects the costs of care. Moreover, if there is increased survival to discharge from hospital, then there will be more use of services in primary and community care, and requirement for help for people recovering at home. Thus the health service costs and the household costs might fall at any stage of the treatment and recovery, and in many different forms. In addition to the costs of alternative forms of care, the economic choice depends on the value of the outcome gained.

Allocation of patients

The referring intensivist contacted the advisory team at Glenfield to confirm eligibility and bed availability. He or she then discussed the trial with the patient’s relative(s), gave written information (see Appendices 1 and 2), and asked for agreement to trial entry and obtained assent from the next of kin (once patients had recovered sufficiently they were told that they had been entered into a clinical trial and were given the opportunity to withdraw; three patients in the conventional arm declined further involvement in the study at this point). The advisor then telephoned the independent central randomisation service (see Appendix 2). Randomisation was to CM or to consideration of ECMO.

To ensure close balance between treatment groups for several patient factors, a dynamic process (minimisation) was used, which took into account the characteristics of the patients already entered into the trial. After the first patient was allocated treatment using simple randomisation, the next patient to enter the trial was allocated to whichever treatment group improved the overall balance according to a pre-selected set of baseline minimisation criteria, namely type of centre (CTC or RH); age (18–30, 31–45, 46–65 years); hours of high pressure and/or high FiO₂ ventilation (0–48, 49–168); mode of trial entry (i.e. hypoxic/hypercarbic); diagnostic group (pneumonia, obstetric ARDS, trauma including surgery within previous 24 hours, other ARDS, and other); and numbers of organs failed (one or two, or three or more) where organ failure was a Sepsis-related Organ Failure Assessment (SOFA) score for that organ of ≥ 2. 28,29 After 40% of recruitment had been completed, an additional step was incorporated such that if four successive randomisations for the same centre had the same allocation, the next allocation was to the other treatment. To protect allocation concealment, this amendment was not revealed to the participating centres.

Interventions

Outcome measures

The primary outcome measure was death or severe disability at 6 months [defined as death by 6 months or before discharge from hospital at any time to end of data collection, or where the answer to the first two questions of the EuroQol 5 dimensions questionnaire (EQ-5D) were ‘confined to bed’ and ‘unable to wash or dress yourself’, i.e. the worst possible scores for the domains for self-care and for mobility].

The secondary outcomes included a range of hospital indices: duration of ventilation, use of high frequency/oscillation/jet ventilation, use of nitric oxide, prone positioning, use of steroids, length of ICU stay, and length of hospital stay – and (for ECMO patients only) mode (VV/VA), duration of ECMO, blood flow and sweep flow.

Death of patients in the trial was recorded during the period of follow-up whenever it occurred. Staff at the CESAR trial data management centre maintained contact with all centres that had patients being treated within the CESAR trial, thus ensuring complete reporting.

In addition, health status at 6 months after randomisation was assessed in terms of activities of daily living, quality of life, respiratory symptoms, cognitive psychological state and lung function.

Six-month follow-up

This was performed by trained researchers blinded to the random allocation in the patients’ homes. Patients and their relatives were instructed not to reveal which treatment was used (see Appendices 1 and 2). A special scarf covered the neck, masking cannulation status. The assessment included SF-36 [Short Form (36 items) health survey],32 EQ-5D,33 St George’s Hospital Respiratory Questionnaire,34 Hospital Anxiety and Depression Scale35 and Mini-Mental State Examination,36 as well as specific sleep questions from the functional limitation profile. 37 Where applicable, effects on the carer were measured using the carer strain index. 38 Lung function was assessed by spirometry. Upper arm movements were assessed, as restriction of these has been previously noted in patients following ECMO. 39 If a patient was still in hospital, a modified assessment was carried out there. If a home visit was unacceptable, patients were offered a telephone interview or postal questionnaire. For those refusing this, permission was requested for information to be sought from their general practitioner.

Sample size

Seventy per cent mortality in the control group was anticipated when carrying out the initial power calculations in 1998/9, based on patients with similar PaO₂/FiO₂ ratio in the NIH ARDS network database (RH Bartlett, University of Michigan, USA, 1999, personal communication), confirmed by the Case Mix Programme (Intensive Care National Audit & Research Centre, ICNARC) database, in which the mortality of the 1506 patients whose PaO₂/FiO₂ ratio was ≤ 100 mmHg was 61.6%. The mean PaO₂/FiO₂ ratio of the ECMO patients11 was 65 mmHg (SD 37 mmHg). Assuming a 10% risk of severe disability among survivors in both arms, alpha = 0.05 (two-sided test) and beta = 0.2, 120 patients would be required in each group (i.e. 240 in total) to detect a reduction in the rate of primary outcome by a quarter from 73% to 55%, a conservative estimate based on the descriptive studies of adult ECMO already discussed. A number of other scenarios were shown on a sample size grid in the published clinical protocol39 (see Appendix 3). For example, the same size sample could detect a reduction by a third if the primary outcome rate in the control group was about 57%. The sample size was reviewed in June 2003 by the independent Data Monitoring Committee (DMC) when recruitment was running at less than 60% of its target. As the primary outcome rate in the control group was then 67%, it was agreed that a lower sample size (180 patients) would be sufficient to allow detection of reduction by a third and the HTA programme agreed an extension of the funding period to allow recruitment of 180 patients.

Statistical analysis

Primary analyses were by intention to treat. Secondary analyses included subgroup analyses, based on the minimisation criteria at trial entry, and a per protocol analysis. The DMC reviewed interim analyses in strict confidence on seven occasions. They were charged with informing the Trial Steering Committee if there was proof beyond reasonable doubt (based on the Peto–Haybittle stopping guidelines)40,41 that the data indicated that any part of the protocol under investigation was either clearly indicated or contraindicated (either for all patients or for a particular subgroup), or it was evident that no clear outcome would be obtained with the current trial design. Except for those who supplied the confidential information, everyone (including the Trial Steering Committee, funders, collaborators and administrative staff) remained ignorant of the results of the interim analysis.

Ethical considerations

The trial was approved by the Trent Multicentre Research Ethics Committee (MREC) as well as relevant Local Research Ethics Committees (LRECs).

Economics methods

Analysis and reporting of costs and economic evaluation

Economics results

Resource use data were collected for all patients included in the CESAR trial, so costs could be estimated for all participants. Although final primary outcome data for clinical effectiveness were available from all but three patients, complete EQ-5D data were missing in 17 cases.

Table 11 shows that patients allocated to ECMO were transported further for care and so used more transport. There was also a trend for them to have more organ systems supported and to stay longer in hospital than those allocated to CM. Surviving patients allocated to ECMO and returning home required more nursing and other therapy and social services, per patient, than those receiving CM, but the mean differences were not statistically significant. All other health-care use was similar between groups.

Table 12 shows that the majority of costs incurred were for health care, and the highest care costs resulted from the initial hospitalisation. Both groups of patients surviving to hospital discharge had considerable time given by family and friends, amounting to a value of £4332 per patient in the ECMO group, and £2212 in the CM group. This excludes the costs of visiting during the initial hospital stay (see below for results of the survey of costs of visiting)

Mean health-care costs per patient were more than twice as high for the patients allocated to ECMO (£73,979) than for those allocated to CM (£33,435), a difference of £40,544 (95% CI £24,799 to £56,288). As is usual, health-care costs were quite skewed and highly variable between patients.

Based on a simple budget impact analysis, and using the same costing assumptions listed above, we have estimated that the additional cost to the health service of a policy of providing access to the ECMO service would be £4,828,320 per year for 120 patients and £14,082,600 per year for 350 patients.

Cost-effectiveness analysis

The base-case analysis (from the NHS viewpoint and so excluding patients’ costs) found the incremental cost-effectiveness of ECMO to be £250,162 per additional survivor without severe disability. Table 13 also presents the results of the sensitivity analysis for alternative methods for cost estimation.

Cost–utility analysis

Table 14 reports the incremental cost–utility ratios for different scenarios from the NHS viewpoint, illustrating the results of the cost–utility analysis according to changes in the key assumptions. The mean gain in QALYs at 6 months post randomisation for those patients allocated to ECMO was 0.03 (95% CI 0.00 to 0.06) and the cost per additional QALY at 6 months post randomisation was £1,631,124.

Individual patient costs were estimated using the number of days at different levels of critical care, and the national NHS prices as the source of unit cost (rather than the number of days at different levels of organ support and unit costs obtained from participating centres) are shown in scenario 2 in Tables 13 and 14, and in both cases reduce costs per outcome gained from the ECMO treatment option.

The predicted lifetime incremental cost per QALY discounted at 3.5% (scenario 3 in Table 14) was £19,252 (95% CI £7622 to £59,100). If discount rates were assumed to be zero (that is, future values are worth the same as current values), total costs and total QALY gain were both higher, and the cost–utility of ECMO improves (scenario 4 in Table 14).

There is considerable uncertainty in these estimates, as the confidence limits in Table 14 show.

Figure 3 illustrates the cost-effectiveness acceptability curve for lifetime estimates,68 showing the probability (vertical axis) that a policy of ECMO would be cost-effective at different thresholds of willingness to pay at 2005 prices (horizontal axis). This shows that ECMO has a more than 50% chance of being cost-effective at any threshold of spending over around £20,000.

FIGURE 3.

Cost-effectiveness acceptability curve – lifetime estimates discounted at 3.5%.

Results of costs of visiting study

A total of 334 visitors visited the six ICUs over the 3-week period. Of these, 17 visitors refused to take part in the study, 24 visitors had to be excluded under the exclusion criteria and 77 visitors could not be recruited for other reasons. Information leaflets and questionnaires were given out to the remaining 216 visitors and 173 questionnaires were returned (response rate 80% of eligible visitors).

Table 15 shows the characteristics of respondents. Visitors were mainly close family members and relatives (95%) who came almost daily until the patient’s discharge. Some made multiple visits at different times during the same day. Relatives spent several hours by the bedside talking to patients, reading out letters/newspapers, showing photographs, and sometimes alerting the nurse to changes in the patient. Some helped with minor tasks such as wiping the patient’s face and adjusting the blanket. Personal care such as body baths, changing bed sheets, etc. was carried out by nursing staff.

Clinical effectiveness

This study showed an important improvement in outcome when a strategy of transferring patients to a specialist centre for consideration of ECMO was used to manage adults with severe but potentially reversible respiratory failure rather than continued conventional ventilation. As hypothesised, transfer for consideration of ECMO reduced the proportion of patients who died or were severely disabled 6 months after randomisation by approximately one-third compared with those in the conventional arm [although the rate in the control arm (52.9%) was lower than expected in the second power calculation (65%)]. The primary outcome measure that the trial was powered to detect was a difference in death or severe disability at 6 months post randomisation. Whilst this is a composite end point, it addresses failings of previous studies by detecting late deaths and also ensures that the survival is meaningful from a societal and individual standpoint. The hospital mortality was also lower in the ECMO arm, although it did not reach statistical significance, but this was not what the study was powered to detect. The APACHE II score is commonly used to estimate disease severity and is a predictor of mortality in patients with ARDS. 71,72 The reported APACHE II score in case series of patients with ARDS varies significantly, ranging between 13.4 and 28.7. 73,74 Whilst the mortality of patients in the conventional arm of CESAR may appear to be high for an APACHE II score of 20, it is comparable with that reported for a similar group of patients (Murray score of 3.4 and PaO₂/FiO₂ 98 and APACHE II 21.5) in which the mortality was 67%. 19 The time from randomisation to death was significantly shorter in the control arm than in the ECMO arm of the study and a higher proportion of patients in the control arm were listed as dying of respiratory failure, and it is likely that this explains the more rapid onset of death. In the ECMO arm the use of extracorporeal support prevents death from respiratory failure allowing the disease process to either recover or progress to fatal multisystem organ failure. It is possible that clinicians in the control arm withdrew care sooner in patients when they felt that further treatment was futile, whilst the ECMO team had a policy of withdrawing intensive care only in very selected cases after several weeks of attempted treatment. The data collected do not allow us to determine if there was a systematic bias to explain the difference in time to death between the two groups; however, the investigators believe that the difference is explained adequately by the effect of ECMO in supporting gas exchange and preventing early death from respiratory failure.

The trial design meant that the risk of bias was low as the clinical ECMO team was blinded to the outcome in the control arm; only the staff and members of the DMC knew the outcome in both arms of the study. In addition, minimisation criteria were used in the randomisation to ensure equality between the groups for variables that in previous series of ECMO patients had been shown to have an impact on outcome. This policy was successful in that both groups had equal numbers of very similar patients.

