Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS) - a randomised controlled trial

Article history

The research reported in this issue of the journal was commissioned by the HTA Programme as project number 01/73/03. The contractual start date was in January 2004. The draft report began editorial review in July 2007 and was accepted for publication in June 2008. As the funder, by devising a commissioning brief, the HTA Programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

None

Copyright statement

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

2009 Queen’s Printer and Controller of HMSO

Study design

The study was a prospective, randomised, double-blind, matching, placebo-controlled design. Patients were allocated to either the pressor or depressor arm depending upon their blood pressure at randomisation.

Recruitment

Of the 10 centres originally expressing an interest in participating in the trial, only five initially took up the offer of funding. Reasons for non-participation included level of intensity of work involved in the trial, lack of adequate acute monitoring facilities and trained staff, competing commercial clinical trials, and perceived inability to recruit patients or research staff. Four sites participating in the trial, Leicester (Leicester General Hospital, Leicester Royal Infirmary, The Glenfield Hospital), Newcastle-upon-Tyne (Freeman Hospital), Bournemouth (Royal Bournemouth Hospital) and Exeter (Royal Devon and Exeter Hospital), were allocated funding for clinical research fellows and agreed to undertake all aspects of the trial. The fifth site, Aintree University Hospital, Liverpool, was funded for a research nurse and undertook only the non-dysphagic depressor limb of the trial. Recruitment began in January 2004 for an initial proposed period of 30 months, although because of low numbers this was extended to 36 months in three of the centres – Leicester, Newcastle and Aintree. This difference in duration of recruitment occurred because two centres could not retain or recruit further research fellows within the time frame of trial recruitment when the initial personnel returned to their clinical training. As recruitment was lower than proposed, and with multicentre research ethics committee (MREC) approval, an additional centre was subsequently enrolled at Ashington (Wansbeck Hospital) in October 2005, a research nurse working with support from the research fellow at Newcastle.

Participants

Patients admitted with a fixed neurological deficit of over 60 minutes duration and a potential diagnosis of an acute stroke were identified by researchers at each of the six participating sites from A&E departments, medical admission and stroke units and general inpatient beds. Stroke was defined as a rapid onset of symptoms and/or signs involving a focal or global loss of function with no other apparent cause. The following inclusion and exclusion criteria were applied:

Consent

Eligible patients interested in the study were invited to read a patient information leaflet detailing the nature of the study along with the potential risks and benefits of participating. After obtaining written and witnessed consent, subjects were randomised. If subjects were unable to give written informed consent, relative assent was accepted or, if this was not feasible, independent clinician assent could be obtained until a relative was available or the patient recovered enough to give consent.

Randomisation

Consenting patients fulfilling the trial entry criteria were randomised by secure internet central randomisation (block size six) to receive either active treatment or matching placebo in a ratio of 2:1 between active treatment and matching placebo (depressor arm) and 1:1 between active treatment and matching placebo (pressor arm). Each researcher had a unique username and password allowing an audit trail of data entry. Researchers were blinded to patients’ treatment randomisation until the end of the trial in April 2007. During the trial each site was asked to maintain a log of patients who were screened detailing whether they were eligible for the study or, if ineligible, giving the reasons for exclusion. Specific baseline neurological assessments performed at randomisation included NIHSS, mRS and Oxfordshire Community Stroke Project (OCSP)83 classification (see Appendix 4e).

Usual care

All routine management of patients with suspected stroke with respect to investigation [including haematology, biochemistry, chest radiology and electrocardiography (ECG)], acute management and rehabilitation were continued as standard local practice, including casual BP observations and the timing of introduction of antithrombotic therapy. Neuroimaging was not a requirement before randomisation in the depressor arm but was necessary before randomisation in the pressor arm to exclude cerebral haemorrhage. Standard secondary preventative treatment was initiated by the local investigators, although decisions regarding future antihypertensives were delayed until the end of the trial intervention (2 weeks); however, no protocol for this was specified by the co-ordinating centre.

Blood pressure measurement and stroke onset

Before randomisation BP was taken as the mean of six supine recordings made over 10 minutes using a validated BP monitor (UA-767 monitor and cuff of the appropriate size) conducted by suitably trained research staff. Hypertension was defined as a mean SBP level of > 160 mmHg and relative hypotension as a mean SBP level of ≤ 140 mmHg. Time of stroke onset required clear definition; for those patients waking with suspected stroke, time of onset was taken as the last time the patient was documented to be free of stroke symptoms.

