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

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 02/09/04. The contractual start date was in November 2003. The draft report began editorial review in September 2007 and was accepted for publication in March 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

None

Copyright statement

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

2009 Queen’s Printer and Controller of HMSO

Disease condition

Bell’s palsy is an acute unilateral paralysis of the facial nerve first described by the Scottish surgeon Sir Charles Bell (1774–1842). 1 Its cause is unknown but animal studies have suggested the possibility that reactivation of herpes viruses may be responsible for demyelination. 2,3 It affects 11–40 people per 100,000 in the population per annum, most commonly in the age group 30–45. 4 The condition presents disproportionately among pregnant women and people who have diabetes, influenza, a cold or some other upper respiratory ailment. On average every year a general practitioner will see one or two patients who have developed the condition. A recent UK study using the General Practice Research Database (GPRD) showed that 36% of patients were treated with oral steroids and 19% were referred to hospital. 5 Although most patients recover well, 30% have a poor recovery with continuing facial disfigurement, psychological difficulties and sometimes facial pain (though the presence and course of pain is unclear from current knowledge). 6 In the absence of an established aetiology, treatment continues to be based upon the established pathophysiology: swelling and entrapment of the nerve.

Two recent Cochrane reviews concerning the treatment of Bell’s palsy have examined the effectiveness of oral prednisolone and aciclovir. 7,8 These found that insufficient data exist to conclude that either or both therapies are effective. Many of the studies included in the reviews either failed to randomise patients or, when correctly randomised, were erroneously interpreted in a favourable light. 9,10 In addition, high-dose steroid therapy has numerous potential side effects including peptic ulceration, hypertension and confusional states. Antiviral therapy is expensive and should be reserved for circumstances where definite benefits are likely to be obtained. Current recommendations suggest that aciclovir needs to be started within 48 hours, though more recent studies of viral replication in patients with Bell’s palsy suggest that this might be extended. 11

Provenance of the Scottish Bell’s Palsy Study

Given this lack of evidence the UK National Institute for Health Research (NIHR) Health Technology Assessment programme commissioned an independent academic group to conduct a randomised clinical trial to determine whether prednisolone or aciclovir, used separately or in combination and used early in the course of Bell’s palsy, improved the chances of recovery at 3 and 9 months.

With this defined as the primary research question, the protocol for the Scottish Bell’s Palsy Study was developed and submitted and is provided as Appendix 1. A small number of variations to the protocol are summarised where they arise.

Governance

We established three committees for the oversight of the study – a Trial Steering Committee (TSC: constitution and personnel listed in Appendix 2); a Data Monitoring and Ethics Committee (DMEC: constitution and personnel listed in Appendix 3); and a Management Committee for the day-to-day monitoring of the progress of the trial, comprising the nine Principal Investigators, Trial Co-ordinator and three Researchers (personnel listed in Appendix 4).

The lead host organisation and the sponsor of the study was the University of Dundee.

Associate host organisations (trial centres) were the Universities of Glasgow, Edinburgh and Aberdeen.

Approvals

In common with many researchers and triallists setting up studies during 2003–4 raising questions in the clinical arena and requiring the participation of patient groups, we found the processes for obtaining approvals demanding and time-consuming in a way that they had not been previously. With other research teams we were invited to summarise our experience for an investigative commission headed by Professor Adrian Grant on behalf of Scotland’s Chief Scientist Office (CSO), and did so as outlined in Appendix 5. We recognise that our experience was not untypical of that of other researchers at the time, but we include our report to the CSO and this account of it because of the depth of feeling that was then commonly reported by researchers.

Ethical approval for the study was provided by the lead research ethics committee, Multicentre Research Ethics Committee (MREC) Scotland (Edinburgh) reference MREC 03/0/74, and by Local Research Ethics Committees (LRECs) where patients were referred to local sites, or where the study recruited patients. Research and Development (R&D) approval was provided by local R&D offices likewise. The Clinical Trials Authority to use prednisolone, aciclovir and lactose placebo was provided by the Medicines and Healthcare Products Regulatory Agency (MHRA), references MF8000/13139 and 13140 respectively. The study was registered with Current Controlled Trials reference ISRCTN 71548196 under the title Bell’s palsy: Early acicLovir and/or prednisoLone in Scotland (‘BELLS’) and from 07/08/2007 its registered status is ‘Completed’.

Study calendar

The study calendar is shown in Table 1. The total duration of the study was 44 months of which 25 months were dedicated to patient recruitment.

The calendar represents an amendment to the original timetable, being an 8-month extension to the study overall, which had comprised 3 months for approvals, 18 months for patient recruitment, 9 months for patient follow-up and 6 months for analysis (i.e. 36 months altogether).

Submission of a paper describing the results of the study to an appropriate journal, and of a draft final report to the funder were scheduled to take place as soon as possible following completion of the analysis of results.

Referrers

Patients identified in primary medical and dental care or accident and emergency (A&E) departments and those who approached NHS24 (a 24-hour medical advice line in Scotland similar to NHS Direct in England and Wales, which also co-ordinates all general practice out-of-hours consultations) with an appropriate description of symptoms, were asked to attend 1 of 17 hospital sites where trial arrangements were in place. The geographical coverage of the BELLS study is shown in Figure 1. The contributing sites are listed in Table 2.

FIGURE 1.

Map of hospital sites contributing to the BELLS study.

We recognised that not all of these patients would be notified to the study or recruited to it. It was important therefore to pilot notification of the condition prior to running the study to determine if general practitioners considered the condition to be of sufficiently significant importance to become involved in a trial, and what proportion of patients would be recruited.

In order to test this we piloted a notification process in one region of Scotland. With the co-operation of the local research networks in Tayside and Fife we asked general practitioners to notify us of all patients presenting with Bell’s palsy over a period of 1 month. As a result of this exercise we determined that we would be able to recruit one-third of those presenting within 48 hours of diagnosis. Of those, we assumed that two-thirds would remain in the trial for review at 9 months. In order therefore to recruit and retain the 480 patients necessary to detect a 12% difference in treatment effect from Scottish recruitment, we needed to recruit continuously for 25 months.

As it was unlikely that individual general practitioners or A&E doctors would be involved more than once in the trial it was essential that their role should be clearly delineated and relatively simple to carry out, and that instruction should be available relatively easily. The involvement of recruiting doctors was restricted to diagnosis followed by determination of the patients’ interest in participating, exclusion of ineligible patients, and a telephone referral to the on-call otolaryngology specialist. The trial process actually constituted a reduction in clinical workload for most general pratitioners, who would normally undertake follow-up of patients without input from hospital colleagues. 12 The trial also offered immediate access to specialist assessment, which would not be provided under normal care. Both of these attributes were found to be very attractive to general practitioners and patients during the planning phase of the trial.

Doctors need to be reminded regularly of an ongoing trial of a condition that occurs relatively sporadically. 13 In addition, there is a high turnover among staff in A&E departments and training grades in general practice and otolaryngology. A variety of strategies publicising the trial were set in motion.

Mailshots

The responsibility for keeping doctors informed about the on-going trial was taken on by SPPIRe14 (Scottish Professionals and Practices Interested in Research, since renamed SPCRN, the Scottish Primary Care Research Network, to fit the SPCRN model). All general practitioners in the four participating regions of Scotland were sent a mailshot outlining the trial and explaining how to take part. We emphasised the importance of the condition and the simplicity of involvement. The mailshots were in colour and designed to be attractive; further, based on evidence from the literature, we highlighted the benefits to patients15 and remuneration to general practitioners16 for taking part, and letters were signed by well-known local general practitioner ‘champions’. 17 Separate mailshots went out to non-principal doctors and registrars.

The trial was also highlighted in Local Medical Committee briefings to general practitioners throughout the country. We estimate that each quarterly mailshot took about a day of researcher time in each of the four participating regions. A&E departments were kept informed by literature and posters from the centre; similarly, general practice co-operatives were informed through literature and posters distributed with SPPIRe’s help, while NHS24 was in direct contact with the study centre. We found that the most attention-grabbing poster was one showing photographs of a patient at onset (see Figure 2). Every mailshot included the project’s web address and telephone contact details.