A potential limitation is the pragmatic design with the conventional treatment undertaken in 43 different hospitals. This design was chosen as the only realistic possibility in the UK. Firstly, there was no funding available for treatment of conventional patients in a single centre. Secondly, there was no single unit in the UK that had the infrastructure to accept such an influx of patients allocated to CM, except for Glenfield Hospital. It was not, however, felt appropriate for Glenfield to treat all the patients in both arms. The reasons for this were that the Glenfield team is known to be enthusiastic in the use of ECMO and could therefore be perceived as both less committed to and less skilled in conventional intensive care management. Indeed, a number of intensivists stated that they did not consider the surgical ICU in the Glenfield ECMO unit to be competent to provide conventional intensive care and would not be willing to transfer patients to a study in which all the treatment for both arms was provided at the Glenfield Hospital. Many intensivists from CTCs also stated that they were unwilling to transfer patients out for conventional treatment in another hospital. In addition to these factors, the ECMO team felt that it would be very difficult for clinical staff and relatives to have patients on different treatments in close proximity in a study with no possibility of cross-over, especially if a patient was doing badly on a particular treatment. The trial team also considered the possibility of protocolising the conventional intensive care received by the control patients. The team approached the Intensive Care Society and also gave numerous presentations at regional intensive care meetings. Unfortunately there was no national consensus and no support for protocolised care. We elected to be pragmatic about the treatment in the control arm, as we knew from the previous pattern of ECMO patient referral that a large number of ICUs would be involved, thereby giving a representative example of ‘normal’ intensive care treatment in the UK. It can be argued that conventional treatment in a specialist centre could give improved results to those seen in the control arm of the CESAR study; this could perhaps be the focus of a future study.

Although the low volume ventilation strategy from the ARDSNet study was recommended for use by treating intensivists, it was not enforced, so patients in the conventional arm received many different approaches during their treatments. It is important to recognise that the patients in the CESAR trial were much more hypoxic than those in the ARDSNet study,3 PaO₂/FiO₂ ratios of 76.2 and 75.0 mmHg for ECMO and control groups respectively versus 138 and 134 mmHg for treatment and control groups respectively in ARDSNet. It is likely that the low compliance with the low volume strategy is in part because of worse lung disease in the CESAR patients than those in ARDSNet. It is possible that if CM had been rigorously protocolised and provided in a single centre or a small number of centres, the outcome in the control group could have been slightly better. However, this could have lead to bias, as the conventional treatment protocol would have been set in 1998–9 and could not have been adapted thereafter, so the protocol would not have included more recent changes in intensive care medicine such as activated protein C,75 sepsis care bundles76,77 and conservative strategy of fluid management. 78 So it is also possible that a superseded CM protocol could have reduced survival in the control arm. By allowing intensivists to provide the best treatment that they could, we allowed adaptation of treatment to include recent advances and also examined the actual outcome of intensive care for severe respiratory failure in the UK.

The reality of intensive care admission for the majority of adult patients with respiratory failure in the UK is that they will not be transferred out from their original hospital to a larger unit however bad their respiratory failure is. Thus the outcome in the control arm should be an accurate reflection of prognosis for patients with severe respiratory failure in the majority of UK ICUs.

By nature of its complexity, ECMO treatment should be provided only in specialist centres. Much as aircraft should be flown only by suitably qualified pilots, the skill set required for safe provision of ECMO needs to be learnt over a number of years in an appropriately skilled ECMO centre. Almost every aspect of the patient and circuit management can result in the instant demise of the patient if not carried out according to established ECMO management protocols. It is beyond the scope of this monograph to include a description of every aspect of ECMO patient management. Although the Glenfield ECMO team is one of the most experienced in the world there was one complication of ECMO cannulation that resulted in the death of the patient. There were no other major complications of ECMO. This concentration of patients with severe respiratory failure within one unit may have led to an expert centre effect in that transferring patients to a surgical ICU that specialises in severe respiratory failure treatment could account for some of the improvement in outcome as the ECMO staff were more used to caring for patients with severe respiratory failure than were the referring units, and possibly were more used to using gentle ventilation with permissive hypoxia and hypercapnia when they knew that ECMO was instantly available should the patient deteriorate. The survival in the treatment arm was the same in the patients who were treated with or without ECMO. This could be because the clinicians correctly identified which patients did not require ECMO and put only the more severely ill on to ECMO (although it is also possible that they were remiss and could have obtained better survival by putting all the patients on ECMO). It is highly unlikely that survival in the ECMO arm would have been so good if all the patients had been treated conventionally by the ECMO team, unless one accepts the hypothesis that three cardiothoracic surgeons can provide better intensive care than that available in the majority of UK ICUs. We do not believe this to be the case. Indeed a recent study comparing intensivists and surgeons in the management of patients with ARDS showed that management of ventilation by intensivists was associated with a trend towards improved hospital survival and fewer days of mechanical ventilation in patients who survived. 79 To paraphrase William of Ockham, the simplest explanation is the most likely to be true. 80 Namely, low volume ventilation has been proven to improve outcome in ARDS,3 but patients with such severe respiratory failure are unable to maintain homeostasis on low volume ventilation, and the use of ECMO allows non-injurious ventilator settings to be used. ECMO is merely a tool that allows lung rest.

The improvement in survival without severe disability seen in the treatment arm of the CESAR trial is an important real world outcome. It is likely that if the trial had not been designed in such a pragmatic fashion it would have failed as there were enormous changes in the NHS during the study, including inauguration and abandonment of local intensive care networks, a shift of commissioning of tertiary care services from regional health authorities to local primary care trusts, and implementation of the European working time directive legislation. The trial would also have failed owing to lack of patient recruitment if the conventional care had been protocolised, as UK intensivists could not agree protocols for national treatment when the CESAR protocol was being written. In addition, most intensivists were unwilling to consider transferring patients for conventional intensive care as they did not consider it ethical to do so.

Another important development during the study was the introduction of an arteriovenous carbon dioxide removal device (Novalung). This was used by one hospital on a patient in the conventional arm of the study, a clear protocol violation. 81,82 This device is not equivalent to ECMO as it provides little oxygenation. Further studies including an RCT will be needed to determine its optimal use.

The policy of ECMO in the UK involved transport to the ECMO centre. This may be hazardous for patients as seriously ill as this cohort. Indeed, five patients in the ECMO arm succumbed before they could be transferred to Glenfield. Of these, three patients died prior to transfer and two died in transit, one from catastrophic pulmonary haemorrhage and one when the oxygen supply in the ambulance failed. There were no transport deaths in the conventional arm. All the transfers were carried out by the ECMO transport team which is specifically trained and highly skilled in ground and air transfer of patients with severe respiratory failure using conventional ventilation. The ventilator used was a Pneupac Ventipac^® (Smiths Group PLC, London, UK) with the addition of a PEEP valve to the breathing circuit. The team consisted of a transport nurse, who was a trained ECMO specialist, in addition to a sister/charge nurse or senior staff nurse and an ECMO Fellow (doctor of registrar grade), both of whom had been on an in-house transport course as well as having undertaken training transports with an experienced team member until considered safe to undertake transports ‘solo’. Ground ambulance was used when estimated transport time was less than 2 hours and rotary wing aircraft was used [Royal Air Force (RAF) Sea King Mk3] when a longer transport time was estimated and weather conditions allowed. Aircraft landed at the Glenfield Hospital helipad, speeding the transfer. One transport from Inverness was undertaken using a combination of ambulance, fixed wing aircraft (RAF Hercules) and helicopter. All transports were co-ordinated by the ECMO co-ordinator. It is possible that outcomes could be further improved by the implementation of a mobile ECMO patient retrieval service, as similar services have shown improved survival in patients transferred on ECMO when compared with those transferred using conventional ventilation prior to starting on ECMO at the base hospital. 83,84

Economics

CESAR was one of the first multicentre trial-based economic evaluations performed in adult critical care units in the UK. The CESAR trial was also the first RCT of adult ECMO with full economic support from the design stages of the trial, including funding for two part-time health economists, which helped the economic research team tackle many challenges in the design, methods, data collection, development and piloting of the economic questionnaire and planning of the analysis. The trial protocol was developed in collaboration with health economists, who were members of the Trial Steering Committee, and an economics working group oversaw the economic data collection and analysis.

Referral for ECMO has been shown in the CESAR trial to improve health outcomes significantly for adult patients with severe, but potentially reversible, respiratory failure when compared with CM. We have shown in this report, however, that the additional average cost per patient of treating this illness by transfer to the ECMO centre is more than double the average cost of treatment with CM. However, the lifetime prediction of cost–utility of £19,000 ($31,000) per QALY is well within those values regarded as affordable by many health-care decision-makers. The CEA Registry, published on the World Wide Web by Tufts University Medical School,85 summarises cost–utility ratios at 2002/3 values reported in health economic evaluation studies. We have chosen some of these values to illustrate how the cost-effectiveness of ECMO compares with other health technologies in cardiovascular and respiratory medicine. For example, anticoagulation therapy with warfarin versus none is cost saving and improves health for people with atrial fibrillation;86 current use of aspirin in patients with coronary heart disease aged 35–84 years costs $11,000 per QALY gained compared with no aspirin;87 and single lung transplant in end stage lung disease in the UK costs $51,000 per QALY gained. 88 It is important to bear in mind when looking at such comparisons that the estimates from our model were based on highly simplified assumptions on length and quality of life for survivors, and that comparisons of cost-effectiveness are subject to many methodological pitfalls. Further detailed research would be needed to build and test a robust model that takes account of geographical location, economies of scale and scope, and long-term quality of life.

The CESAR trial was funded as part of the NIHR HTA programme, and, during the trial, access to ECMO in the UK was restricted to participants in the trial. Findings from the trial and its economic evaluation will now become key information for the UK NHS decision-makers on whether to fund ECMO for adults beyond the trial setting. Although our study was based on the largest UK study of cost functions of critical care, and compared like for like with the costs of critical care treatment across the participating units, there will also continue to be questions to resolve about any omitted costs of services (such as hospital overheads or financial ‘insurance’ costs to reflect uncertainty of predicted case load, which were not included in our cost estimates). In any business case, the final price agreed per case treated will alter the purchaser’s view of cost-effectiveness in a way that can be remodelled using the data from this study.

The findings are also relevant to other countries where ECMO is provided or being considered, although local costs, health services and practice may vary, as may travel distances (from treatment centres). Local economic models would need to be constructed to assess cost-effectiveness in different contexts.

We found that our hospital cost estimates were sensitive to critical care unit costing methods. National data on costs of NHS critical care were not available at the outset of the CESAR trial, but are now published as tariffs for providers (NHS hospital trusts)52 to use in contracts with third-party payers. A parallel research study ran alongside the trial in order to estimate the costs of patients according to the type of organ support received during their stay. Subsequent analysis demonstrated grouped numbers of organs supported on a daily basis in the critical care unit was the best predictor of the costs of care. 63 Although it is likely that these costs are reliable estimates of true resource costs, the NHS financial system uses different (non-case-mix adjusted) values that predict lower costs per outcome gained.

Not surprisingly, the cost-effectiveness would be improved where costs of transport and of ECMO provision could be reduced. These two factors may be inversely related. Provision of ECMO is likely to be most clinically and economically efficient (lower cost per successful case treated) in larger critical care units. It is also likely that the clinical effectiveness of smaller units would be reduced compared with busier units. However, long-distance air travel could be minimised with a larger number of well-placed critical care units, which would inevitably be smaller and less economically efficient. Almost all the air transport was provided by the RAF in the CESAR trial. This was relatively expensive, and the RAF does not aim to be a routine service provider for the NHS. Air transport costs may be reduced by implementation of a dedicated air ambulance system for patient retrieval. We would recommend further careful modelling of the most cost-effective solution for different settings.

The analysis reported here has taken the viewpoint of public sector and, especially, NHS efficiency, and so patient costs were not included in the analyses of cost-effectiveness. In the UK, health care is not a direct cost to patients as it is funded through general taxation. In other parts of the world, the additional costs would affect insurance financing. We have shown that, in the UK, costs after hospital discharge to patients and their informal carers were doubled following allocation to ECMO. Although most of these were not financial costs but voluntary time costs, there are likely to be knock-on financial and emotional effects. The costs for relatives of visiting the patient whilst in hospital were not directly measured for patients participating in the CESAR trial. However, we conducted a parallel study of costs of visiting intensive care in six participating hospitals. The results of the study in six centres in the CESAR trial suggested an average cost per single visit of around £69 at 2007 prices for out of pocket expenses. When time costs and income loss are included, the visiting cost is increased by £59 per visit. Given that the visitors interviewed were present daily with their relative or friend, the extra length of stay in the ECMO group suggests that visiting costs would have been much higher for this group than for the CM group. More analysis from the six CESAR hospitals participating in the main survey of visiting costs will be reported elsewhere.

Trial Steering Committee

R Adfield, E Allen, F Clemens, E Coates, N Cooper, K Diallo, D Edbrooke, D Elbourne, G Faulkner, J Fawcett, D Field, R Firmin, D Goldhill, B Gutteridge, P Hardy, S Harris, C Hibbert, S Holden, N Jones, H Killer, M Mugford, W Nganasurian, G Peek, M Pepperman, D Piercy, S Robertson, J Scott, A Tattersfield, M Thalanany, R Tiruvoipati, K Tomlin, A Truesdale, N Webster, A Wilson.