Time window

Patients were eligible for pressor therapy within 0–12 hours of stroke onset, whereas those eligible for depressor therapy could be treated up to 36 hours from onset. The initial protocol allowed recruitment into the depressor arm only up to 24 hours from onset, but this was amended in May 2005 to increase recruitment of patients who would potentially benefit from intervention. Although BP reduction may have differential time effects related to the ischaemic penumbra and reducing stroke recurrence it was anticipated that BP elevation would be important only when the penumbra was viable, and therefore patients eligible for pressor therapy were only randomised during the hyperacute time window (0–12 hours) when salvageable penumbra was likely to be present.

Dysphagia

Patients were defined as dysphagic or non-dysphagic on the basis of a standardised bedside swallow assessment by appropriately trained staff, performed as part of the routine clinical assessment of a patient with suspected stroke in all participating centres. It was anticipated that 25% of patients would initially be dysphagic, affecting the ability to take medication orally. To ensure inclusion of this important subgroup, patients were stratified by the presence of dysphagia; such patients were independently randomised to sublingual or intravenous therapy.

Trial medication supplies

All drugs were centrally manufactured by the pharmaceutical company (DHP) and shipped directly to the individual centres. The local production of suspension at the time of drug administration was necessary because of the short shelf life of suspension preparations.

Depressor arm

Hypertensive, non-dysphagic patients were randomly assigned to receive either oral lisinopril 5 mg or oral labetalol 50 mg or oral matching placebo. Hypertensive, dysphagic patients received either sublingual lisinopril 5 mg and intravenous placebo, or intravenous labetalol 50 mg bolus injection (over a period of at least 1 minute) and sublingual placebo, or sublingual and intravenous placebo. All patients were asked to remain supine for a 30-minute period following each intravenous bolus injection. Placebo and active tablets were matched for size, shape and colour; similarly, labetalol and phenylephrine and placebo vials for intravenous administration were matched for size, shape and colour.

Brachial artery BP was monitored at 30-minute intervals for 4 hours post dose; patients developing symptomatic or asymptomatic hypotension (SBP < 140 mmHg) during this period had study medication discontinued. At 4 hours in those patients not achieving the target SBP of 145–155 mmHg or a 15 mmHg reduction in SBP from levels at randomisation, further treatment doses were given: non-dysphagic patients received oral lisinopril 5 mg or oral labetalol 50 mg or oral matching placebo; dysphagic patients received sublingual lisinopril 5 mg and intravenous placebo, or intravenous labetalol 50 mg bolus injection (over a period of at least 1 minute) and sublingual placebo, or sublingual and intravenous matching placebo.

BP was monitored for a further 4 hours post dose (i.e. until 8 hours post randomisation). Again, in those patients not achieving the target SBP of 145–155 mmHg or a 15 mmHg reduction from baseline SBP at 8 hours, a further treatment dose was given: non-dysphagic patients received further oral lisinopril 5 mg or oral labetalol 50 mg or matching placebo; dysphagic patients received further sublingual lisinopril 5 mg (and intravenous placebo) or intravenous labetalol 50 mg bolus injection (over a period of at least 1 minute) (and sublingual placebo) or sublingual and intravenous matching placebo. No further trial medication was give after 8 hours until 24 hours after the initial dose following randomisation.

The established treatment regimes for non-dysphagic patients were then continued for a 2-week period as follows: oral lisinopril 5, 10 or 15 mg once daily in the morning with matching placebo in the evening to give a twice-daily dosage regime or oral labetalol 50, 100 or 150 mg twice daily or oral matching placebo twice daily. Dysphagic patients received the established treatment regimes for 72 hours as follows: sublingual lisinopril 5, 10 or 15 mg once daily and intravenous placebo, or intravenous labetalol 50, 100 or 150 mg bolus injection (over a period of at least 1 minute) twice daily and sublingual placebo, or sublingual and intravenous matching placebo.