FIGURE 2.

Posed portrait photographs (at rest, smiling, eyes tight shut, eyebrows raised). Note: This patient was graded HB5 by the panel of assessors.

Recruiters

Heads of ear, nose and throat (ENT) departments at 20 hospitals in Scotland that could contribute to the trial as recruiting sites were approached, and 17 agreed to join. It was never anticipated that the trial would recruit in the island regions; however, both potential centres in NHS Forth Valley (Stirling Royal Infirmary, Falkirk & District Royal Infirmary) and also that for NHS Dumfries & Galloway (Dumfries & Galloway Royal Infirmary) declined to join, reducing the national coverage to an estimated 88% of the Scottish population. In all cases, staffing difficulties were cited as the reason for non-participation. The three main Scottish dental institutions (Dundee Dental Hospital, Glasgow Dental Hospital and Edinburgh Dental Institute) were also approached but rather than act as recruiting sites agreed to refer potential patients to the nearest site. The 17 sites (with additional premises at Ninewells Hospital and Royal Alexandra Hospital) finally organised and provisioned with study medications and stationery were the ENT wards and clinics listed in Table 2. The head of each contributing clinic or department was formally designated Local Principal Investigator with site-specific approvals from their LREC and R&D division; these are listed in Appendix 7.

Each trial site was supplied with stationery (site folders; patient information sheets, consent forms and case record forms – see Appendices referred to later); instructions for the process of randomisation; and patient packs comprising the trial medications in appropriate storage locations (e.g. drugs cupboards).

Prior to the start of recruitment all sites were briefed by the Local Principal Investigator or a member of the BELLS team or both. The briefing was provided as part of the standard educational programme and potential recruiters were taken step-by-step through the processes of recruitment as follows.

Patients

Patients were referred to participating sites after presentation at GP surgeries, A&E, NHS24 or (rarely) their dentist. After the diagnosis of Bell’s palsy was confirmed then inclusion and exclusion criteria were examined. See Table 3 for a full listing of inclusion and exclusion criteria.

Interventions

Patients satisfying the criteria for entry into the Scottish Bell’s Palsy Study and who were willing to join it, and who had provided signed witnessed consent, were immediately randomised into the trial as follows. In order to accommodate the intended 2 × 2 factorial design (see Table 4) patients were randomised to prednisolone/placebo and to aciclovir/placebo as follows, with all processes necessary to achieve balance attended to by the randomisation unit at HSRU.

In Table 4 we use the shorthand abbreviations that will be used throughout this report to distinguish between the treatment groups, specifically:

and

Medications were prescribed according to the doses described in Table 5.

The four treatment combinations were provided in packs labelled Treatment 1, 2, 3, 4 with all participants masked (referrers, recruiters, patients and researchers, and, later, assessors). The bottles, labelling and capsules are shown in Figure 3.

FIGURE 3.

(a) Study medications: bottles (ten days’ treatment). (b) Study medications: capsules (one day’s dose).

Patients were requested to commence the first dose on site, even if there was sufficient time only to complete a half-day’s dose.

Identification of coded treatments

The identification of treatments was established by code break in the presence of the Chief Investigator, Trial Statistician and Trial Co-ordinator on 20 March 2007 by agreement with the TSC and DMEC, after the last patient was followed up and all primary and secondary outcomes obtained.

For clarity in the sequel, the identification of treatments is provided in Table 6.

Researchers

The geographical coverage of the study was split into four regions, each staffed by one researcher as shown in Table 7.

After interview and appointment researchers were briefed to practise as outlined in Appendix 14, in order to achieve as uniform an approach as possible. During the first patient visit (as well as completing study instruments; see later) the researcher completed Form C (checklist, see Appendix 15) and Form B (patient details, see Appendix 16). In particular, Form C contains the check item that the treatment dispensed to the patient was that allocated.

Patients were assessed during a home visit 3–5 days after randomisation, i.e. up to 8 days after onset of symptoms; again after 3 months; and finally at a third assessment after 9 months, if they were still unrecovered (House–Brackmann grade II–VI) at 3 months.

The preceding paragraph encapsulates two variations to protocol made on clinical grounds within weeks of the commencement of patient randomisation. These were:

Assessors

The fifth and final group of participants were the assessors, whose role was to assess the patients’ recovery status (House–Brackmann grading I to VI) on the basis of the posed photographs taken by the researcher during patient visits. These were experts in their field (one otolaryngologist, one neurosurgeon, one plastic surgeon) and were blinded to the patient treatment allocation, and to the timing of the visit (onset, 3 months or 9 months) throughout the assessment period. A typical set of the four required posed photographs is shown as Figure 2. (This patient’s signed consent for publication is available on file.)

Assessors provided independent gradings for each patient visit, based on the four posed portrait photographs.

Patients graded ‘well’ at 3 months (House–Brackmann grade I) did not receive a 9-month visit.

The identities of the members of the panel of assessors are provided in Appendix 17.

In order to achieve a clear definition of the attainment of recovery we wanted to make the assumption that in Bell’s palsy no patient’s condition worsened from one visit to the next. In fact there were just four cases where this assumption failed (0.8%; three patients were graded I–II–I, i.e. ‘well–ill–well’ at the respective assessment visits, and one was graded III–I–II, i.e. ‘ill–well–ill’). Given the small number of such cases and the comparatively greater variation in individual gradings by experts, we elected in all four cases to allow the minority judgement to over-rule the majority or median judgement, the patients being regraded II–II–I and III–II–II respectively, and thus we achieved a trajectory that, for the purposes of an exploration of recovery after onset of Bell’s palsy, is satisfactorily defined.

Objectives

The trial objectives are listed in Table 8.

Primary outcomes

Secondary outcomes

There are three secondary outcomes for patients on the BELLS study, measured once at each visit.

Methods used to enhance the quality of measurements

All participants were briefed similarly (including patients, through the medium of the Patient Information Sheet and discussion with the referring and recruiting clinicians). General practitioners were provided with instructions for referral on the study website. Referrers followed identical procedures as far as it was possible to contrive this. Researchers used the same model of camera (Sony DSC–P12), with the same settings, and requested the same poses of their patients; follow-up procedures (phone calls, visits) were managed identically. Assessors calibrated their measurements through an initial training period with discussion (assessment of 10 sample portrait sets, with a discussion of differences, followed by assessment of a further 20 sample portrait sets); assessors were at all times made aware of any ‘large’ discrepancies in their grading of patient recovery (i.e. any difference in grading exceeding one grade point) and in all such cases the portrait sets were reassessed.

At the centre there was double entry of data and all discrepancies were identified, discussed and corrected.

Two statisticians independently pursued separate analyses of the data.

Unblinding took place in the presence of the Chief Investigator, one principal investigator and the study co-ordinator, who independently interpreted the decoding key and agreed that interpretation.

Sample size

The relevant Cochrane reviews suggested potential effect sizes from 4% to 17%. A difference in complete recovery of 10–12% or more was considered to be clinically meaningful. Randomising 240 patients per active treatment (e.g. aciclovir or not; a total of 480 patients) was calculated to provide 80% power to detect a difference of the order of 12% at the 5% level. Since the study design is factorial the attained power is the same for each pair-wise comparison of treatments (assuming no interaction between treatments and groups). Assuming an incidence rate of 24 per 100,000 per annum based on population access and age range we would have anticipated 2235 cases to have occurred in the study catchment area during the recruitment period. We therefore aimed to refer approximately one-third of all cases of Bell’s palsy arising in Scotland during the study period, and after excluding ineligible cases, to recruit approximately one-quarter of all cases.

Thus the number of patients required to achieve the intended design is 240 per treatment arm, as shown in Table 12 (in brackets after the treatment code).

We aimed, therefore, to assess 720 patients for eligibility (approximately one-third of all cases in Scotland over the 25-month recruitment period) and to randomise 540 of those to treatment (three-quarters: in other words, to randomise one-quarter of all cases in Scotland) in order to achieve 480 completed patients (about nine-tenths of those randomised; this retention rate represents a very high proportion but one that was realised in fact).