Project management group

E Allen, F Clemens, N Cooper, K Diallo, Y Doyle, D Edbrooke, D Elbourne, G Faulkner, R Firmin, D Francis, P Hardy, S Harris, C Harvey, C Hibbert, N Jones, H Killer, M Mugford, G Peek, D Piercy, S Robertson, M Thalanany, R Tiruvoipati, K Tomlin, A Truesdale, A Wilson.

Data co-ordinating centre, London

E Allen, F Clemens, K Diallo, D Elbourne, P Hardy, D Piercy, S Robertson, K Tomlin, A Truesdale.

Clinical co-ordination centre, Glenfield

M Aslam, G Faulkner, R Firmin, S Harris, C Harvey, H Killer, N Jones, C McCulloch, G Peek, J Redfern, R Reeves, N Roberts, A Sheward, L Smith, A Sosnowski, A Tebbat, R Tiruvoipati.

Economic evaluation

E Coates, N Cooper, V Knights.

Data Monitoring Committee

D Altman, R Doll (died 2005), T Evans, D Macrae.

Follow-up group

J Sanderson-Mann, P Sinfield, C Tarrant, H Watkinson, A Wilson.

Randomisation service

G McPherson, A Walker.

IT support

M Bennett, A King.

Independent categorisation of causes of deaths

C Waldmann, D Goldhill.

Recruiting centres and named collaborating doctors and nurses

Numbers in parentheses denote the number of patients recruited by that centre:

Airedale General Hospital (2), J Scriven, K Price; Alexandra Hospital (1), T Leach, D Bagnall, L Clements; Arrowe Park Hospital (1), J Chambers, P Grice, C Taylor; Ayr Hospital (6), I Taylor, M Dunlop, D Kerr; Bassetlaw District General Hospital (1), R Harris, W Lee, P Wootton; Bedford Hospital (10), D Niblett, F Barchard, F Bertasius; Castle Hill Hospital (8), S Gower, J Dickson, K Roberts; Cheltenham General Hospital (2), W Doherty, A Culpepper, S Maisey; Chesterfield & North Derbyshire Royal Hospital (2), RP Wroth, L Barton, D Handley; Chorley & South Ribble District General Hospital (1), M Calleja, J Baldwin; Derby Hospitals NHS Foundation Trust (2), P Harris, K Greatorex, J Herring, L Thomas; East Surrey Hospital (1), B Bray, B Keeling; Frimley Park Hospital (3), L Shaikh, J Thomas; Glan Clwyd District General Hospital (1), B Tehan, L Burgoyne, K Owen; Glenfield Hospital (8), R Firmin, G Peek, D Turner, L Marriot, J Morton, L Randall; Gloucestershire Royal Hospital (8), C Roberts, A Bailey, E Maggs; Hereford County Hospital (1), JD Hutchinson, L Davies, L Kehoe; Huddersfield Royal Infirmary (2), J O’Riordan, S Ainley, S Maguire; Hull Royal Infirmary (3), I Smith, D Muir, N Smith; Kent & Sussex Hospital (1), P Sigston, A Collins; Kettering General Hospital (3), L Twohey, C Harland, J Thomas; King’s Mill Hospital (1), M Ross, M Platt, A Tinsley; Leicester General Hospital (2), P Spiers, J Cadwallader; Leicester Royal Infirmary (6), D Turner, K Coulson; Leighton Hospital (3), A Martin, T Schiavone, M Smith; Llandough Hospital (1), A Turley, C Taylor, S Bennett, R Kyte; Luton & Dunstable Hospital (10), M Patten, M Kermack; Macclesfield District General Hospital (4), J Hunter, H Cooper, J Rhodes; Manchester Royal Infirmary (1), R Slater, W Cook; Milton Keynes General Hospital (1), P Chambers, J McHugh; Newham University Hospital (1), S Holbeck, C McMullen, L Woodbridge; Ninewells Hospital and Medical School (1), JR Colvin, B Soutar; North Manchester General Hospital (1), M Longshaw, E Jones; Northern General Hospital (3), S Michael, J Sutherland, L Wadsworth; Nottingham City Hospital (2), M Levitt, C Crocker, M Hope; Pilgrim Hospital (3), M Spittal, D Connolly, I Hamilton; Prince Charles Hospital (1), BJ Jenkins, J Davies; Prince Philip Hospital (4), M Esmail, L Evans; Queen Elizabeth Hospital (6), F McAuley, E Britton-Smith, A Jackson, V McLean; Raigmore Hospital (1), CA Lee, G Calder; Rotherham District General Hospital (2), D Harling, D O’Malley, H Proctor; Royal Albert Edward Infirmary (1), R Saad, J Hilton, M Taylor; Royal Bolton Hospital (4), W Price, S Westwell; Royal Hallamshire Hospital (7), D Edbrooke, K Bailey, S Smith; Royal Liverpool University Hospital (1), G Masterson, T Rowan; Royal Preston Hospital (1), P Duncan, C Richardson; Sandwell General Hospital (1), JM Bellin, A Markham, M Willis; Scunthorpe General Hospital (1), T Samuel, R Sharawi, A Holmes, S Snelson; Southend Hospital (1), D Higgins, J Lee, P Tyler; Southport & Ormskirk Hospital NHS Trust (1), D Jayson, G Levens, H Rymell, M Smith, J Webb; St Mary’s Hospital (1), C Wareham, J Bean, A Read; Staffordshire General Hospital (1), J Hawkins, J Lewis, N Worral; Stepping Hill Hospital (3), J Rigg, K Berry, S Swire; The Horton Hospital (2), J Everatt, G Walker, K Marchant; The Ipswich Hospital (1), M Garfield, C Calder, M Parfitt; The Royal London Hospital (4), D Kennedy, S Nourse, I O’Connor; University Hospital Aintree (1), E Shearer, P Hale, S Tabener; University Hospital of Hartlepool (3), V Gupta, L Morgan; University Hospital of North Staffordshire NHS Trust (1), B Carr, T Proctor, A Normington; University Hospital of Wales (1), G Findlay, M Smithies, E Hutcheon; Victoria Hospital (1), D Kelly, M Drummond; Walsgrave Hospital (2), J Little, D Watson, T Mason, G McMillan; Warrington Hospital (1), J Little, T Mason, G McMillan; Warwick Hospital (5), J Aulakh, H Reading; Watford General Hospital (1), V Page, T Stambach, C Armstrong, W Dore; West Suffolk Hospital (4), J Cardy, P Oats; Worcestershire Royal Hospital (4), N Volpe; Wrexham Maelor Hospital (3), WC Edmondson, K Miller; Wycombe Hospital (2), T Dexter, R Bryson, G Toovey.

Other hospitals providing data

Addenbrookes Hospital; Amersham Hospital; Biggleswade Hospital; Cannock Chase Hospital; Chapel Allerton Hospital; Coventry & Warwickshire Hospital; Freeman Hospital; Goodmayes Hospital; Hammersmith Hospital; Harefield Hospital; Hawthornes Care Centre; Hope Hospital; Leigh Infirmary; Lister Hospital; Mile End Hospital; North Middlesex Hospital (A Chan, R Lo, GL Dabuco, N Mathew); Northwick Park Hospital; Papworth Hospital; St James’s University Hospital; St Thomas’ Hospital; Southern General Hospital (M Garrioch); University Hospital, North Tees (P Ritchie, F Bage, L Williams); Wythenshawe Hospital.

Contribution of authors

Giles Peek (Consultant in Cardiothoracic Surgery and ECMO) was the lead clinical investigator for the CESAR trial. He was involved in the design and conduct of research and the interpretation and reporting of results, and was a member of the project management team. Diana Elbourne (Professor of Healthcare Evaluation) was the lead investigator for statistics and trial design and management for the CESAR trial and was involved in design and conduct of research, the project management team and Data Monitoring Committee, and interpretation and reporting of results. Miranda Mugford (Professor in Health Economics) was the lead investigator for economics input to the CESAR trial, involved in design and conduct of economics research, and interpretation and reporting of results; she was also a member of the project management team. Ravindranath Tiruvoipati (Clinical Research Fellow) was involved in the recruitment of centres and patients, the clinical conduct of research, the project management team, and the interpretation and reporting of results. Andrew Wilson (Professor of Primary Care Research) was the lead investigator for the follow-up of participants in the CESAR trial, involved in the design and conduct of research, the project management team, and interpretation and reporting of results. Elizabeth Allen, Felicity Clemens and Pollyanna Hardy (Lecturers in Medical Statistics) were all involved in the design and conduct of research, the project management team, and interpretation and reporting of results. Richard Firmin (Consultant in Cardiothoracic Surgery, Director of ECMO Services) was an investigator for the CESAR trial and a member of the project management team, and involved in design and conduct of research, and interpretation and reporting of results. Clare Hibbert (Health Economics Research Fellow) was an investigator for economics input to the CESAR trial and a member of the project management team, and involved in design and conduct of economics research, and interpretation and reporting of results. Nicky Jones (Clinical Research Fellow) was involved in recruitment of centres and patients and clinical conduct of research, and was a member of the project management team. Hilliary Killer (ECMO Unit Manager) was a member of the project management team. Mariamma Thalanany (Health Economics Researcher) was an investigator for economics input to the CESAR trial and a member of the project management team, and involved in design and conduct of economics research, and interpretation and reporting of results. Ann Truesdale (Trials Adviser) was involved in design and conduct of research, recruitment of centres, ethics approvals, data management, and interpretation and reporting of results, and was a member of the project management team.

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.

CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure

Giles J Peek,^1* Felicity Clemens,² Diana Elbourne,² Richard Firmin,¹ Pollyanna Hardy,^2,3 Clare Hibbert,⁵ Hilliary Killer,¹ Miranda Mugford,⁴ Mariamma Thalanany,⁴ Ravin Tiruvoipati,¹ Ann Truesdale² and Andrew Wilson⁶

Address: ¹Department of Cardiothoracic Surgery, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK; ²Medical Statistics Unit, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK; ³Clinical Epidemiology and Biostatistics Unit, Royal Children’s Hospital, Melbourne, Australia; ⁴School of Medicine Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK; ⁵School of Health and Related Research, University of Sheffield and RTI Health Solutions, Williams House Manchester Science Park, Manchester ME15 6SE, UK; and ⁶Department of Health Sciences, University of Leicester, Leicester General Hospital, Leicester, LE5 4PW, UK

Email: Giles J Peek* - giles.peek@uhl-tr.nhs.uk; Felicity Clemens - Felicity.clemens@lshtm.ac.uk; Diana Elbourne - diana.elbourne@lshtm.ac.uk; Richard Firmin - richard.firmin@uhl-tr.nhs.uk; Pollyanna Hardy - polly.hardy@mcri.edu.au; Clare Hibbert - chibbert@rti.org; Hilliary Killer - hilliary.killer@uhl-tr.nhs.uk; Miranda Mugford - m.mugford@uea.ac.uk; Mariamma Thalanany - M.Thalanany@uea.ac.uk; Ravin Tiruvoipati - rt67@leicester.ac.uk; Ann Truesdale - ann.truesdale@lshtm.ac.uk; Andrew Wilson - aw7@le.ac.uk

* Corresponding author

Published on 23 December 2006 in BMC Health Services Research 2006, 6:163. doi:10.1186/1472-6963-6-163. Available online at: http://www.biomedcentral.com/1472-6963/6/163.

Methods/Design

Design

The most scientifically rigorous design to assess effects of health interventions is that of an RCT. The design will be similar to the highly successful UK neonatal ECMO RCT[6] suitably adapted for the adult population. The design will be ‘pragmatic’ ie it will, as far as possible, mirror usual practice in the UK. The procedures are illustrated schematically in Figure 1 below, and detailed in the text.

FIGURE 1.

Organisation of the trial.

Primary hypotheses

The primary hypotheses are that, for patients with severe, but potentially reversible, respiratory failure, ECMO:

1. Will increase the rate of survival without severe disability by six months post-randomisation.

2. Will be cost effective from the viewpoints of the NHS and society, compared to conventional ventilatory support.

Inclusion criteria

i) Centres

1. ECMO: This will be provided in the Glenfield Hospital, Leicester, which has 17 years of experience and is the only ELSO-recognised adult ECMO centre in the UK.

2. Conventional treatment centres (CTC): These are either centres acknowledged by Critical Care Network leads (where established) to provide an appropriately high standard of conventional care for ECMO-eligible patients, or they are units which treat ≥ 350 patients per year, and can provide pressure controlled ventilation and veno-venous haemofiltration.