At 72 hours the dysphagic patients had their swallow reassessed, and those patients remaining dysphagic at 72 hours received treatment with lisinopril or labetalol or matching placebo suspension via nasogastric or percutaneous endoscopic gastrostomy (PEG) feeding tube. Those patients who regained their swallow received lisinopril or labetalol or matching placebo suspension orally. Therefore, all dysphagic patients received two trial treatment packages. The first trial treatment pack enabled sublingual and intravenous active treatment and/or matched placebo treatment for 72–96 hours. The second trial treatment pack contained lisinopril or labetalol or placebo tablets to be crushed locally and made into a suspension to be administered via nasogastric/PEG tube or orally according to the patient’s swallow until 2 weeks.

Pressor arm

Hypotensive patients with or without dysphagia were recruited within 12 hours of stroke onset to the pressor arm of the study. Before study treatment all patients were required to have neuroimaging to exclude primary intracerebral haemorrhage (PICH) or other non-ischaemic stroke pathology. As induced hypertension may be associated with haemorrhage or oedema11 it was not considered safe to expose patients with PICH to pressor therapy. The patient’s hydration status was also assessed by clinical examination and laboratory estimation of urea and creatinine before study treatment to ensure that patients were euvolaemic. To reduce the risk of potential hypovolaemia, normal saline was infused at a rate of 100 ml/hour throughout the treatment period in all patients. BP monitoring and treatment were carried out in an acute stroke or high-dependency unit (dictated by a nurse–patient ratio of 1:2) during the medication infusion period. Patients were fitted with chest leads for continuous ECG recording and an appropriately sized cuff of the Finapres/Portapres non-invasive beat-to-beat BP monitor. The cuff was fitted to the middle finger or thumb of the hemiparetic arm and maintained at heart level. After achievement of a satisfactory BP signal and the stabilisation of BP (mean 2-minute BP levels not varying by > 10 mmHg over ≥ 10 minutes), patients received either intravenous phenylephrine at a rate of 60 µg/minute (1 ml/minute) or matching intravenous placebo. Phenylephrine 30 mg (10 mg/ml)/placebo was diluted in 500 ml of 0.9% sodium chloride. Pressor therapy was continued for up to 24 hours after stroke onset (minimum pressor stimulus 12 hours). As it was considered unlikely that the benefits of pressor therapy would extend beyond the period of penumbral viability, it was not considered ethical to expose patients to the potential risks of pressor therapy beyond this time. Furthermore, the costs and inconveniences of continuous non-invasive BP monitoring did not justify the continuation of therapy for longer. The infusion rate was adjusted by 30 µg/minute (0.5 ml/minute) increments at 30-minute intervals to maintain an increase in SBP to the target SBP of 150 mmHg (range 145–155 mmHg) or a 15 mmHg increase above baseline values. A maximum infusion rate of intravenous phenylephrine of 180 µg/minute (3 ml/minute) or of intravenous matching placebo was allowed.

Changes to protocol

The following changes were made to the original trial protocol (all dates quoted are those of MREC amendment approval):

1. Protocol amendments 1 and 2 were approved in February 2004 to incorporate the dosing regime for use of intravenous labetalol and to add on the baroreceptor sensitivity/blood pressure variability substudy respectively. The results of this substudy will not be reported here.

2. Protocol amendment 3, approved in May 2004, permitted the use of transcranial ultrasound to monitor cerebral blood flow and autoregulation in the cerebral blood flow/cerebrovascular autoregulation substudy (this substudy was funded by the Stroke Association and the results are not considered in this report).

3. Protocol amendments 4 and 5 were initially submitted for further substudies; however, following the introduction of the European Clinical Trials Directive these were subsequently approved as separate studies in their own right.

4. Protocol amendment 6 in July 2004 permitted the inclusion of dysphagic patients on previous antihypertensive therapy to improve recruitment. Patients receiving previous antihypertensive therapy who were not dysphagic were considered for the COSSACS study. This protocol amendment also allowed inclusion of those with a pre-stroke mRS score of 3 or less (having previously been 2 or less).

5. Protocol amendment 7 in February 2005 allowed the collection of health economic data, which was described in the initial trial protocol as a cost-effectiveness analysis. The protocol was amended to specify inclusion of health economics and the use of a patient diary, the EuroQoL 5-dimensional questionnaire (EQ-5D), at 2 weeks and 3 months, along with a structured telephone interview at 3 months if patients were willing (see Appendix 4c). Non-consent to this phase of the study did not exclude patients from the main study.