Explanation of any interim analyses and stopping rules

No formal interim analysis was scheduled or requested; however, as part of a quality control exercise an analysis of completed data was carried out in August 2005 at the request of the Chair of the study DMEC, and managed by the host institution. A statistician co-opted to the committee to analyse the partial data remained blinded to the treatment key, having been made aware only of the contrasts by Tayside Pharmaceuticals, the drug manufacturers. At the conclusion of this analysis the team was requested to continue recruitment and follow-up; no other illumination of progress was provided.

Randomisation

Subgroup analyses

Post hoc analyses were performed of (1) the effectiveness of prednisolone and its dependence on the time of commencement of administration of treatment after onset of symptoms, and (2) the effectiveness of prednisolone and its dependence on the severity of symptoms at onset. We also examined (3) the inter- and intra-assessor reliability of the primary outcome measurement.

Participant flow

The flow of participants through each stage of the study is shown in Figure 4. Specifically, this shows for each treatment group the numbers of participants randomly assigned, how many received the intended treatment, how many completed the study protocol, and how many were analysed for the primary outcome (‘Completed’).

FIGURE 4.

CONSORT Framework diagram, BELLS study. AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group; n/a, not available.

Protocol deviations from study as planned, together with reasons

In two cases patients were recruited to the study but later it was decided that the diagnosis of Bell’s palsy was probably mistaken.

In one case a patient with diabetes was recruited to the study. It is not known how this occurred.

In a small number of cases, it became apparent during the researchers’ follow-up visits that the delay between onset of symptoms and the commencement of treatment probably exceeded 72 hours. It is unlikely that this aspect of the consent process was neglected: in fact, patients’ definition of the onset of symptoms, and consequently of the time of onset of symptoms, was in a few cases very vague indeed.

It is our belief that signed consent was always obtained at the time of recruitment; however, the signed consent form along with the patient case record form was occasionally returned to hospital notes rather than being retained in the site folder. In these cases strenuous efforts, usually successful, were always made to locate and retrieve the signed consent form.

In nine cases, patients received a treatment different to that allocated, and in one case a patient was sent away with no treatment at all. Although stocks were monitored and maintained, occasionally they were not available for issue at the site (simply, they were temporarily mislaid). In these cases an alternative was offered and the alternative noted.

In one case, a patient successfully recruited to the study and randomised to treatment was not offered the allocated treatment: instead a 7-day regime of prednisolone and aciclovir in combination was prescribed. It is not known how this breakdown between briefing and practice occurred.

Under intention to treat (ITT) all these patients were followed up and their data retained in the analysis of results.

Recruitment

The study ran during 2003–7 and included 25 months’ recruitment and 9 months’ patient follow-up. At an estimated 30 cases/100,000/year (estimates vary from 11 to 40 cases/100,000/year31) in the Scottish population (5.04 million, of whom 4.10 million are aged over 16, the minimum age for recruitment to this clinical trial) and with an estimated geographical trial catchment area of 88%, we sought to refer one-third of all cases (approximately 720) and to recruit three-quarters of those (approximately 540) to achieve our target of 480 completed patients (see Table 12).

In the event we assessed 752 patients for eligibility and randomised 551 of those to treatment, of whom 496 patients completed follow-up, as shown in Table 13.

The pattern in weekly recruitment and overall retention to target over the 108 weeks of recruitment to the BELLS study are shown in Figures 5 and 6. Summary totals are shown in Table 13.

FIGURE 5.

Weekly recruitment to the BELLS study.

FIGURE 6.

Retention to target on the BELLS study.

Despite a very flexible and convenient system for patient appointments and assessment, not all patients were assessed at all the required time points: altogether there were 19 missed appointments (of course, there were many more missed appointments for the 55 patients of the 551 randomised into the trial who did not complete follow-up, chronic missed appointments being the most common reason for loss to follow-up). The number of attained appointments for the collection of data on the BELLS Study is shown in Table 14.

We noted a small number of cases (31) where the patient was graded well (HBI) at the baseline visit. In fact this is not clinically very remarkable. One of several characteristics of Bell’s palsy is that it is capable of very rapid recovery, and there were many anecdotal reports amongst patients visited soon after onset commenting that they felt ‘better already’ and those visited at 3 months who reported that the condition ‘cleared up soon after you came to see me the first time’.

Eight patients received their first visit after completing the 10-day course of treatment; and three patients received their final assessment a year after onset. The reasons for this were always related to the difficulty of following up a mobile population and arranging a visit that was convenient to the patient.

Baseline data

Table 15 shows the baseline characteristics of groups. The patients were balanced for gender, the mean age was 44 years, and the degree of initial facial paralysis was moderate to severe. Most patients (53%) initiated treatment within 24 hours of onset of symptoms, 32% within the 24–48-hour period, and 15% from 48–72 hours.

Outcomes and estimation

Any patient graded ‘well’ (i.e. House–Brackmann I) at 3 months was deemed ‘completed’, and no visit was made to the patient at 9 months. Altogether 496 patients (90% of all those recruited) completed follow-up.

Primary outcome

Following the classical procedure for a factorial design, we first independently assessed outcome in the marginal treatment groups prednisolone versus no prednisolone (P vs P′; i.e. AP + OP vs AO + OO) and aciclovir versus no aciclovir (A vs A′; i.e. AP + AO vs OP + OO).

Table 16 presents the unadjusted and adjusted outcome data on patients who completed the study. Altogether 357 patients had recovered by 3 months and did not require a further visit. Of the remainder, 80 had recovered at 9 months, leaving 59 with a residual facial nerve deficit.

TABLE 16 - Primary outcome at 3 and 9 months unadjusted (u)/adjusted (a)a for baseline characteristics

Adjusted for age, gender, baseline House–Brackmann (HB) grade, aciclovir (Yes/No) and prednisolone (Yes/No) and time to start of treatment.

	Treatment % (n)	No treatment % (n)	OR (95% CI)	p value
Prednisolone
HB I at 3 months	83.0% (205/247)	63.6% (152/239)	2.79 (1.82 to 4.35) (u) 2.44 (1.55 to 3.84) (a)	< 0.001 (u) < 0.001 (a)
HB I at 9 months	94.4% (237/251)	81.6% (200/245)	3.81 (2.01 to 7.56) (u) 3.32 (1.72 to 6.44) (a)	< 0.001 (u) < 0.001 (a)
Aciclovir
HB I at 3 months	71.2% (173/243)	75.7% (184/243)	0.79 (0.53 to1.21) (u) 0.86 (0.55 to 1.34) (a)	0.304 (u) 0.504 (a)
HB I at 9 months	85.4% (211/247)	90.8% (226/249)	0.60 (0.34 to 1.07) (u) 0.61 (0.33 to 1.11) (a)	0.072 (u) 0.105 (a)

The analysis in this section was pre-specified and all analyses were based on intention-to-treat.

The effect of adjustment was to attenuate odds ratios in the case of the prednisolone comparison, and thus adjustment acted conservatively. Unadjusted odds ratios (column 4) were respectively 2.79 and 3.81 (prednisolone at 3 months and 9 months); and 0.79 and 0.60 (aciclovir at 3 months and 9 months).

There were significant differences in complete recovery at 3 months between the prednisolone comparison groups (83.0% for prednisolone, 63.6% for no prednisolone, a difference of + 19.4%; 95% confidence interval (CI): + 11.7% to + 27.1%, p < 0.001); but no significant difference between the aciclovir comparison groups (71.2% for aciclovir and 75.7% for no aciclovir, a difference of – 4.5% (95% CI: – 12.4% to + 3.3%, p = 0.30, adjusted 0.50). Nine-month assessments of patients at House–Brackmann grade I were: 94.4% for prednisolone compared with 81.6% for no prednisolone, a difference of + 12.8% (95% CI: + 7.2% to + 18.4%, p < 0.001); and 85.4% for aciclovir and 90.8% for no aciclovir, a difference of – 5.3% (95% CI: – 1.0% to + 0.3%, p = 0.07, adjusted 0.10).