3. Referral hospitals (RH): In addition to the centres described under (b) above, patients meeting ECMO entry criteria may be entered into the trial from other hospitals, if these hospitals are prepared to transfer the patient to a designated CTC should the allocation be to conventional management.

ii) Patients

Adult patients (18–65 years) with severe, but potentially reversible respiratory failure. Severe respiratory failure will be defined as a Murray score (appendix 1)[16] ≥ 3.0, or uncompensated hypercapnea with a pH < 7.20. This level of hypercapnea was selected to reflect common intensive care clinical practice. The Murray score must be calculated using all 4 parameters (PaO₂/FIO₂, Positive End Expiratory Pressure (PEEP), Lung compliance and Chest X-ray appearance). The Murray score of 3.0 is a MINIMUM entry criterion. Since patients may deteriorate quickly and conventional treatment must be optimised prior to referral into the trial, intensivists will also have the option to discuss registration of the patient for the trial as soon as the Murray score exceeds 2.5. If the patient then continues to deteriorate, prior identification of available beds, and discussion of the trial with the relatives, will allow rapid randomisation and trial entry.

Exclusion criteria prior to trial entry

• Duration of high pressure (> 30 cmH₂O of peak inspiratory pressure) and/or high FIO₂ (> 0.8) ventilation > 7 days[13].

• Intra-cranial bleeding.

• Any other contra-indication to limited heparinisation.

• Patients who are moribund and have any contra-indication to continuation of active treatment.

Moribund patients are those who the duty ECMO consultant feels have a very low chance of meaningful survival with ECMO treatment.

Allocation of patients

Selection bias at entry will be minimised by the procedures described below and shown schematically in Figure 1. Potentially eligible patients may be entered into the trial from any participating intensive care unit in the UK. [If a hospital has not yet received ethics committee approval, patients can be entered under an Emergency Inclusion Protocol (EIP)]. The referring intensivist will contact a member of the clinical advisory team to confirm that the patient is eligible for the trial, and that beds for ECMO and conventional management are available. These beds will then be ‘held’ for at least two hours. If these conditions are met, the referring intensivist will discuss the trial with the patient’s relative(s), give written information, and ask for agreement to trial entry. The relative will be asked to sign the assent form indicating that he/she believes his/her relative would not object to taking part in the study. The intensivist will then speak to the advisory team and, if the assent procedure has been completed, the advisor will telephone the independent central randomisation service to register the identifying details, and to give information about key prognostic factors. Randomisation will then be to conventional management or to consideration of ECMO support.

Minimization criteria will be used to ensure a balance of key prognostic factors between groups using the following criteria:

Type of centre (CTC or RH)

Age (18–30, 31–45, 46–65)

Hours of high pressure and/or high FIO₂ ventilation (0–48, 49–168)

Mode of trial entry (i.e. hypoxic/hypercarbic)

Diagnostic group (pneumonia, obstetric acute respiratory distress syndrome (ARDS), trauma including surgery within previous 24 hours, other ARDS, and other)

Numbers of organs failed 1–2 or 3 or more, failure being defined as an individual SOFA score for that organ of ≥ 2)[17,18].

If a patient is referred into the trial when there is no intensive care unit (ICU) or ECMO bed available that patient will not be entered. If beds become available subsequently, the patient is still suitable and the referring intensivist still wants to enter the patient then they will be randomised in the normal fashion. The fact that these patients were referred but were unable to be entered will be recorded.

Referrals for trial entry from hospitals not registered as trial centres; Emergency Inclusion Protocol (EIP)

During the study period ECMO will not be offered outside the framework of the trial to patients eligible for trial entry. If, exceptionally, a UK hospital from outside the study wishes to refer a patient, the transport team from the ECMO centre will go to the hospital and assess the patient. If the patient is suitable then they will call the central randomisation service and the patient will be randomised in the normal fashion. If the patient draws conventional treatment, the ECMO team will transport the patient to the nearest available CTC, and if selected for ECMO they will transport the patient back to Glenfield hospital.

Interventions

1. Conventional management

Patients randomised to conventional ventilatory support will receive the intensive care provided as standard in one of a number of participating CTCs. This may occasionally involve transfer (see Transport, below) from an RH. Conventional ventilatory support can include any treatment modality thought appropriate by the patient’s intensivist (excluding ECMO or other extracorporeal techniques). Intensivists will have full discretion to treat patients as they think appropriate. It will be recommended that intensivists adopt the low volume ventilation strategy. Adherence to this strategy is defined for the purposes of CESAR as a plateau pressure < 30 cmH₂O (or if plateau pressure is not measured the peak inspiratory pressure). This will usually mean a tidal volume of 4–8 ml/kg body weight as defined in the low tidal volume ventilation strategy according to the ARDS Network group[19].

Each CTC will produce their own statement of the general philosophy of treatment. This will be based on a pro-forma, which will detail their approach to ventilation, nutrition, antibiotics and other treatment issues. This pro-forma will also collect basic data regarding the size of unit, number of staff, cases treated per year etc.

2. ECMO

Patients randomised to ECMO will be transferred (see Transport, below) to the ECMO centre for consideration of ECMO support. During the trial, adult ECMO will only be available as part of the trial. There will be no crossover to ECMO for patients allocated to conventional management. ECMO will be provided according to published Glenfield Hospital treatment protocols[9]. This protocol is very similar to those used in other ELSO recognised adult ECMO centres[14], and is summarised below:

Veno-venous ECMO via percutaneous cannulation is used if the patient’s haemodynamic status is sufficiently stable to make cardiac assist (via veno-arterial access) unnecessary. Blood is drained from the right atrium through a cannula introduced via the right jugular or femoral veins, and is returned via the contra-lateral femoral vein. Circuits are designed to allow full support of gas exchange i.e. blood flow of 120 ml/kg/min. One or two (depending on body weight) Medos Hi-Lite 7000LT poly-methyl pentene lungs with heat exchangers are arranged in parallel with counter current gas flow, 100% oxygen is used as the sweep gas. Stockert (Sorin Biomedical) roller pumps with bladder box servo control or venous pressure servo-regulation are used. Blood raceway tubing is Tygon S-65-HL (Norton Performance Plastics). Normothermia is maintained. The circuit and patient are managed 24 hours per day by a trained ‘ECMO Specialist’ capable of performing surveillance and emergency repairs to the circuit.

During ECMO, ventilator settings are gradually reduced to allow lung rest, i.e. peak inspiratory pressure 20 cmH₂O, end expiratory pressure 10 cmH₂O, rate 10 breaths per minute and FIO₂ 30%. Anticoagulation is maintained with heparin to keep the activated clotting time (ACT) between 160 and 220 seconds. Patients are fed enterally or parenterally into the circuit, as indicated. Invasive procedures are avoided to reduce the risk of haemorrhage, and therefore any additional venous access necessary, e.g. for haemofiltration, is achieved via the circuit. Patients are diuresed to dry weight. Haemoglobin concentrations are maintained at 14 g/dl, and platelet counts are kept > 100,000 per ml. Patients are weaned from ECMO and decannulated when chest X-ray appearance and lung compliance have improved, and adequate gas exchange without excessive ventilation (peak pressure less than 30 cmH₂O, and FIO₂ less than 60%) can be demonstrated during a ‘trial-off’ ECMO.

Patients developing liver failure either during or after ECMO (defined as a serum bilirubin > 200 uMol/L) are supported with MARS (Molecular Absorbent Recirculating System, Teraklin GMBH, Rostock, Germany).

If the patient’s condition alters such that ECMO is no longer possible or appropriate then ECMO will not be initiated. However such a patient’s outcome will be analysed as part of the ECMO group (intention to treat).

3. Transport

Patients who are in a designated CTC will not need to be transported if they are randomised to conventional management. All other trial patients will need transport, which will be provided by a team from the ECMO centre. If the transport team decides that it is not safe to move the patient then s/he will remain in the original unit until s/he is considered safe to transfer, or recovers or dies. Such outcomes will also be analysed as part of the treatment option to which the patient was randomised i.e. analysis is by intention to treat.

Outcome measures

Primary

Death or severe disability at six months (defined as death by 6 months or before discharge from hospital at any time to end of data collection, or where the answer to the first two questions of the Euroqol questionnaire (EQ5D) are ‘confined to bed’ and ‘unable to wash or dress yourself’).

Secondary

1. Hospital indices: duration of ventilation, use of high frequency/oscillation/jet ventilation, use of nitric oxide, prone positioning, use of steroids, length of ICU stay, length of hospital stay. Some data will be recorded daily (see ‘Economic issues’, below). For ECMO patients only, data will be collected on mode (VV/VA), duration of ECMO, blood flow and sweep flow.

2. Health status 6 months after randomisation. This will include activities of daily living, quality of life, respiratory symptoms, cognitive psychological state and lung function. Where applicable carer strain will also be assessed. (See also ‘economic issues’ below.)

3. Surviving patients will be asked to give agreement for information to be held by the NHS Central Register if appropriate, further funding may be requested later for longer-term follow-up including lung function tests.

Six month follow-up

Assessment of outcome at the 6 month follow-up will be performed by trained researchers who will interview and examine patients in their homes. Patients and their relatives will be instructed not to reveal which treatment was used. Patients will wear a special scarf to cover the neck, masking the presence or absence of cannulation wounds. The assessment will include a generic measure of health status (SF36[20]) and quality of life (Euroqol EQ5D[21]), respiratory related quality of life (St George’s Hospital Respiratory Questionnaire[22]), psychological state (Hospital Anxiety and Depression Scale[23]) and cognitive function (Mini-Mental State Examination[24]). The interview will also include specific questions on sleep (from the Functional limitation profile[25]). Lung function will be assessed by spirometry. Where applicable, effects on the carer will be measured using the carer strain index[26]. If a home visit is unacceptable, patients will be offered a telephone interview or postal questionnaire. For those unwilling to be assessed by interview or questionnaire, permission will be requested for information to be sought from the patient’s general practitioner.

Longer term follow-up

Further follow up will be the subject of a separate protocol. So that the study organisers do not lose contact with patients should they move addresses, and also to follow up on health status, patients are being asked to give their agreement for their contact details to be sent to the NHS Central Register.

Economic issues

The primary objective of the economic evaluation is to assess incremental cost-effectiveness of ECMO in terms of additional survival with and without disability at six months post-randomisation. This will be done by determining the costs to health services and households, assessing cost-effectiveness from the viewpoint of the NHS and also from the societal viewpoint. The overall approach will be to describe the care received by patients in both arms of the trial, identifying use of health services with potentially important costs or changes in household resources.

The trial will assess the cost of treatment to the health and social services and to patients and their families in each treatment group. An incremental cost-effectiveness ratio will be calculated and compared to that for similar life-extending treatments. Information for the costs of inpatient and domiciliary care will be collected using methods adapted from the neonatal ECMO trial [21–23].

Costs of care will be estimated by recording use of key health care services as part of the data set for each person in the trial, and separately estimating costs associated with each item of health care use. Service use will be measured as daily level of intensive care support, until discharge to an ordinary ward. Subsequent health care costs will be based on days of inpatient care, and use of transport, outpatient and primary care services. Resource use after discharge from hospital will be collected by questionnaire at 6 month follow up. After discharge home, trial participants will be sent an ‘aide memoire’ to record health service contacts.

Societal costs will be estimated for this trial as the net total costs to health services and to patients. Societal costs of illness can also include the costs borne by relatives and friends of visiting, supporting and caring for the patient. It is likely that visiting costs will differ between trial arms. A literature review found no studies of visiting costs for adult patients. A pilot study conducted outside the CESAR trial has established a survey method for measuring costs[24] and will be conducted in a sub-sample of ICUs taking part in the trial and willing to do the additional research, in order to describe typical visiting costs for patients in ECMO and conventional centres.

To estimate levels of intensive care, data will be collected within the trial about the nature and duration of organ system support for individual patients. Data will be collected at the same time as the trial from participating intensive care centres and the ECMO centre to estimate costs of each level of care using a standard methodology [25,26]. Health care service use after discharge will be derived from a questionnaire to patients at 6 months. Patients agreeing to participate will be invited to complete a simple diary as a memory aid to assist completion of the 6-month questionnaire. Household costs will be determined according to any changes the patients may have experienced in household circumstances (including major costs related to the illness and changes in economic activities).

Cost-effectiveness in terms of disability free survival and quality-adjusted life years gained will be estimated based on 6-month responses to the Euroqol EQ5D questionnaire.

Finally, the implications of the trial for efficient provision of ECMO services in the UK will be considered. Until the end of the trial, ECMO will only be available in one centre. Cost analysis will be done to assess sensitivity of cost-effectiveness ratios to transport and local volume of service in the ICU and ECMO unit in order to predict the best configuration of ECMO services, if the treatment is effective.

Data collection instruments for economic evaluation

1. For trial patients and relatives

1. Daily organ support chart to be completed by caregivers in intensive care units for each patient in the trial

2. Patient’s diary of events after discharge – to be completed and kept by patient to help answer questions at 6 months.

3. EQ5D health related quality of life questionnaire

4. Patient’s and relative’s costs questionnaire: versions for survivors, and for relatives of patients who die (self completed)

2. For participating centres

1. ICU cost estimates derived from a national DH funded study conducted by one of the trial investigators [27,28] for each ICU (and equivalent for ECMO centre during final year of trial)

2. Daily ward costs from participating hospitals (based on finance data)

3. Transport costs

Other health and social care unit costs will be based on nationally available data (e.g. Netten and Dennett, PSSRU, University of Kent 1999 or NHS reference costs) or special costing exercises by researchers.

Methods of data collection and analysis for the economic evaluation alongside a national, multi-centre trial in the UK: Conventional ventilation or ECMO for Severe Adult Respiratory failure (CESAR)

Mariamma M Thalanany,1 Miranda Mugford,^1* Clare Hibbert,² Nicola J Cooper,³ Ann Truesdale,⁴ Steven Robinson,⁴ Ravindranath Tiruvoipati,^5,6 Diana R Elbourne,⁴ Giles J Peek,⁵ Felicity Clemens,⁴ Polly Hardy^4,7 and Andrew Wilson³ on behalf of the CESAR Trial Group

¹School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, UK

²Health Economics & Decision Science, School of Health & Related Research, University of Sheffield S1 4DA, UK

³Department of Health Sciences, University of Leicester LE1 7RH, UK

⁴London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK

⁵Glenfield Hospital, Leicester,UK, LE3 9QP, UK,

⁶Frankston Hospital, Victoria, Australia 3199

⁷Clinical Epidemiology and Biostatistics Unit, Royal Children’s Hospital, Melbourne, Australia

Email: MMT: m.thalanany@uea.ac.uk

MM: m.mugford@uea.ac.uk*

CH: Clare.Hibbert@astrazeneca.com

NJC: njc21@le.ac.uk

AT: ann.truesdale@lshtm.ac.uk

SR: steven.robertson@sgul.ac.uk

RT: travindranath@hotmail.com

ERD: diana.elbourne@lshtm.ac.uk

GJP: giles.peek@uhl-tr.nhs.uk

FC: Felicity.clemens@lshtm.ac.uk

PH: polly.hardy@mcri.edu.au

AW: aw7@le.ac.uk

* Corresponding author

Published on 30 April 2008 in BMC Health Services Research 2008, 8:94. doi:10.1186/1472-6963-8-94. Available online at: http://www.biomedcentral.com/1472-6963/8/94 .

Methods

Economic questions about treatment of severe respiratory failure

The economic evaluation addresses the question of value for money of the alternative treatment options. The economic question asks ‘for patients with severe but potentially reversible respiratory failure, is ECMO cost-effective from the viewpoints of the NHS and society?’. This question can be rephrased ‘is the additional cost of achieving an important gain in outcome within the range that the health funding system, or society, is willing to pay’?

The objectives of the economic evaluation are:

• To compare the costs of a policy of referral for ECMO with those of conventional treatment.

• To assess the cost-effectiveness of referral for ECMO compared with conventional treatment in terms of additional survival with and without disability at six months post-randomisation.

• To assess the cost-utility of referral for ECMO compared with conventional treatment in terms of utility gain as measured by EQ-5D at 6 months follow-up.

• To assess the cost-utility of referral for ECMO compared with conventional treatment in terms of utility gain as measured by EQ-5D, and other sources, over a predicted lifetime.

Design of the economic evaluation alongside the CESAR trial

The design of this economic evaluation alongside the CESAR trial is based on published recommendations [for example, 16]. This involves defining: the type of economic evaluation to be conducted; the comparator form of care; the perspective and time horizon for costs and outcomes; appropriate outcome measures for each perspective and type of evaluation; identification, measurement and valuation of resources; estimation of unit costs; and a plan for economic analysis, which includes decisions on discounting future costs and consequences, tackling uncertainties and presentation of results.

Type of economic evaluation

The first planned analysis is a cost effectiveness analysis (CEA) with increase in survival without severe disability at six months (the primary outcome in the CESAR trial) as the main outcome measure. A short term cost-utility analysis (CUA) was also planned in which health benefits are quantified in terms of quality-adjusted life-years (QALYs), and measured using the instrument EQ-5D at 6 months. Lifetime CUA is planned using a decision model based on CESAR trial results and including additional data for predicted lifetime QALYs and health care costs.

Comparator

The ideal comparator for any economic evaluation designed to assess the cost effectiveness in a particular context is the most commonly used treatment for the condition in that context. The CESAR trial was designed as a pragmatic comparison, where patients allocated to conventional care were receiving treatment that would be the normal form of care in the NHS. To ensure that the patients in the control group received as near as possible the best practice of care, the CESAR trial protocol specified aspects of service provision that must be considered, including facilities available at the participating ICUs, experience of treating such patients, and certain aspects of the clinical treatment protocol for ventilated patients. Full details are given in the CESAR trial protocol [11]. In general, however, the comparator group was intended to be representative of NHS care provision (in qualifying ICUs) for acute respiratory failure during the period of the trial.

Perspective or viewpoint for analyses

In the UK, the National Institute for Health and Clinical Excellence (NICE) proposes that applicants presenting economic analyses for NICE appraisals should take a NHS perspective [17]. However, there are aspects of public patient choice and valuation that may not be considered in such an analysis. Economic evaluators are guided to take a societal viewpoint if possible [16]. As the ECMO technology may be adopted for review by NICE or a similar agency in the UK, it was decided that the perspective for the CESAR trial should include both the NHS and societal perspectives. The latter viewpoint is important, as the results of this study are likely to have economic impacts other than through health care requirements if there is significantly increased survival of either able bodied or disabled adults. It is also anticipated that the results of the trial may provide useful information for a wider international audience where different ranges of services are provided within the health system.

Time horizon for economic evaluation

The follow-up duration for the CESAR trial is 6 months. This does not allow the full long term cost and benefits to be measured. However, it satisfies the recommendation of the American Thoracic Society for cost-effectiveness analyses of ICU therapies to have a minimum follow-up period of 6 months [10]. However, to meet our fourth objective, prediction and modelling longterm (lifetime) costs and benefits are also planned.

Outcome measures for economic evaluation

Survival without severe disability

Death of patients in the trial was recorded during the period of follow up whenever it occurred. Staff at the CESAR trial data management centre maintained contact with all centres with patients being treated within the CESAR trial ensuring complete reporting. For those discharged from hospital, contact was sought either through their home, or through their family doctors, if patients consented to be approached in either of these ways. Any further deaths would be reported in this way. Severe disability in survivors at six months was defined as those who were unable to care for themselves and were confined to bed: that is who had worst possible scores for the Euroqol EQ-5D domains for self care and for mobility.

Quality-adjusted life-years (QALYs)

The calculation of QALYs was planned to be based on assessment of health related quality of life at six months from randomisation. The EQ-5D is a standardised instrument used for measuring health outcomes. Quality-adjusted health utility weights for each patient are calculated for the CESAR trial using UK specific utility values for each patient’s response to the EQ-5D at 6 months. We could find no previous models for estimation of QALYs gained at 6 months in similar patients, and so they are estimated assuming that the value of the health state at trial entry was zero, and that over the months of survival, patients have experienced linearly increasing quality of life up to the level at 6 months.

Estimates of lifetime QALYs are predicted based on assumptions of gradual improvement of quality of life up to 2 years from randomization [18-22], and of predicted life expectancy based on age specific rates for the population of England and Wales. Age and sex specific life expectancy is calculated for each surviving patient in the trial using UK life tables [23]. It is assumed that, at 24 months post randomization, all surviving trial patients attained the same average life expectancy and health state as adults of similar age in the UK population. It is assumed that average health states for different age groups would be the same as those obtained from the 1996 Health survey for England [24].

Cost estimation

Identifying resource use

For the CESAR trial relevant aspects of resource use were identified using expert advice (managers, medical, nursing and patient representatives all commented on the draft lists) and also considering the items included in the economic evaluation of neonatal ECMO [12]. A list of resource items important from one or more viewpoints is given in Table 1. This includes resource use associated with initial stay in intensive and high dependency care units at different levels of care (measured by number of organs supported – see below), use of ambulance transport, stays in other hospital wards before discharge, costs of visiting incurred by relatives whilst patients are in hospital, resource use after discharge up to six months, major changes in household, out-of-pocket expenses of patient and family, loss of paid and unpaid working time, changes in working time, and informal care.

TABLE 1 - Items of resource use in the CESAR trial

Resource items	Instrument for data collection within CESAR trial	Source of unit cost data	References to sources
From trail entry to discharge from hospital
Days of organ support	Daily organ support form	ICU costing study	[36,37]
Days on ECMO	Daily organ support form	ICU costing study	[36,37]
Days on conventional ventilation	Daily organ support form	ICU costing study	[36,37]
Days in intensive care	Daily organ support form	ICU costing study	[36,37]
Days of other hospital stay before discharge	Outcomes data sheet	PSSRU – http://www.pssru.ac.uk/uc/uc2005contents.htm	[25]
Miles transported by air ambulance	Transport forms (a) and (b)	cost provided by transport provider
Miles transported by land ambulance	Transport forms (a) and (b)	cost provided by ambulance trusts
From discharge to follow-up at 6 months
Telephone contacts with GP	Events diary and patient cost questionnaire	PSSRU	[25]
Contacts with NHS direct	Events diary and patient cost questionnaire	NHS direct personal communication
Visits to GP	Events diary and patient cost questionnaire	PSSRU	[25]
Home visits by nurse	Events diary and patient cost questionnaire	PSSRU	[25]
Visits to counsellor	Events diary and patient cost questionnaire	PSSRU	[25]
Visits to physiotherapist	Events diary and patient cost questionnaire	PSSRU	[25]
Visits to occupational therapist	Events diary and patient cost questionnaire	PSSRU	[25]
Visits by health visitor	Events diary and patient cost questionnaire	PSSRU	[25]
Days of inpatient stay	Events diary and patient cost questionnaire	PSSRU	[25]
Outpatient visits	Events diary and patient cost questionnaire	PSSRU	[25]
A&E visits	Events diary and patient cost questionnaire	PSSRU	[25]
Visits to day hospital/ day care	Events diary and patient cost questionnaire	PSSRU	[25]
Days in residential care	Events diary and patient cost questionnaire	PSSRU	[25]
Days in nursing home	Events diary and patient cost questionnaire	PSSRU	[25]
Medication	Events diary and patient cost questionnaire
PSSRU	[25]
Visits by social worker	Events diary and patient cost questionnaire	PSSRU	[25]
Visits by homecare worker	Events diary and patient cost questionnaire	PSSRU	[25]
Aids & adaptations	Events diary and patient cost questionnaire	Reported by participants and some estimated from personal enquiries by researcher to equipment suppliers
Value of hours of informal care	Events diary and patient cost questionnaire	ONS	[30]
Miles of private car use for health care	Events diary and patient cost questionnaire	Automobile Association (AA)	[28]
Out-of-pocket expenses	Events diary and patient cost questionnaire	Reported by CESAR trial patients
Major changes in household	Events diary and patient cost questionnaire	Reported by CESAR trial patients
Childcare costs	Events diary and patient cost questionnaire	Reported by CESAR trial patients
Change in employment	Events diary and patient cost questionnaire	Reported by CESAR trial patients
Change in benefits or allowances	Events diary and patient cost questionnaire	Reported by CESAR trial patients
Loss of income from employment	Events diary and patient cost questionnaire	Reported by CESAR trial patients
Other costs	Events diary and patient cost questionnaire	Reported by CESAR trial patients
Other changes	Events diary and patient cost questionnaire	Reported by CESAR trial patients

Measuring resource use

Resource use data are collected prospectively for every trial participant at various points of his/her progress from recruitment to follow-up using a series of data forms and questionnaires. Some, but not all, of these are additional to the instruments planned for the CESAR trial management and clinical outcome data collection [11]. These instruments are:

1. Daily organ support form – completed by intensive care staff for each trial participant on a daily basis, and used to classify intensity of resources used during the intensive care ECMO/conventional treatment period.

2. Transport form (a) at trial entry – completed by Glenfield Hospital transport team to record transfer of trial participants to ECMO centre or conventional treatment centres.

3. Transport form (b) – completed by Glenfield transport team to record ambulance journey of participants returning either to the original recruiting hospital or another intensive care unit after ECMO.

4. Outcomes data sheet – completed by medical staff and records date on death of patient (if applicable), date of discharge, date of transfer to another hospital/home, use of ambulance for transfer etc.

5. Events Diary – to be completed and kept by every participant to document all services used from discharge to follow-up as an aide memoire to help them to answer questions at 6 months. This included information about informal help received as well as formal services.

6. Patient cost questionnaire at 6-month follow up – administered by trained interviewer at patient’s home or by telephone to collect resource use data from discharge to follow-up, covering items recorded in (e) above.

7. GP proforma – completed by GPs to collect medication use of those patients who refuse the 6-month follow-up but give permission for use of GP records.

The Events Diary (e) and the Patient cost questionnaire (f) were piloted with five patients discharged from Glenfield Hospital ICU, and the GP proforma (g) piloted with 5 general practitioners. Interviewers were trained in the administration of the patient cost questionnaire (f). As it was anticipated that many Ambulance Trusts across UK may become involved in transporting trial patients, all ambulance trusts were contacted and agreement obtained to provide costs of patient journeys (including overhead & running costs) as and when it took place during the trial.