Although neither the results at 3 months nor 9 months were statistically significant, we noted that recovery rates were higher in the no-aciclovir group than in the aciclovir group.

Next we pursued the corresponding four-arm analysis, i.e. comparison of the four delivered treatments (AP, AO, OP, OO). The trial was not powered for this, but primarily it provided an opportunity to assess any interaction between the active therapies (aciclovir and prednisolone) and secondly it provided a very convenient and interpretable comparison for clinicians and researchers (and for this reason was also adopted in the health costs analyses in Chapter 7).

Table 17 and Figure 7 demonstrate the proportion of patients assessed as making a full recovery, i.e. having normal facial function (House–Brackmann I) at baseline, 3 and 9 months in the four treatment subgroups.

TABLE 17 - Proportion of patients making a full recovery (House–Brackmann I) at 3 and 9 months

AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group.

Treatment	0 months	3 months	9 months
OP	10/127 = 7.9%	107/124 = 86.3%	122/127 = 96.1%
AP	10/124 = 8.1%	98/123 = 79.7%	115/124 = 92.7%
OO	6/122 = 4.9%	77/119 = 64.7%	104/122 = 85.2%
AO	8/123 = 6.5%	75/120 = 62.5%	96/123 = 78.0%

FIGURE 7.

Proportion of patients making a full recovery (House–Brackmann I) at three and 9 months. AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group.

There was no significant aciclovir–prednisolone interaction at 3 months or at 9 months (p = 0.32, p = 0.72 respectively).

We found a marginally significant aciclovir effect when added to placebo (AO vs OO, p = 0.078) and when added to prednisolone (AP vs OP, p = 0.074); however, there was consistency in the effect previously noted: aciclovir added to prednisolone tended to decrease the recovery rate, and also the recovery rate in those receiving aciclovir was lower than in the group receiving double-placebo.

We noted as before a highly significant prednisolone effect (p < 0.001).

We repeated the foregoing analysis of primary outcome for patients making a ‘good’ recovery, i.e. House–Brackmann grade I or II, with the results shown in Table 18.

TABLE 18 - Proportion of patients making a good recovery (House–Brackmann I or II) at 3 and 9 months

Adjusted for age, gender, baseline House–Brackmann (HB) grade, aciclovir (Yes/No) and prednisolone (Yes/No) and time to start of treatment.

	Treatment	None	OR (95% CI)	p value
	Unadjusted % (n)a	Unadjusted % (n)a
Prednisolone
HB I/II at 3 months	93.9 (232/247)	77.8 (186/239)	4.41 (2.35 to 8.19)	<0.001
HB I/II at 9 months	97.2 (244/251)	94.7 (232/245)	1.95 (0.74 to 5.41)	0.176
Aciclovir
HB I/II at 3 months	84.0 (204/243)	88.0 (214/243)	0.71 (0.41 to 1.19)	0.239
HB I/II at 9 months	95.1 (235/247)	96.8 (241/249)	0.65 (0.26 to 1.71)	0.372

The proportions making a good recovery (House–Brackmann I or II) at 3 months and 9 months in the four treatment subgroups shown are in Figure 8.

FIGURE 8.

Proportion of patients making a good recovery (House–Brackmann I or II) at 3 and 9 months. AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group.

There was no significant aciclovir–prednisolone interaction at 3 months or at 9 months (p = 0.78, p = 0.87 respectively). There were significant differences in complete recovery at 3 months between the prednisolone comparison groups (93.9% for prednisolone, 77.8% for no prednisolone, a difference of + 16.1% (95% CI + 10.1% to + 22.2%, p < 0.001); but otherwise there were no significant differences to be identified between the treatment comparison groups at 3 months or at 9 months.

Secondary outcomes

All the analyses in this section were pre-specified.

Reduction in neurological disability scores

We explored differences in House–Brackmann score at baseline and 9 months, and examined which treatment combination led to the greatest reduction.

We first looked at treatment differences A versus A′ and P versus P′. The mean reduction was greater for those not receiving aciclovir (2.54) than for those receiving aciclovir (2.44) but the difference was not significant (p = 0.345). Similarly, and surprisingly in the context of other results, the mean reduction was greater for those not receiving prednisolone (2.59) than for those receiving prednisolone (2.39) but the difference was not significant (p = 0.074).

We then looked at the extent of reduction for the four different therapies: the mean reduction from greatest to least was 2.64 (OO), 2.54 (AO), 2.45 (OP) and 2.33 (AP); however, there is no evidence that any treatment combination achieved a greater reduction than any other.

Measurement of pain

We first distinguished between patients who reported themselves as ‘in pain, attributed to Bell’s palsy’ and those reporting no pain attributable to their diagnosis. Figure 9 shows the proportion of patients describing themselves as in pain at onset, after 3 months and after 9 months.

FIGURE 9.

Proportion of patients describing themselves as ‘in pain’ at onset, after 3 months and after 9 months. AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group.

In all four treatment groups there was significantly reduced incidence of pain after 3 months, with no significant additional reduction therafter.

We next assessed patients according to their score on the BPI. Table 19 gives the number of patients assessed, the mean score and standard deviation (SD) for the BPI in each of the treatment groups at onset, after 3 months and after 9 months. The lower number of 9-month visits in groups OP and AP confirms the more rapid recovery of patients randomised to receive prednisolone.

TABLE 19 - Number of patients, mean BPI score and SD for the BPI score

AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group.

Treatment group	0 months			3 months			9 months
	n	Mean	SD	n	Mean	SD	n	Mean	SD
OP	125	10.9	19.6	122	1.2	5.4	23	1.6	4.1
AP	124	9.9	16.7	123	1.8	7.2	27	1.2	6.0
OO	118	17.6	22.8	118	2.2	9.3	46	1.8	6.9
AO	122	13.8	1.4	120	1.8	6.8	48	1.9	5.7

In all cases the high coefficient of variation is explained by the high proportion of patients scoring 0 (‘no pain’) during their visit assessment.

The lower BPI scores at the baseline visit in patients who had started oral steroids confirms their rapid effectiveness in reducing the swelling associated with the underlying inflammatory pathophysiology.

Measurement of self-assessed appearance

First we assessed patients according to whether they reported themselves to be dissatisfied or otherwise concerned with their appearance (Part I of the DAS59). Figure 10 gives the proportion of patients expressing themselves as ‘dissatisfied with appearance’ at onset, after 3 months and after 9 months. Patients randomised to prednisolone were least bothered by their appearance at 3 months, and those most bothered were those who received aciclovir. Those on prednisolone alone (OP) are significantly less bothered by their appearance at 9 months.

FIGURE 10.

Proportion of patients dissatisfied with appearance. AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group.

The DAS is a measuring instrument with wide applicability and (unlike the BPI) the patients were not instructed to restrict their concerns about appearance to symptoms and consequences of Bell’s palsy. Thus, there were references to (e.g.) anxieties about weight and hairline (men) and weight, size and the signs of ageing (women). We attribute the apparent increase in anxiety at the 9-month visits, in all treatment groups, to an increasing willingness to engage with these other issues, once the immediate and pressing issues of Bell’s palsy became diminished with the passage of time.

We next assessed patients according to their score on the DAS59 (Part II). Table 20 gives the number of patients assessed, the mean score and standard deviation for the DAS59 in each of the treatment groups at onset, after 3 months and after 9 months.

TABLE 20 - Number of patients, mean DAS59 score and SD for the DAS59 score

AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group.

Treatment group	0 months			3 months			9 months
	n	Mean	SD	n	Mean	SD	n	Mean	SD
OP	125	72.0	36.5	121	42.8	32.1	24	30.8	28.8
AP	121	69.8	36.8	122	42.0	32.3	27	48.2	39.1
OO	116	75.7	39.7	117	39.9	28.2	46	49.7	38.1
AO	121	74.6	41.5	120	46.5	37.3	47	50.0	32.3

The reductions noted in all treatment groups after the first 3 months were all statistically significant (p < 0.001 in all cases); the prednisolone-only group (OP) appears unique in that the reduction continues to the 9-month assessment whereas in the three other treatment groups the mean score rises. However, all the perceived differences are non-significant (OP: p = 0.091; AP: p = 0.387; OO: p = 0.074; AO: p = 0.573).