Two items of resource use not collected alongside the trial are: resource use associated with and following a patient’s death in ICU, and cost incurred by relatives whilst visiting patients in intensive care/ hospital stay. These items were excluded from the data collection from CESAR trial patients due to the practical difficulty of collecting data and due to the lack of a well-defined methodology available at the early stages of planning the CESAR trial. However, the cost of visiting patients in intensive care was thought likely to be an important social cost, and is being estimated by a separate study in a sample of CESAR centres and is described in more detail under ‘Estimating unit costs’ below.

Resource data collection for the economic evaluation

Following recruitment, the progress of all participants is tracked initially until their discharge from hospital so that resource use, and clinical progress, can be accurately measured and collected at each stage. During the intensive treatment period (ECMO or conventional ventilation) data are collected on number of days spent in each treatment mode, including daily information on number of organs supported and the level of critical care (ICU or HDU). After transfer to another hospital or another ward within the same hospital after the acute phase of the illness, resource use is measured as number of in-patient days up to discharge.

Details of all ambulance use related to transferring trial patients at recruitment are collected by the Glenfield transport team and details of all other ambulance journeys (for example transfer between hospitals) are collected by the relevant hospitals and sent to the research team. Data collected include date, time, origin and destination of journey, mode of transport (road ambulance, fixed wing aircraft, or helicopter), duration of journey, and distance travelled by patient.

After discharge from hospital, each participant is sent details of the forthcoming interview and the ‘events diary’ to record resource use. The patient is asked to give permission for one of a series of options to take place 6 months after trial entry: (1) face-to-face interview, (2) telephone interview, (3) postal questionnaire and (4) collection of resource use from GP records. Those patients still in hospital at six months if fit enough are asked to give permission to be interviewed at their hospital bedside using a very short resource use questionnaire.

Estimating unit costs

In order to estimate total cost of treatment for each trial participant, the respective quantities of resource use are multiplied by their corresponding unit costs. Some resources used by participants are in the form of actual costs (not charges) and do not need any valuation. For example, cost of ambulance journeys are obtained directly from the relevant ambulance service providers and incorporate all overhead and running costs. The unit costs of most items of resource use are obtained from nationally available sources [25,26]. Use of medication is valued using the price of drugs listed in the British National Formulary [27]. Informal care is valued by the opportunity cost method suggested by Posnett & Jan [28]. Average cost per day of ICU and ECMO is obtained from a separate study and weighted/adjusted for each centre in the CESAR trial (see ‘Cost/day of ICU including ECMO unit care’ below). Cost of visiting is also derived from a separate study (see ‘Costs of visiting patients in intensive care’ below). Costs of private travel will be estimated using Automobile Association (AA) [28] motoring costs.

Valuation of informal care time

Informal time will be valued using weights suggested for Posnett & Jan’s [29] scenarios: working time were output is replaced; working time where output is not replaced; non-work time of those in paid employment and those not in paid employment; and finally time for those not in paid employment where unpaid housework is not replaced. Average wage rates of men and women in the United Kingdom needed for estimating time costs is obtained from Office of National Statistics (ONS) [30].

Predicted future costs of lifetime care

It was assumed that survivors at 6 months would continue to have similar average daily costs of care as at the 6 months follow up point, until 24 months post randomization. At 24 months, the average health service expenditure for the surviving patients in the CESAR trial was assumed to be the same as that of similar age groups in the UK. The age groups used in predicting future costs and benefits were: 16-44 years, 45-64 years, 65-74 years and 75-84 years. Data on health services costs for these age groups have been published in the proceedings of Parliament [31]. The same age groups were used as the basis for estimating both patients’ long-term costs and their benefits.

Price year, inflation, currency and discounting

Resources and costs will be measured in the year in which they occur using appropriate unit costs for each year of resource use. All costs are then revalued for analysis and reporting to 2005 UK values using health care inflation estimates.

The follow-up duration for the short term analyses is 6 months and therefore discounting is not necessary. For the lifetime estimates, costs and QALYs were discounted at 3.5%, based on UK Treasury guidelines [32].

Cost per day of ICU including ECMO unit care

The task of achieving a case-mix adjusted daily costs of ICU care was achieved through a prospective, observational, longitudinal multi-centre study (the ‘Critical Care HRG study’), concurrent with the CESAR trial, involving a volunteer sample of 70 critical care units, where monthly data on critical care unit expenditure together with daily data on patients’ organ support were collected for a two/three-month period [33]. The sample of participating critical care units had good geographical coverage in England with smaller numbers from Scotland and Northern Ireland, but none from Wales. An average daily cost of ICU was estimated by collecting data on the monthly expenditure of intensive care units and apportioning this sum by their monthly throughput of patients. Case-mix adjustment of this average daily cost was achieved by a weighting based on the number of organs supported on that day.

Data collection: Data on patients’ organ support requirements were collected on a daily basis by the critical care unit staff using specially designed data collection booklets. These data were collected for consecutive admissions during the study period. At the same time, the intensive care units and hospital finance departments were sent questionnaires to document their monthly expenditure on consumables (drugs and fluids, disposable equipment, nutritional products and blood and blood products), staff (consultant medical staff and other medical staff), clinical support services (radiology tests and laboratory services), professionals allied to medicine (physiotherapists, clinical pharmacists, dieticians, medical technical officers, information technologists, clinical and biomedical scientists, speech and language therapists, clinical psychologists and occupational therapists), support staff (personnel officers and directorate accountants) and specialised bed therapy. Data were also collected on the organizational characteristics of the intensive care units and the monthly number of patient days, number of staffed beds, number of patient admissions etc. An average daily cost was calculated using the following formula:

Σ ( Monthly expenditure on staff + consumables + clinical support services ) Monthly number of total patient days

The average daily cost in critical care ICU had to be adjusted to reflect the severity of illness or degree of organ support required by patients. For this purpose, data provided by 46 critical care units in the Critical Care ICU HRG study [34] were used. Only those critical care units that supplied data on their expenditure, organ support and unit characteristics were included in this analysis. The aim was to develop an appropriate model from which estimates of daily case-mix adjusted costs could be determined.

Different ways of modelling the organ support and expenditure data were explored. The model of choice was informed by the Breusch-Pagan and Hausman specification tests [35] that favoured a random-effects model based on the number of organs supported on a daily basis; clustered to include 0-1 organ, 2 organs and ≥ 3 organs. This model offered a simple and reproducible system of estimating case-mix adjusted costs of care. Daily organ support weights were 0.577 for 0-1 organ supported, 1.137 for 2 organs supported and 1.156 for ≥ 3 organs supported [36]. These weights will be applied to average daily costs of patients participating in the CESAR trial. A total cost per patient of their ICU stay was calculated by weighting patients’ average daily cost according to the number of organs supported on a daily basis and summing these daily costs for each patient.

Internal validation of the average daily cost data collected was not performed, however external validation was possible using data collected by the Critical Care National Cost Block Programme [37]. Twenty-one intensive care units in this study (30%) contributed data to the Cost Block Programme for the financial year 2000-2001. Although the Cost Block Programme collected data for a different time period and using a different configuration of units, the similarity between the mean costs per patient day is striking, in particular, the costs of consumables and clinical support services. The study by Hibbert et al [33] had wider coverage of resources with respect to professionals allied to medicine and an in-built allowance for capital equipment, which may be responsible for a slightly higher mean costs per day (£1302, 2003 price year) compared to £1028 (2001 price year, £1119 inflated to 2003 price year) for the Cost Block Programme.

The completeness of the returned data was investigated by each resource item and expressed as a percentage of the number of responses divided by the total number of 18 possible responses which reflected the quantity of data sought from participating centres. Data on nursing and administrative staff together with drugs and fluids yielded the highest number of responses (77%). Data on clinical and biomedical scientists and clinical psychologists yielded the lowest number of responses at 14%.

Not all CESAR centres participated in the Critical Care HRG study. Separate visits or contacts by correspondence were made with all CESAR centres that did not participate in the ICU HRG costing study, including the ECMO centre, to collect the same expenditure data in order to estimate the daily cost in the same way. Forty hospitals recruited patients up until the 31st March 2005. Given that more than one hospital recruited, in some cases, more than one patient during each financial year and patients could have received treatment in both an ICU and an HDU, one hundred and sixteen cost questionnaires were sent out in total to account for this (58 for the ICU and combined ICU / High Dependency Units (HDUs) and 58 for the separate HDUs – where provided). The types of critical care units i.e. which of the participating critical care units had both an ICU and an HDU or operated as a combined ICU / HDU, were not known, so each critical care unit was sent two cost questionnaires for each financial year when a patient was recruited to the trial. Thirteen hospitals completed the expenditure questionnaires however, only 11 hospitals returned data on both their unit characteristics and expenditure, which were needed in order to apportion the expenditure data correctly (i.e. down to an average daily cost). In order to estimate average daily costs for each CESAR hospital for the financial year in which a patient/ patients were treated, missing data were substituted with mean estimates obtained from the responding hospitals by financial year.

Figure 1 shows the whole process of estimating unit costs of ICU stay, derivation of weights for number of organs supported and how this feeds into the cost estimation in the trial. A fuller description of this part of the research is included in Clare Hibbert’s PhD thesis [36].

FIGURE 1.

Unit cost flowchart for hospital critical care.

Costs of visiting patients in intensive care

A pilot study of the costs of visiting [38] was carried out in December 2001 at an ICU in the UK. The daily costs per visit estimated in the pilot study are shown in Table 2. The pilot study informed the methods for a multi-centre study in six intensive care units in the UK which are registered with the CESAR trial. The aim was to estimate the average cost of visiting patients in intensive care. All adults including primary carers visiting the intensive care units during a three week duration were requested to complete a questionnaire that asked them about their time spent in visiting and travel, out-of-pocket expenses, employment status, loss of income etc. Data from this study will be used to estimate the average cost of visiting per day.

TABLE 2 - Cost of time forgone, lost pay, out-of-pocket expenses per visit to ICU at UK 2 2005 prices (source: Thalanany et al [38])

Daily costs	Range (£)	Mean (£)	Median (£)
Lost pay (n = 5)*	17.36–65.10	50.72	54.72
Cost of time forgone (n = 54)	5.04–208.32	46.21	24.06
Out-of-pocket expenses	0.00–509.54	29.30	9.39

Analysis and reporting of costs and economic evaluation

Estimation of costs for each patient

Costs falling upon the health sector (health & social services), upon patients or their families, and other costs such as help from friends will be presented in total and disaggregated form. Resource use and unit costs described above will be used for to estimate mean, medians, standard deviations and ranges of costs for each patient in the CESAR trial.

Cost effectiveness analysis

Incremental cost-effectiveness ratio (ICER)

With the availability of patient level data on costs and effects it is possible to summarize uncertainty in the ICER as a confidence interval. As cost data are typically not normally distributed, non-parametric bootstrapping will be used to generate confidence intervals.

Cost-utility analysis

Lifetime incremental cost-utility ratios will be estimated using bootstrap estimation methods [39,40], and using data and simplifying assumptions described in previous paragraphs.

Sensitivity analysis and uncertainty

Sensitivity analysis based on testing specific assumptions and probabilistic analysis will be used to explore the uncertainty in the results [41,42]. Items to be tested in sensitivity analyses are listed in Table 3. Primary analysis will be on complete case basis, where a complete case is defined as cases meeting the CESAR trial clinical effectiveness data analysis. Estimation of the key cost variables is based on between 40 and 50 data items representing different aspects of resource use from each participant. If any single item is missing, the cost variable will also be incomplete. We predict that the complete case analysis will contain a small proportion of the total number of trial participants and thus have a high potential for bias and imprecision. Any missing resource item values will be replaced with imputed values and re-analysed as part of the sensitivity analysis. Missing data will be imputed using Rubin’s multiple imputation method [43] with solas v3.20 (Statistical Solutions Inc, Co Cork, Eire).

TABLE 3 - Items to test during sensitivity analysis

	Ranges and thresholds
Days on ECMO	Highest & lowest observations
Length of stay in Critical Care Unit (ICU & HDU)	Highest & lowest calculated costs
Total length of stay in hospital	Highest & lowest calculated costs
Cost per day on organ support	Highest & lowest calculated costs
Distance from ECMO centre (cost of transport)	Replacing air with road transport
Change in difference in survival	Upper & lower CI of the attributable benefit
Other items with significant cost difference	Highest & lowest observations
Assumption of linear increasing utility for survivors over first 6 months	Assume constant utility at 6 month reported rate

Generalising the results to different settings

It would be beneficial to health care decision makers if economic study results could be generalised from one setting to another as this would avoid having to repeat every study in every setting. Factors which may vary in different settings are: unit costs of resources, geographical variations in demography or epidemiology of disease, clinical practice patterns, incentives to health care professionals and availability of resources. To facilitate estimation of the transferability of economic data from the CESAR trial to other health care setting, such factors in the study population will be described, and resource use and prices reported separately.

Health Technology Assessment reports published to date

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

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

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4. Screening for fragile X syndrome.

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

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

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8. Preschool vision screening.

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   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.

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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.

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

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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.

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

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

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

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19. Systematic reviews of trials and other studies.

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

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

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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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6. Assessing the costs of healthcare technologies in clinical trials.

   A review by Johnston K, Buxton MJ, Jones DR, Fitzpatrick R.

7. Cooperatives and their primary care emergency centres: organisation and impact.

   By Hallam L, Henthorne K.

8. Screening for cystic fibrosis.

   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.

   By Brazier J, Deverill M, Green C, Harper R, Booth A.

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.

13. ‘Early warning systems’ for identifying new healthcare technologies.

    By Robert G, Stevens A, Gabbay J.

14. A systematic review of the role of human papillomavirus testing within a cervical screening programme.

    By Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, et al.

15. Near patient testing in diabetes clinics: appraising the costs and outcomes.

    By Grieve R, Beech R, Vincent J, Mazurkiewicz J.

16. Positron emission tomography: establishing priorities for health technology assessment.

    A review by Robert G, Milne R.

17. The debridement of chronic wounds: a systematic review.

    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.

    By Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.

19. A systematic literature review of spiral and electron beam computed tomography: with particular reference to clinical applications in hepatic lesions, pulmonary embolus and coronary artery disease.

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

20. What role for statins? A review and economic model.

    By Ebrahim S, Davey Smith G, McCabe C, Payne N, Pickin M, Sheldon TA, et al.

21. Factors that limit the quality, number and progress of randomised controlled trials.

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

22. Antimicrobial prophylaxis in total hip replacement: a systematic review.

    By Glenny AM, Song F.

23. Health promoting schools and health promotion in schools: two systematic reviews.

    By Lister-Sharp D, Chapman S, Stewart-Brown S, Sowden A.

24. Economic evaluation of a primary care-based education programme for patients with osteoarthritis of the knee.

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

1. The estimation of marginal time preference in a UK-wide sample (TEMPUS) project.

   A review by Cairns JA, van der Pol MM.

2. Geriatric rehabilitation following fractures in older people: a systematic review.

   By Cameron I, Crotty M, Currie C, Finnegan T, Gillespie L, Gillespie W, et al.

3. Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research.

   By Davies SC, Cronin E, Gill M, Greengross P, Hickman M, Normand C.

4. Community provision of hearing aids and related audiology services.

   A review by Reeves DJ, Alborz A, Hickson FS, Bamford JM.

5. False-negative results in screening programmes: systematic review of impact and implications.

   By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

6. Costs and benefits of community postnatal support workers: a randomised controlled trial.

   By Morrell CJ, Spiby H, Stewart P, Walters S, Morgan A.

7. Implantable contraceptives (subdermal implants and hormonally impregnated intrauterine systems) versus other forms of reversible contraceptives: two systematic reviews to assess relative effectiveness, acceptability, tolerability and cost-effectiveness.

   By French RS, Cowan FM, Mansour DJA, Morris S, Procter T, Hughes D, et al.

8. An introduction to statistical methods for health technology assessment.

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

9. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review.

   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.

11. Cost and outcome implications of the organisation of vascular services.

    By Michaels J, Brazier J, Palfreyman S, Shackley P, Slack R.

12. Monitoring blood glucose control in diabetes mellitus: a systematic review.

    By Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R.

13. The effectiveness of domiciliary health visiting: a systematic review of international studies and a selective review of the British literature.

    By Elkan R, Kendrick D, Hewitt M, Robinson JJA, Tolley K, Blair M, et al.

14. The determinants of screening uptake and interventions for increasing uptake: a systematic review.

    By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J.

15. The effectiveness and cost-effectiveness of prophylactic removal of wisdom teeth.

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

16. Ultrasound screening in pregnancy: a systematic review of the clinical effectiveness, cost-effectiveness and women’s views.

    By Bricker L, Garcia J, Henderson J, Mugford M, Neilson J, Roberts T, et al.

17. A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.

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

18. Liquid-based cytology in cervical screening: a rapid and systematic review.

    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.

20. Routine referral for radiography of patients presenting with low back pain: is patients’ outcome influenced by GPs’ referral for plain radiography?

    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.

    By O’Meara S, Cullum N, Majid M, Sheldon T.

22. Using routine data to complement and enhance the results of randomised controlled trials.

    By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

23. Coronary artery stents in the treatment of ischaemic heart disease: a rapid and systematic review.

    By Meads C, Cummins C, Jolly K, Stevens A, Burls A, Hyde C.

24. Outcome measures for adult critical care: a systematic review.

    By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM, Daly K, et al.

25. A systematic review to evaluate the effectiveness of interventions to promote the initiation of breastfeeding.

    By Fairbank L, O’Meara S, Renfrew MJ, Woolridge M, Sowden AJ, Lister-Sharp D.

26. Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

    By Parkes J, Bryant J, Milne R.

27. Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

    By Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C.

28. Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial.

    By Baxter-Jones ADG, Helms PJ, Russell G, Grant A, Ross S, Cairns JA, et al.

29. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis.

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

30. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists in the medical management of unstable angina.

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

31. A randomised controlled trial of prehospital intravenous fluid replacement therapy in serious trauma.

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

32. Intrathecal pumps for giving opioids in chronic pain: a systematic review.

    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.

36. A randomised controlled trial to evaluate the effectiveness and cost-effectiveness of counselling patients with chronic depression.

    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.

    By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

39. The management of dyspepsia: a systematic review.

    By Delaney B, Moayyedi P, Deeks J, Innes M, Soo S, Barton P, et al.

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.

5. Eliciting public preferences for healthcare: a systematic review of techniques.

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

6. General health status measures for people with cognitive impairment: learning disability and acquired brain injury.

   By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

7. An assessment of screening strategies for fragile X syndrome in the UK.

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

8. Issues in methodological research: perspectives from researchers and commissioners.

   By Lilford RJ, Richardson A, Stevens A, Fitzpatrick R, Edwards S, Rock F, et al.

9. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy.

   By Cullum N, Nelson EA, Flemming K, Sheldon T.

10. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

    By Hampson SE, Skinner TC, Hart J, Storey L, Gage H, Foxcroft D, et al.

11. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

    By Jobanputra P, Parry D, Fry-Smith A, Burls A.

12. Statistical assessment of the learning curves of health technologies.

    By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT.

13. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review.

    By Dinnes J, Cave C, Huang S, Major K, Milne R.

14. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wounds healing by secondary intention.

    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

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.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

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

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

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

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

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

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

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

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

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

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

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

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, Riemsma 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 cost-effectiveness 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.

27. Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial.

    By Hay AD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S, et al.

28. A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the management of insulin-treated diabetes mellitus (MITRE).

    By Newman SP, Cooke D, Casbard A, Walker S, Meredith S, Nunn A, et al.

29. Sensitivity analysis in economic evaluation: an audit of NICE current practice and a review of its use and value in decision-making.

    By Andronis L, Barton P, Bryan S.

30. Trastuzumab for the treatment of primary breast cancer in HER2-positive women: a single technology appraisal.

    By Ward S, Pilgrim H, Hind D.

31. Docetaxel for the adjuvant treatment of early node-positive breast cancer: a single technology appraisal.

    By Chilcott J, Lloyd Jones M, Wilkinson A.

32. The use of paclitaxel in the management of early stage breast cancer.

    By Griffin S, Dunn G, Palmer S, Macfarlane K, Brent S, Dyker A, et al.

33. Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma.

    By Dundar Y, Bagust A, Hounsome J, McLeod C, Boland A, Davis H, et al.

34. Bortezomib for the treatment of multiple myeloma patients.

    By Green C, Bryant J, Takeda A, Cooper K, Clegg A, Smith A, et al.

35. Fludarabine phosphate for the firstline treatment of chronic lymphocytic leukaemia.

    By Walker S, Palmer S, Erhorn S, Brent S, Dyker A, Ferrie L, et al.

36. Erlotinib for the treatment of relapsed non-small cell lung cancer.

    By McLeod C, Bagust A, Boland A, Hockenhull J, Dundar Y, Proudlove C, et al.

37. Cetuximab plus radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck.

    By Griffin S, Walker S, Sculpher M, White S, Erhorn S, Brent S, et al.

38. Infliximab for the treatment of adults with psoriasis.

    By Loveman E, Turner D, Hartwell D, Cooper K, Clegg A

39. Psychological interventions for postnatal depression: cluster randomised trial and economic evaluation. The PoNDER trial.

    By Morrell CJ, Warner R, Slade P, Dixon S, Walters S, Paley G, et al.

40. The effect of different treatment durations of clopidogrel in patients with non-ST-segment elevation acute coronary syndromes: a systematic review and value of information analysis.

    By Rogowski R, Burch J, Palmer S, Craigs C, Golder S, Woolacott N.

41. Systematic review and individual patient data meta-analysis of diagnosis of heart failure, with modelling of implications of different diagnostic strategies in primary care.

    By Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, et al.

42. A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO trial.

    By Gray AJ, Goodacre S, Newby DE, Masson MA, Sampson F, Dixon S, et al. , on behalf of the 3CPO study investigators.

43. Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation.

    By Ara R, Pandor A, Stevens J, Rees A, Rafia R.

44. Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation.

    By Jones J, Shepherd J, Baxter L, Gospodarevskaya E, Hartwell D, Harris P, et al.

45. Methods to identify postnatal depression in primary care: an integrated evidence synthesis and value of information analysis.

    By Hewitt CE, Gilbody SM, Brealey S, Paulden M, Palmer S, Mann R, et al.

46. A double-blind randomised placebo-controlled trial of topical intranasal corticosteroids in 4- to 11-year-old children with persistent bilateral otitis media with effusion in primary care.

    By Williamson I, Benge S, Barton S, Petrou S, Letley L, Fasey N, et al.

47. The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model.

    By Bond M, Pitt M, Akoh J, Moxham T, Hoyle M, Anderson R.

48. Rehabilitation of older patients: day hospital compared with rehabilitation at home. A randomised controlled trial.

    By Parker SG, Oliver P, Pennington M, Bond J, Jagger C, Enderby PM, et al.

49. Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis.

    By Renfrew MJ, Craig D, Dyson L, McCormick F, Rice S, King SE, et al.

50. The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation.

    By Picot J, Jones J, Colquitt JL, Gospodarevskaya E, Loveman E, Baxter L, et al.

51. Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness.

    By Daniels J, Gray J, Pattison H, Roberts T, Edwards E, Milner P, et al.

52. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

    By Honest H, Forbes CA, Durée KH, Norman G, Duffy SB, Tsourapas A, et al.

53. The effectiveness and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults: a systematic review and economic model.

    By Bond M, Mealing S, Anderson R, Elston J, Weiner G, Taylor RS, et al.

54. Gemcitabine for the treatment of metastatic breast cancer.

    By Jones J, Takeda A, Tan SC, Cooper K, Loveman E, Clegg A.

55. Varenicline in the management of smoking cessation: a single technology appraisal.

    By Hind D, Tappenden P, Peters J, Kenjegalieva K.

56. Alteplase for the treatment of acute ischaemic stroke: a single technology appraisal.

    By Lloyd Jones M, Holmes M.

57. Rituximab for the treatment of rheumatoid arthritis.

    By Bagust A, Boland A, Hockenhull J, Fleeman N, Greenhalgh J, Dundar Y, et al.

58. Omalizumab for the treatment of severe persistent allergic asthma.

    By Jones J, Shepherd J, Hartwell D, Harris P, Cooper K, Takeda A, et al.

59. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma.

    By Boland A, Bagust A, Hockenhull J, Davis H, Chu P, Dickson R.

60. Adalimumab for the treatment of psoriasis.

    By Turner D, Picot J, Cooper K, Loveman E.

61. Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal.

    By Holmes M, C Carroll C, Papaioannou D.

62. Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura: a single technology appraisal.

    By Mowatt G, Boachie C, Crowther M, Fraser C, Hernández R, Jia X, et al.

63. Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

    By Bond M, Hoyle M, Moxham T, Napier M, Anderson R.

64. Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

    By Stevenson M, Lloyd-Jones M, Papaioannou D.

65. The effects of biofeedback for the treatment of essential hypertension: a systematic review.

    By Greenhalgh J, Dickson R, Dundar Y.

66. A randomised controlled trial of the use of aciclovir and/or prednisolone for the early treatment of Bell’s palsy: the BELLS study.

    By Sullivan FM, Swan IRC, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al.

67. Lapatinib for the treatment of HER2-overexpressing breast cancer.

    By Jones J, Takeda A, Picot J, von Keyserlingk C, Clegg A.

68. Infliximab for the treatment of ulcerative colitis.

    By Hyde C, Bryan S, Juarez-Garcia A, Andronis L, Fry-Smith A.