Measurement of self-assessed health utility

Table 21 gives the number of patients assessed, the mean score and standard deviation for the HUI3 in each of the treatment groups at onset, after 3 months and after 9 months.

TABLE 21 - Number of patients, mean HUI3 score and SD for the HUI3 score

AO, aciclovir–placebo group; AP, aciclovir–prednisolone group; OO, placebo–placebo group; OP, placebo–prednisolone group.

Treatment group	0 months			3 months			9 months
	n	Mean	SD	n	Mean	SD	n	Mean	SD
OP	125	0.80	0.24	121	0.92	0.16	22	0.83	0.25
AP	124	0.80	0.21	121	0.90	0.18	27	0.85	0.26
OO	114	0.76	0.20	117	0.91	0.12	46	0.90	0.15
AO	120	0.79	0.21	119	0.90	0.13	47	0.86	0.17

The quality of life measured using HUI3 at 9 months was significantly higher for patients who did not receive prednisolone than for those who did (p = 0.04). Given that the secondary measures were obtained only in patients who had not recovered at 3 months and given the problem of multiple testing, this result should be interpreted with caution.

Ancillary analyses

We performed one additional analysis of time to recovery against treatment group, fitting a non-parametric Kaplan–Meier survival model for the time to recovery. We found a highly significant beneficial prednisolone effect (p < 0.001 for OP vs OO, p < 0.001 for AP vs AO) and a marginally significant aciclovir effect (p = 0.079 for AO vs OO, p = 0.081 for AP vs OP) with the suggestion that its addition to treatment may slow or impede recovery; and there was negligible aciclovir–prednisolone interaction (p = 0.536).

Key outcome measures for each treatment group are shown in Table 22.

Adverse events and side effects

Introduction

Health-care resources are always scarce. The cost of a particular treatment can be seen not as its monetary value but as the foregone benefits [i.e. years of life, better quality of life (QoL)] of an alternative treatment that we cannot provide when we decide to use these scarce resources in a particular way. This is the notion of opportunity cost – the central concept of economics – that is used to help identify how we can get the maximum benefit from the limited resources available (i.e. obtain an efficient allocation of resources). Economic evaluation provides guidance on how best to use resources as it is a systematic analysis comparing the resources used (costs) and benefits of alternative courses of action. 32 An economic evaluation, in this context, would involve assessing the relative costs and benefits associated with the alternative treatments, included in this clinical trial for the treatment of Bell’s palsy. 33

How an economic evaluation brings together information on costs and effects is illustrated in Figure 11. The vertical axis represents the difference in costs between an experimental (e.g. an ‘active treatment’ for Bell’s palsy) and a control treatment (e.g. a ‘placebo’). The difference in cost will reflect the difference in the value of the resources used to provide treatment (e.g. medications) as well as the resource consequences of treatment (e.g. the costs of the use of health services during the follow-up period). The horizontal axis represents differences in effectiveness between the two approaches, which might be measured in clinical terms, e.g. the reduction in House–Brackmann grading score, or other measures such as quality-adjusted life-years (QALYs). The latter combines estimates of both QoL with estimates of length of life. The wider the definition of effectiveness used, usually, the more likely it is to measure outcomes of importance to individuals.

FIGURE 11.

Relationship between the difference in costs and effects between a new (experimental) intervention and a standard (control) intervention.

In the north-west (NW) and south-east (SE) quadrants of Figure 11 a clear decision about which treatment should be preferred is provided because one or the other treatment ‘dominates’. In the NW quadrant the experimental treatment is more costly and provides less benefit and therefore the control treatment is more efficient (is dominant). In the SE quadrant the opposite situation occurs and the experimental treatment is more efficient (is dominant) as it is less costly and provides more benefit. The circle in the centre of the figure represents the possibility that no meaningful differences in costs or benefits exist between the treatments and for practical purposes the two interventions are equally efficient. In the two remaining areas of the figure, the north-east (NE) and south-west (SW) quadrants, a judgement is required as to whether the more effective treatment is worth the extra cost. To aid these judgements, information can be provided in terms of an incremental cost-effectiveness ratio (ICER). This is the difference in mean costs between treatment and the control groups divided by the difference in mean effectiveness between treatment and control groups. The higher the ICER for the comparison of one intervention with another, then the less likely it is that this intervention will be considered efficient.

Aim

The purpose of this section is to assess the cost-effectiveness of early administration of prednisolone and or aciclovir compared with placebo for treatment of Bell’s palsy in an adult population in the UK.

Three separate analyses are presented, which correspond to the factorial design of the trial:

• prednisolone versus no prednisolone (P vs P′)

• aciclovir versus no aciclovir (A vs A′)

• AP versus OP versus AO versus OO.

As described below the methods used to make these three comparisons are similar. The study was designed as a 2 × 2 factorial design. The first two analyses can be conducted as there is no evidence of any interaction between prednisolone and aciclovir. Arguably, for an economic evaluation the more useful comparison is the four-arm comparison. However, as the study was not powered to compare the four treatments the results of any economic evaluation are subject to a further lack of precision.

Methods

The trial, as is commonly the case, was not powered to detect difference in the cost-effectiveness of the different treatments. Thus, a modelling approach was adopted as a way of gaining precision in the cost-effectiveness estimates.

Model structure of the two-arm models

Decision tree models were constructed to compare the cost-effectiveness of prednisolone against no prednisolone and aciclovir against no aciclovir. Figure 12 shows the structure of the model for prednisolone, and a tree with a similar structure was used for the aciclovir cost-effectiveness analysis. Within these models it is assumed that the different trial interventions affect the probability of being cured or not cured. The consequences of being cured or not cured are assumed to be independent of the initial therapy to which an individual was allocated. The definition of ‘cured’ follows that already used in the analysis of treatment differences: namely, an individual is classified as being cured if he or she has a value for the House–Brackmann grading system equal to 1.

FIGURE 12.

Bell’s palsy decision tree model: prednisolone vs no prednisolone.

Model structure of the four-arm model

A further decision tree model was developed for the third comparison performed (see Figure 13). This decision tree has four decision branches, which reflect the four groups provided by the 2 × 2 factorial trial design. Again it has been assumed that the costs of the consequences of being cured or not cured are independent of the initial treatment a person was allocated to.

FIGURE 13.

Decision tree model for early treatment for Bell’s palsy: prednisolone alone vs aciclovir alone vs prednisolone + aciclovir vs no treatment (placebo).

Health-care resource use and costs

The costs estimates used in the model were based on the cost of the initial treatments, and follow-up costs. Follow-up costs included the use of resources in primary and secondary care, the unit costs of these resources, and the subsequent use of other medications.

Estimation of utilities

Data were collected on HUI3 at baseline, 3 months and, if trial participants were not cured at 3 months, they were assessed also at 9 months. Two analyses of covariance adjusting for baseline HUI3 scores were used to obtain utility weights for participants who were cured and not cured at 3 and 9 months. Table 36 shows the results of these analyses. These data were used to estimate the utility scores for those cured at 3 months, those cured at 9 months and those not cured. In order to reflect the statistical imprecision surrounding these estimates when used in the model, normal distributions were attached to the mean values based upon the results of a regression analysis. These data were used in both the two-arm and the four-arm models. Table 36 also reports data for HUI3 at baseline for all participants from the trial analyses.

With the information in Table 36 utility weights were calculated using the area under the curve method. For instance, for a participant cured at 3 months the QALY weight used in the model would be:

Substituting values into this expression gives:

A similar approach was used to estimate QALYs for those cured at 9 months and QALYs for those not cured.

Results

Two-arm models

Prednisolone vs no prednisolone model

Cost-effectiveness analysis

When the proportion of cases cured is used as the measure of effectiveness, prednisolone has a lower mean cost and is more effective than the no prednisolone alternative, i.e. it is the SE quadrant of Figure 11 (see Table 37). Thus, prednisolone dominates the ‘no prednisolone intervention.

TABLE 37 - Deterministic cost-effectiveness results. Prednisolone vs No prednisolone model

Cured cases defined as HB score = 1.

incremental cost-effectiveness ratio.

Treatment	Cost (£)	Cured casesa at 9 months (%)	ICERb
Prednisolone	231.98	94.4%
No prednisolone	248.05	81.6%	Dominated

Cost–utility analysis

Table 38 shows cost-effectiveness deterministic and probabilistic results when QALYs are used as the effectiveness. This table shows the likelihood of a particular treatment to be considered cost-effective for alternative values of willingness to pay for an extra QALY. As Table 38 shows, the results of the cost–utility analysis are similar to those from the cost-effectiveness analysis.

TABLE 38 - Cost-effectiveness results. Prednisolone vs No prednisolone model

Treatment	Cost (£)	QALYs	ICER	Probability that intervention is cost-effective for different threshold values for society’s willingness to pay for a QALY
				10,000	20,000	30,000	50,000
Prednisolone	231.98	0.718		79.3%	77.5%	77.0%	76.0%
No prednisolone	248.05	0.717	Dominated	20.7%	22.5%	23.0%	24.0%

The results of the probabilistic analysis indicate that prednisolone is likely to be considered a cost-effective treatment at all values for society’s willingness to pay for a QALY. A further illustration of these results is provided by the scatterplot (Figure 14) and the cost-effectiveness acceptability curves (Figure 15).

FIGURE 14.

Incremental cost-effectiveness scatterplot. Prednisolone vs no prednisolone model.

FIGURE 15.

Cost-effectiveness acceptability curves. Prednisolone vs no prednisolone model.

Figure 14 shows the scatterplot of the difference in cost and effects pairs for the comparison of prednisolone with no prednisolone from the Monte Carlo simulation (represented by the clear squares on the figure). A high proportion of the dots are allocated within the SE quadrant. This means that, for those cases, prednisolone produced more QALYs and was less costly than no prednisolone, and therefore prednisolone is cost-effective for these iterations. The opposite argument applies to those cases that fall within the NW quadrant (for these iterations the no prednisolone option is cost-effective). Finally, for those iterations that fall within the NE and SW quadrants the decision for or against prednisolone will depend on the threshold value of WTP for an extra QALY.

Figure 15 shows the cost-effectiveness acceptability curves derived using the cost-effectiveness data. These curves show how likely a particular option would be considered cost-effective for alternative values for society’s willingness to pay for an extra QALY. As this figure shows there is approximately an 80% chance that prednisolone will be considered cost-effective compared with no prednisolone for values for a cost per QALY that society might consider worthwhile.

Aciclovir vs no aciclovir model

Cost-effectiveness analysis

Table 39 shows the incremental cost per case cured for the comparison of aciclovir with no aciclovir. The no aciclovir alternative has on average lower costs and a higher proportion of individuals recovered. Therefore, on average no aciclovir dominates aciclovir treatment.

TABLE 39 - Deterministic cost-effectiveness results: Aciclovir vs No aciclovir model

Cured cases defined as HB score = 1.

ICER, incremental cost-effectiveness ratio.

Treatment	Cost (£)	Cured casesa at 9 months (%)	ICER
No aciclovir	235.33	90.8%
Aciclovir	246.63	85.4%	Dominated

Cost–utility analysis

In terms of incremental cost per QALY, the results suggest that no aciclovir is on average more effective and less costly that aciclovir, and probabilistic analysis reinforces this finding (see Table 40).

TABLE 40 - Cost-effectiveness results: Aciclovir vs No aciclovir model

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Treatment	Cost (£)	QALYs	ICER	Probability that intervention is cost-effective for different threshold values for society’s willingness to pay for a QALY
				10,000	20,000	30,000	50,000
No aciclovir	235.33	0.718		91.1%	85.1%	82.2%	79.0%
Aciclovir	246.63	0.717	Dominated	8.9%	14.9%	17.8%	21.0%

The scatterplot (Figure 16) of the incremental cost and QALY pairs from the Monte Carlo simulation shows that the majority of the iterations lie within the NW quadrant (e.g. aciclovir more costly and less effective than no aciclovir). The cost-effectiveness acceptability curves (Figure 17) show that aciclovir was unlikely to be considered cost-effective at values compared with no aciclovir.

FIGURE 16.

Incremental cost-effectiveness scatterplot. Aciclovir vs no aciclovir model.

FIGURE 17.

Cost-effectiveness acceptability curves. Aciclovir vs no aciclovir model.

Comparison of all four randomised groups in the four-arm model

Cost-effectiveness analysis

Table 41 shows the deterministic cost-effectiveness analysis results. On average prednisolone only is the least costly and most effective of the four alternative interventions out of the prednisolone-only, aciclovir-only, aciclovir and prednisolone, and placebo-only arms model, i.e. it dominates the other interventions.

TABLE 41 - Deterministic cost-effectiveness results. Four-arms model

Cured cases defined as HB score = 1.

incremental cost-effectiveness ratio.

Treatment	Cost (£)	Cured casesa at 9 months (%)	ICERb
Prednisolone	230.61	96.1%
Aciclovir and prednisolone	244.02	92.7%	Dominated
No treatment (placebo)	246.47	85.6%	Dominated
Aciclovir	258.93	78.0%	Dominated

Cost–utility analysis

Prednisolone only is on average less costly and produces more QALYs than any of the other treatments (see Table 42). Furthermore, it has approximately an 80% chance of being considered cost-effective compared with the other treatments. This is illustrated by the cost-effectiveness acceptability curves (Figure 18), which indicate that collectively the other interventions have only a 20% chance of being considered cost-effective.

TABLE 42 - Results of cost–utility analysis

ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

Treatment	Cost (£)	QALYs	ICER	Probability that intervention is cost-effective for different threshold values for society’s willingness to pay for a QALY
				10,000	20,000	30,000	50,000
Prednisolone	230.62	0.719		79.1%	77.4%	76.9%	75.9%
Aciclovir and prednisolone	244.02	0.718	Dominated	0.0%	0.0%	0.0%	0.1%
No treatment	246.47	0.717	Dominated	12.5%	9.5%	7.2%	5.2%
Aciclovir	258.93	0.716	Dominated	8.4%	13.1%	15.9%	18.8%

FIGURE 18.

Cost-effectiveness acceptability curves. Four-arms model.

Outcome dependent on the time delay to commencement of treatment

Where the time delay was known, we compared the recovery rate at 3 months and at 9 months, only for those patients treated with prednisolone with the recovery rate for those not treated with prednisolone, according to whether the time delay between onset and the commencement of treatment was less than 24 hours, less than 48 hours or less than 72 hours. The recovery rates are shown in Table 43.

In all cases there is the suggestion that treatment commenced within 24 hours leads to lower recovery rates than treatment commenced within 24–72 hours. Collapsing both tables to a 2 × 2 factorial format permits a comparison of treatment (prednisolone with non-prednisolone) and time to commencement of treatment (a delay of less than 24 hours compared with a delay of 24–72 hours).

At 3 months treatment with prednisolone is more effective than treatment without prednisolone (82.7% recovery vs 64.0%; OR = 2.69; 95% CI: 1.71 to 4.20; p < 0.001); comparison of the recovery rates at 3 months suggests that treatment delayed by at least 24 hours is useful (67.7% recovery for those treated within 24 hours vs 73.5% for those treated later; OR = 0.49; 95% CI: 0.31 to 0.78; p = 0.002). At 9 months, the recovery rate after treatment with prednisolone is significantly higher than the recovery rate without prednisolone treatment (95.7% vs 83.2%; OR = 4.53; 95% CI: 2.14 to 9.17; p < 0.001); the effect of a 24-hour delay before commencing treatment is still apparent (87.1% if treatment commences early, 89.6% otherwise; OR = 0.52; 95% CI: 0.26 to 0.99; p = 0.046).