69. Rimonabant for the treatment of overweight and obese people.

    By Burch J, McKenna C, Palmer S, Norman G, Glanville J, Sculpher M, et al.

70. Telbivudine for the treatment of chronic hepatitis B infection.

    By Hartwell D, Jones J, Harris P, Cooper K.

71. Entecavir for the treatment of chronic hepatitis B infection.

    By Shepherd J, Gospodarevskaya E, Frampton G, Cooper, K.

72. Febuxostat for the treatment of hyperuricaemia in people with gout: a single technology appraisal.

    By Stevenson M, Pandor A.

73. Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal.

    By Stevenson M, Scope A, Holmes M, Rees A, Kaltenthaler E.

74. Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

    By Greenhalgh J, Bagust A, Boland A, Fleeman N, McLeod C, Dundar Y, et al.

75. Mifamurtide for the treatment of osteosarcoma: a single technology appraisal.

    By Pandor A, Fitzgerald P, Stevenson M, Papaioannou D.

76. Ustekinumab for the treatment of moderate to severe psoriasis.

    By Gospodarevskaya E, Picot J, Cooper K, Loveman E, Takeda A.

77. Endovascular stents for abdominal aortic aneurysms: a systematic review and economic model.

    By Chambers D, Epstein D, Walker S, Fayter D, Paton F, Wright K, et al.

78. Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation.

    By Chen Y-F, Jowett S, Barton P, Malottki K, Hyde C, Gibbs JSR, et al.

79. Cessation of attention deficit hyperactivity disorder drugs in the young (CADDY) – a pharmacoepidemiological and qualitative study.

    By Wong ICK, Asherson P, Bilbow A, Clifford S, Coghill D, R DeSoysa R, et al.

80. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening.

    By Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, et al.

81. The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a systematic review and economic evaluation.

    By Black C, Clar C, Henderson R, MacEachern C, McNamee P, Quayyum Z, et al.

82. Randomised preference trial of medical versus surgical termination of pregnancy less than 14 weeks’ gestation (TOPS).

    By Robson SC, Kelly T, Howel D, Deverill M, Hewison J, Lie MLS, et al.

83. Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes.

    By Jeffcoate WJ, Price PE, Phillips CJ, Game FL, Mudge E, Davies S, et al.

84. VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers.

    By Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, et al.

85. A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: the VULCAN trial

    By Michaels JA, Campbell WB, King BM, MacIntyre J, Palfreyman SJ, Shackley P, et al.

86. Communication of carrier status information following universal newborn screening for sickle cell disorders and cystic fibrosis: qualitative study of experience and practice.

    By Kai J, Ulph F, Cullinan T, Qureshi N.

87. Antiviral drugs for the treatment of influenza: a systematic review and economic evaluation.

    By Burch J, Paulden M, Conti S, Stock C, Corbett M, Welton NJ, et al.

88. Development of a toolkit and glossary to aid in the adaptation of health technology assessment (HTA) reports for use in different contexts.

    By Chase D, Rosten C, Turner S, Hicks N, Milne R.

89. Colour vision testing for diabetic retinopathy: a systematic review of diagnostic accuracy and economic evaluation.

    By Rodgers M, Hodges R, Hawkins J, Hollingworth W, Duffy S, McKibbin M, et al.

90. Systematic review of the effectiveness and cost-effectiveness of weight management schemes for the under fives: a short report.

    By Bond M, Wyatt K, Lloyd J, Welch K, Taylor R.

91. Are adverse effects incorporated in economic models? An initial review of current practice.

    By Craig D, McDaid C, Fonseca T, Stock C, Duffy S, Woolacott N.

1. Multicentre randomised controlled trial examining the cost-effectiveness of contrast-enhanced high field magnetic resonance imaging in women with primary breast cancer scheduled for wide local excision (COMICE).

   By Turnbull LW, Brown SR, Olivier C, Harvey I, Brown J, Drew P, et al.

2. Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation.

   By Thompson Coon J, Hoyle M, Green C, Liu Z, Welch K, Moxham T, et al.

3. The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation.

   By Fleeman N, McLeod C, Bagust A, Beale S, Boland A, Dundar Y, et al.

4. Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer.

   By Mowatt G, Zhu S, Kilonzo M, Boachie C, Fraser C, Griffiths TRL, et al.

5. Effectiveness and cost-effectiveness of arthroscopic lavage in the treatment of osteoarthritis of the knee: a mixed methods study of the feasibility of conducting a surgical placebo-controlled trial (the KORAL study).

   By Campbell MK, Skea ZC, Sutherland AG, Cuthbertson BH, Entwistle VA, McDonald AM, et al.

6. A randomised 2 × 2 trial of community versus hospital pulmonary rehabilitation for chronic obstructive pulmonary disease followed by telephone or conventional follow-up.

   By Waterhouse JC, Walters SJ, Oluboyede Y, Lawson RA.

7. The effectiveness and cost-effectiveness of behavioural interventions for the prevention of sexually transmitted infections in young people aged 13–19: a systematic review and economic evaluation.

   By Shepherd J, Kavanagh J, Picot J, Cooper K, Harden A, Barnett-Page E, et al.

8. Dissemination and publication of research findings: an updated review of related biases.

   By Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, et al.

9. The effectiveness and cost-effectiveness of biomarkers for the prioritisation of patients awaiting coronary revascularisation: a systematic review and decision model.

   By Hemingway H, Henriksson M, Chen R, Damant J, Fitzpatrick N, Abrams K, et al.

10. Comparison of case note review methods for evaluating quality and safety in health care.

    By Hutchinson A, Coster JE, Cooper KL, McIntosh A, Walters SJ, Bath PA, et al.

11. Clinical effectiveness and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes: systematic review and economic evaluation.

    By Cummins E, Royle P, Snaith A, Greene A, Robertson L, McIntyre L, et al.

12. Self-monitoring of blood glucose in type 2 diabetes: systematic review.

    By Clar C, Barnard K, Cummins E, Royle P, Waugh N.

13. North of England and Scotland Study of Tonsillectomy and Adeno-tonsillectomy in Children (NESSTAC): a pragmatic randomised controlled trial with a parallel non-randomised preference study.

    By Lock C, Wilson J, Steen N, Eccles M, Mason H, Carrie S, et al.

14. Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.

    By Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FGR, Gillespie I, et al.

15. A randomised controlled multicentre trial of treatments for adolescent anorexia nervosa including assessment of cost-effectiveness and patient acceptability – the TOuCAN trial.

    By Gowers SG, Clark AF, Roberts C, Byford S, Barrett B, Griffiths A, et al.

16. Randomised controlled trials for policy interventions: a review of reviews and meta-regression.

    By Oliver S, Bagnall AM, Thomas J, Shepherd J, Sowden A, White I, et al.

17. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review.

    By McDaid C, Maund E, Rice S, Wright K, Jenkins B, Woolacott N.

18. A systematic review of outcome measures used in forensic mental health research with consensus panel opinion.

    By Fitzpatrick R, Chambers J, Burns T, Doll H, Fazel S, Jenkinson C, et al.

19. The clinical effectiveness and cost-effectiveness of topotecan for small cell lung cancer: a systematic review and economic evaluation.

    By Loveman E, Jones J, Hartwell D, Bird A, Harris P, Welch K, et al.

20. Antenatal screening for haemoglobinopathies in primary care: a cohort study and cluster randomised trial to inform a simulation model. The Screening for Haemoglobinopathies in First Trimester (SHIFT) trial.

    By Dormandy E, Bryan S, Gulliford MC, Roberts T, Ades T, Calnan M, et al.

21. Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis.

    By Black C, Sharma P, Scotland G, McCullough K, McGurn D, Robertson L, et al.

22. A randomised controlled trial of cognitive behaviour therapy and motivational interviewing for people with Type 1 diabetes mellitus with persistent sub-optimal glycaemic control: A Diabetes and Psychological Therapies (ADaPT) study.

    By Ismail K, Maissi E, Thomas S, Chalder T, Schmidt U, Bartlett J, et al.

23. A randomised controlled equivalence trial to determine the effectiveness and cost–utility of manual chest physiotherapy techniques in the management of exacerbations of chronic obstructive pulmonary disease (MATREX).

    By Cross J, Elender F, Barton G, Clark A, Shepstone L, Blyth A, et al.

24. A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure.

    By McKenna C, Burch J, Suekarran S, Walker S, Bakhai A, Witte K, et al.

25. Avoiding and identifying errors in health technology assessment models: qualitative study and methodological review.

    By Chilcott JB, Tappenden P, Rawdin A, Johnson M, Kaltenthaler E, Paisley S, et al.

26. BoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A.

    By Shaw L, Rodgers H, Price C, van Wijck F, Shackley P, Steen N, et al. , on behalf of the BoTULS investigators.

27. Weighting and valuing quality-adjusted life-years using stated preference methods: preliminary results from the Social Value of a QALY Project.

    By Baker R, Bateman I, Donaldson C, Jones-Lee M, Lancsar E, Loomes G, et al.

28. Cetuximab for the first-line treatment of metastatic colorectal cancer.

    By Meads C, Round J, Tubeuf S, Moore D, Pennant M and Bayliss S.

29. Infliximab for the treatment of acute exacerbations of ulcerative colitis.

    By Bryan S, Andronis L, Hyde C, Connock M, Fry-Smith A and Wang D.

30. Sorafenib for the treatment of advanced hepatocellular carcinoma.

    By Connock M, Round J, Bayliss S, Tubeuf S, Greenheld W and Moore D.

31. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection.

    By Jones J, Colquitt J, Shepherd J, Harris P and Cooper K.

32. Prasugrel for the treatment of acute coronary artery syndromes with percutaneous coronary intervention.

    By Greenhalgh J, Bagust A, Boland A, Saborido CM, Fleeman N, McLeod C, et al.

33. Alitretinoin for the treatment of severe chronic hand eczema.

    By Paulden M, Rodgers M, Griffin S, Slack R, Duffy S, Ingram JR, et al.

34. Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer.

    By Fleeman N, Bagust A, McLeod C, Greenhalgh J, Boland A, Dundar Y, et al.

35. Topotecan for the treatment of recurrent and stage IVB carcinoma of the cervix.

    By Paton F, Paulden M, Saramago P, Manca A, Misso K, Palmer S, et al.

36. Trabectedin for the treatment of advanced metastatic soft tissue sarcoma.

    By Simpson EL, Rafia R, Stevenson MD and Papaioannou D.

37. Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia.

    By Edlin R, Connock M, Tubeuf S, Round J, Fry-Smith A, Hyde C, et al.

38. The safety and effectiveness of different methods of earwax removal: a systematic review and economic evaluation.

    By Clegg AJ, Loveman E, Gospodarevskaya E, Harris P, Bird A, Bryant J, et al.

39. Systematic review of the clinical effectiveness and cost-effectiveness of rapid point-of-care tests for the detection of genital chlamydia infection in women and men.

    By Hislop J, Quayyum Z, Flett G, Boachie C, Fraser C, Mowatt G.

40. School-linked sexual health services for young people (SSHYP): a survey and systematic review concerning current models, effectiveness, cost-effectiveness and research opportunities

    By Owen J, Carroll C, Cooke J, Formby E, Hayter M, Hirst J, et al.

41. Systematic review and cost-effectiveness evaluation of ‘pill-in-the-pocket’ strategy for paroxysmal atrial fibrillation compared to episodic in-hospital treatment or continuous antiarrhythmic drug therapy.

    By Martin Saborido C, Hockenhull J, Bagust A, Boland A, Dickson R, Todd D.

42. Chemoprevention of colorectal cancer: systematic review and economic evaluation.

    By Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan, RF, et al.

43. Cross-trimester repeated measures testing for Down’s syndrome screening: an assessment.

    By Wright D, Bradbury I, Malone F, D’Alton M, Summers A, Huang T, et al.

44. Exploring the needs, concerns and behaviours of people with existing respiratory conditions in relation to the H1N1 ‘swine influenza’ pandemic: a multicentre survey and qualitative study

    By Caress A-L , Duxbury P, Woodcock A, Luker KA, Ward D, Campbell M, et al.

45. Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant

    By Yates L, Pierce M, Stephens S, Mill AC, Spark P, Kurinczuk JJ, et al.

46. The impact of communications about swine flu (influenza A H1N1v) on public responses to the outbreak: results from 36 national telephone surveys in the UK

    By Rubin GJ, Potts HWW, Michie S.

47. The impact of illness and the impact of school closure on social contact patterns

    By Eames KTD, Tilston NL, White PJ, Adams E, Edmunds WJ.

48. Vaccine effectiveness in pandemic influenza – primary care reporting (VIPER): an observational study to assess the effectiveness of the pandemic influenza A (H1N1)v vaccine

    By Simpson CR, Ritchie LD , Robertson C, Sheikh A, McMenamin J.

49. Physical interventions to interrupt or reduce the spread of respiratory viruses: a Cochrane review

    By Jefferson T, Del Mar C , Dooley L, Ferroni E, Al-Ansary LA, Bawazeer, GA et al.

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