We can currently neither identify nor suggest a convincing rationale for delaying treatment for 24 hours, in the face of all the evidence (or conventional wisdom) that early commencement of treatment is an important adjunct to successful resolution of Bell’s palsy.

Neither at 3 months nor at 9 months is any interaction between treatment and commencement of administration evident (p = 0.73 and p = 0.97).

Outcome dependent on severity at onset

We looked at 9-month recovery rates for those patients treated with prednisolone and for those not treated with prednisolone, and explored the extent to which the severity of the episode of Bell’s palsy as measured at onset dictated recovery. There were 34 patients graded I at onset who were also graded I at 3 months and not visited at 9 months. We characterised those graded II to IV at onset as ‘moderate’, and those graded V to VI at onset as ‘severe’. The recovery rates are shown in Table 45.

The 9-month recovery rate is substantially higher in both treatment groups when the severity at onset is only moderate; also the 9-month recovery rate is higher in the prednisolone subgroups, irrespective of severity. The 9-month recovery rate in the prednisolone group is 93.8% compared with 80.4% in the non-prednisolone group (OR 3.66; 95% CI: 1.92 to 7.28; p < 0.001); the 9-month recovery rate in the moderately affected group is 90.7% compared with 78.3% in the severely affected group (OR 2.69; 95% CI: 1.49 to 4.82; p < 0.001). The interaction is non-significant (p = 0.182).

Assessors’ concordance

The three assessors considered altogether 1172 patient photo sets in order to provide our primary outcome measure. When all three assessors agreed to within one grade, the median or majority grade (the decision is equivalent) was the one awarded for that patient visit. Otherwise, all three assessors were invited to provide a new assessment, when the median grade was the one awarded. Throughout, all the assessors were masked to the treatment and the time of the visit (i.e. whether the portrait records derived from the onset visit, or the 3-month or 9-month visit). The extent of agreement is summarised in Table 46.

So Judge 1 was in agreement with Judge 2 in 97% of cases, with Judge 3 in 95% of cases, and Judge 2 with Judge 3 in 96% of cases. The kappa values awarded are all ‘moderate’. 40

We also tested the assessors for consistency by sending them 92 repeat photo sets for assessment without additional explanation. The agreements were as shown in Table 47.

All repeat gradings were within one grade of the original decision. In the terminology of Landis and Koch, the consistency of Judge 1’s assessments is ‘almost perfect’ and that of both Judge 2 and Judge 3 is ‘substantial’.

Strengths and limitations of the study

This study, which was independently funded by the HTA, has several advantages compared to earlier trials, which have lacked power and produced inconsistent results. We have recruited double the number of patients that were included in the Cochrane systematic reviews. We recruited the majority of patients from primary care, thus reducing the selection bias inherent in hospital-based studies. The high acceptance of randomisation and low drop-out rate during the study suggest that these results are likely to be generalisable to other settings with similar populations. We used drugs that are relatively inexpensive and readily available worldwide. The diagnosis and absence of exclusion factors was confirmed by experienced, trained otorhinolaryngologists. The randomisation procedure and allocation to treatment was managed by an experienced, dedicated, independent trials unit. The assessment of outcomes using validated study tools was undertaken by observers who were masked to treatment allocation. The factorial design has permitted separate assessment of the effectiveness of both treatments as well as serving to exclude the possibility of a beneficial or antagonistic interaction.

We used the House–Brackmann scale to grade lower motor neurone facial nerve function because it reliably assigns patients to a recovered status. The scale has been criticised for not being sufficiently sensitive to change, and for having grades that are sometimes difficult to assign because patients may have contrasting degrees of function in different parts of their face. Alternative scales such as Sydney or Sunnybrook are available, but are more demanding to use for frontline clinicians. We used posed, static images rather than moving video clips as we believe these were adequate for our purpose. However, researchers noticed both asymmetry and slowness in blinking in patients, and that this was one of the last symptoms to disappear. Patients’ enunciation was occasionally compromised and in a few cases the disability was very severe. Neither of these is evident from static poses, and both would be readily identifiable even in short video clips. The cameras issued to researchers were inexpensive and (even in 2004) possessed the capability to record and save many minutes of moderately high quality video material. This capability was not used. We visited patients three times over 9 months, but would have preferred to visit more frequently in the early course of the illness to capture more detail about the recovery process and to obtain serology. We did not collect 9-month data on the subgroup whose facial nerve function had fully recovered at 3 months because patients with Bell’s palsy who improve do not subsequently deteriorate. We considered that we were likely to be underpowered to detect significant differences in the secondary end points with this design.

The economic analysis used a modelling framework to estimate relative efficiency. This approach has the advantage of making the best use of the limited data available but it made the assumption that the main determinant of relative efficiency is whether or not the Bell’s palsy was cured or not. If a standard trial-based cost-effectiveness analysis had been conducted with the available data it is likely that on average broadly similar results would have been achieved but the results would have lacked precision. Furthermore, the lack of data on costs and the decision not to follow up those deemed cured at 3 months would have necessitated similar assumptions being made in order to handle the missing cost and utilities data.

The data on costs used within the model came from a sample of only 74 of the trial participants – only a small proportion (15%) of the total trial sample. This led to a reduction in the precision of the estimates. Despite this limitation these data appear representative of the whole sample and the reasons for non-response were unconnected to the therapy the participant received or their outcomes. With respect to the estimation of QALYs measurements of health state utilities were censored for those trial participants who were judged to be cured at the 3-month follow-up. Therefore, an assumption was made within the modelling exercise that was tantamount to imputing utility data using the ‘last value carried forward’ method. Ordinarily this approach, while simple, is normally considered to be a poor method of imputation. 41,42 However, in this situation it may not be wholly unrealistic as these trial participants were judged to be cured at the time of censoring. Nevertheless, it assumes that there is no possible further improvement in health status for these people nor is there any possibility of relapse. This latter situation is clinically implausible unless there is a new episode of Bell’s palsy. The results of the economic evaluation would have been strengthened by further data on both costs and health state utilities.

Within the model the results are driven by the probability of being cured at 3 months and to a lesser extent, the probability of being cured at 9 months. Both probabilistic and deterministic sensitivity analyses were conducted. The probabilistic sensitivity analysis focused on the statistical imprecision surrounding the model parameters using parameter distributions that were plausible and based upon the available data. Further deterministic sensitivity analysis was conducted to address uncertainty in the model structure or uncertainty surrounding model parameters that were obtained from outwith the randomised controlled trial (RCT). The results of these sensitivity analyses indicate that conclusions are only sensitive to assumptions on the probability of being cured for the aciclovir versus no aciclovir model.

Overall, based on the data available it appears that treatment of Bell’s palsy with prednisolone is likely to be considered cost-effective while treatment with aciclovir is highly unlikely to be considered cost-effective. Given the limited data available on costs and utilities, further data would be useful to confirm findings. Similarly, although it is unlikely to change the conclusion, further data on costs and outcomes in the longer term (i.e. for a follow-up greater than 9 months) would also serve to confirm the findings of the study.

Implications for practice

Of the two most common treatments for Bell’s palsy the results of this study indicate that prednisolone may improve outcomes and potentially lower net NHS costs than other treatments (including doing nothing). Should the NHS subsequently recommend the adoption of prednisolone for the firstline treatment of people presenting with the symptoms of Bell’s palsy the following factors should be considered: contraindications to prednisolone, severity at onset and time of commencement of treatment.

Primary research

Important questions unanswered by our study design include:

1. the extent of recovery within the first four weeks on steroid therapy

2. any benefit in using steroids if started after 72 hours

3. the optimally effective dose of prednisolone in the 25–100-mg range that has been used in other studies

4. the hazards, if any, pertaining to short courses of high-dose steroid

5. the contribution of serological studies to the underlying cause of Bell’s palsy

6. confirmation whether higher tissue concentrations of antiviral agents – e.g. higher doses or esterified forms – may have benefits we were unable to detect

7. whether static poses accurately reflect the extent of functional disability compared to moving images or direct observation by an experienced clinician.

Evidence synthesis

We have agreed to undertake an update of the Antivirals in Bell’s Palsy (Cochrane review) and this was submitted in February 2009.

Trial Steering Committee

Professor Chris van Weel, University of Nijmegen (Chair); Dr Ian Williamson, University of Southampton; Professor Sally Wyke, University of Stirling; Mrs Caryl Hamilton (Patient representative).

Data Monitoring and Ethics Committee

Professor Marion Campbell, University of Aberdeen (Chair); Dr Carl Counsell, University of Aberdeen; Mr Rodney Mountain, University of Dundee; co-opted member: Dr Simon Ogston, University of Dundee (Statistician).

Local Principal Investigators

Mr Kim Ah-See, Aberdeen Royal Infirmary; Mr Natarajan Balaji, Monklands Hospital, Airdrie; Mr Hasan Beg, Victoria Hospital, Kirkcaldy; Mr Quentin Gardiner, Perth Royal Infirmary; Mr Musheer Hussain, Ninewells Hospital, Dundee; Mr Alastair Kerr, Western General Hospital and Royal Infirmary, Edinburgh; Mr John Marshall, Southern General Hospital, Glasgow; Mr William McKerrow, Raigmore Hospital, Inverness; Ms Mary Shanks, Crosshouse Hospital, Kilmarnock; Mr David Simpson, Stobhill Hospital, Glasgow; Mr Guy Vernham, St John’s Hospital, Livingston; Miss Aileen White, Royal Alexandra Hospital, Paisley.

Scottish School of Primary Care (SSPC)

Dr Lucy McCloughan (SPPIRe); Marie Pitkethly, Kim Stringer (East of Scotland); Susan Campbell, Amanda Cardy (North of Scotland); Dr Colette Fulton (South East of Scotland); Colin Cowan, June McGill (West of Scotland); Dr Karen Bell (NHS Ayrshire and Arran); Dr Brian Rae (NHS North Glasgow).

Contribution of authors

Additional to their roles on the BELLS Trial Management Committee or as advisers to it (R Hernández, K Stewart) and to their specific contributions to the production of this report and the approval of this version, the contributions of authors are as follows: FM Sullivan (trial design, links to primary care in Scotland, overall oversight as Chief Investigator); IRC Swan (trial design, links to ENT in Scotland, assessment of primary outcome); PT Donnan (trial design, statistics); JM Morrison (trial design, primary care, detection and assessment of psychological distress); BH Smith (trial design, primary care, assessment of pain); B McKinstry (primary care, recruitment methodology); RJ Davenport (neurosciences, assessment of primary outcome); LD Vale, R Hernández (health economics); JE Clarkson (trial design, links to dentistry in Scotland); K Stewart (plastic surgery, assessment of primary outcome); V Hammersley, S Hayavi, A McAteer, D Gray (patient contact, data collection); F Daly (trial coordination, statistics, data collection).

Publications

Sullivan F, Daly F. The Scottish Bell’s Palsy Study. Scottish Primary Care 2006;47:10.

Sullivan FM, Swan IRC, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al. Early treatment with prednisolone or aciclovir in Bell’s palsy. N Engl J Med 2007;357:16,1598–1607.

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.

DATA MONITORING AND ETHICS COMMITTEE REPORT TEMPLATE 1

DATA MONITORING AND ETHICS COMMITTEE REPORT TEMPLATE 2

DMEC Report Date:

Report Number:

1. 1. Title:

2. 2. Trial progress

   1. 2.1 Trial recruitment

      1. 2.1.1. Plan of recruitment

         1. Start date of recruitment =

         2. End date of recruitment =

         3. Recruitment period =

         4. Expected average monthly recruitment =

         5. Recruiting centres =

      2. 2.1.2 Recruitment to date

         1. Recruitment period to date =

         2. Total recruitment to date =

         3. Observed average monthly recruitment =

         4. Recruitment stratified by centre =

         5. Expected recruitment period (based on current recruitment rate) =

         6. End date of recruitment (based on expected recruitment patterns) =

            Please insert a graph showing the planned and observed recruitment rates

      3. 2.1.3. Recruitment based on eligibility

         1. Inclusion/exclusion

         2. Number ineligible

         3. Non-consent

         4. Protocol violation

   2. 2.2 Internal validity

      1. Comparability of selected baseline characteristics between the treatment groups

   3. 2.3 External validity

      1. Selected baseline characteristics of trial participants and non-participants

      2. Selected baseline characteristics of subjects in high and low recruiting centres

   4. 2.4 Protocol compliance

      1. Number of patients withdrawn from treatment but continued being followed up

      2. Number of patients who have been lost to follow-up

      3. Number of patients with missing follow-up data

   5. 2.5 Frequency of primary events (if applicable)

3. 3. Did you submit any data for interim analysis of efficacy?

   1. Yes/No

4. 4.  Analysis of safety data.

   1. These are to be presented overall and by group:

   2. 4.1 Serious adverse events

      These are defined as any untoward medical occurrence that at any dose:

      • Results in death

      • Is life threatening

      • Requires inpatient hospitalisation or prolongation of existing hospitalisation

      • Results in persistent or significant disability/incapacity

      • Is a congenital anomaly/birth defect

      To be summarised here but reported immediately to the Chairs of the DMEC subgroup and ethics committee and if appropriate to the Medicines Control Agency

   3. 4.2 Other adverse events

   4. 4.3 Abnormal laboratory tests (if applicable)

5. 5. List any new publications on the safety and efficacy of the trial medications and provide copies.

6. 6. List any new national or international guidelines on the treatment of the disease being studied and provide copies.

Health Technology Assessment reports published to date

1. Home parenteral nutrition: a systematic review.

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

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

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

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

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

4. Screening for fragile X syndrome.

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

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

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

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

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

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

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

8. Preschool vision screening.

   A review by Snowdon SK, Stewart-Brown SL.

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

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

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

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

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

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

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

    By Munro J, Booth A, Nicholl J.

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

    By Petticrew M, Watt I, Sheldon T.

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

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

1. Antenatal screening for Down’s syndrome.

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

2. Screening for ovarian cancer: a systematic review.

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

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

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

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

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

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

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

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

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

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

   By Song F, Glenny AM.

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

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

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

   By Law J, Boyle J, Harris F, Harkness A, Nye C.

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

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

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

    By Ebrahim S.

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

    By McQuay HJ, Moore RA.

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

    By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C.

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

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

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

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

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

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

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

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

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

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

19. Systematic reviews of trials and other studies.

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

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

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

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

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

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

   A review by Briggs AH, Gray AM.

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

   By Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H.

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.

   By Simpson WM, Johnstone FD, Boyd FM, Goldberg DJ, Hart GJ, Gormley SM, et al.

5. Methods for evaluating area-wide and organisation-based interventions in health and health care: a systematic review.

   By Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Burney PGJ.

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, Reimsma R.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

13. A systematic review of atypical antipsychotics in schizophrenia.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    By Townsend J, Buxton M, Harper G.

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

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

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

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

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

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

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

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

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

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

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

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

27. Evaluating non-randomised intervention studies.

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

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

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

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

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

30. The value of digital imaging in diabetic retinopathy.

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

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

    By Law M, Wald N, Morris J.

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

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

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

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

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

    By Royle P, Waugh N.

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

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

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

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

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

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

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

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

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

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

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

    By Beard S, Hunn A, Wight J.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

42. Involving South Asian patients in clinical trials.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    By Raftery J, Roderick P, Stevens A.

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

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

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

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

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

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

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

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

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

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

26. Indirect comparisons of competing interventions.

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

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

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

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

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

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

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

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

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

    By Cochrane T, Davey RC, Matthes Edwards SM.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

22. Pressure relieving support surfaces: a randomised evaluation.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

43. Telemedicine in dermatology: a randomised controlled trial.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

43. Contamination in trials of educational interventions.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

   By Loveman E, Frampton GK, Clegg AJ.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

   By Taylor RS, Elston J.

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

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

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

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

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

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

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

    By Hobart J, Cano S.

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

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

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

    By Bryant J, Baxter L, Hird S.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    By Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A.

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 placebocontrolled 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 costeffectiveness 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.

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