6. Protocol amendment 8, approved in June 2005, extended the window of recruitment for the depressor arm from 24 to 36 hours post stroke. As it was felt that any effect of pressor therapy would occur only whilst the penumbra remained viable, the time window for the pressor arm remained 12 hours from stroke for the duration of the study. In addition, the original trial was scheduled to recruit until the end of June 2006, and this was extended to the end of December 2006 to recruit a sufficient number of patients into each arm.

7. Because of limited recruitment to the pressor phase of the study this limb of the trial was terminated after consultation with the Health Technology Assessment (HTA) Programme and MREC in April 2005.

Study objectives

The primary objective was to assess the effects of acute pressor and depressor BP manipulation on 2-week death and dependency following acute stroke.

The secondary objectives were to:

• establish the safety of acute pressor (0–12 hours post stroke) and depressor (0–36 hours post stroke) BP manipulation in stroke patients as assessed by the absence of early (72 hours) neurological deterioration

• investigate if beneficial or detrimental effects of BP manipulation are influenced by stroke type (ischaemic versus haemorrhagic)

• determine if alternative therapeutic routes (sublingual, intravenous) for administering depressor therapy are effective at lowering BP in dysphagic stroke patients

• investigate if beneficial or detrimental effects of BP manipulation are influenced by time to treatment

• assess the cost-effectiveness and cost–utility of active treatment in relation to death and dependency, mortality and quality-adjusted life-years (QALYs) gained over a period of 2 weeks and 3 months.

Outcome measures

Data were collected on time and cause of death up to 3 months following the index event. Dependency was measured at baseline and at 2 weeks using the Barthel Index and the mRS) (see Appendices 4a and 4b). Neurological deficit was assessed using the NIHSS, which was recorded at baseline and at 24, 48 and 72 hours and again after 2 weeks. BP was recorded at baseline, at 4, 8 and 24 hours and at 2 weeks by taking the average of six readings using the UA-767 BP machine. Information was collected regarding routine haematological and biochemical parameters (full blood count, urea and electrolytes, glucose, cholesterol), ECG findings and the results of neuroimaging. An EQ-5D questionnaire was performed at 2 weeks and again at 3 months (if patients were willing to undergo this) following the approval of protocol amendment 7. Baseline and 2-week assessments were performed by trained research staff in the participating centres, whereas 3-month follow-up was performed centrally by telephone from the coordinating centre.

Serious adverse events

Reporting of all serious adverse events (SAEs) was required for all patients up to 2 weeks (i.e. the intended duration of study medication). Information was collected regarding severity (mild, moderate, severe or fatal), causality in terms of relation to treatment (definite, uncertain or no causality) and system affected (e.g. neurological, respiratory). All expected SAEs were reported to the Trial Steering Committee and the Data Safety Monitoring Committee on a 6-monthly basis. Reporting of sudden unexpected serious adverse events (SUSARs) was mandatory, as per the European Clinical Trials Directive (fatal or life-threatening events reported within 7 days, non-life-threatening events reported within 15 days to the sponsor).

Sample size

It was postulated that there would be a 60% death or dependency rate at 2 weeks in the placebo arm of the trial39 with a dropout rate of 15%. Therefore, in the depressor arm of the trial 1650 patients (550 in each group) would need to be recruited to have an 80% power at the 5% significance level to detect a relative reduction of 15% (or absolute risk reduction of 9%) in death and dependency between either of the two treatment groups and the placebo group. Assuming a standard deviation of 30 mmHg in casual SBP measurements in each group, the minimum detectable BP difference between the active treatment and placebo groups with 500 patients in each group and an 80% power at the 5% significance level is 5.1 mmHg.

It was anticipated that approximately 20% of patients would have an admission SBP of ≤ 140 mmHg. 39 Therefore, recruiting 400 patients (200 in each group) to the pressor arm of the trial would have an 80% power at the 5% significance level to detect a relative reduction of 25% in death and dependency between the active treatment and placebo groups, assuming a patient dropout rate of 15%.

Therefore, if both depressor and pressor arms of the trial were undertaken, a total of 2050 patients would have to be recruited to the trial, at a rate of approximately seven patients per centre per month during a 30-month recruitment period, assuming that 10 centres were actively recruiting. Stroke registers maintained by the acute stroke units prior to participating in the CHHIPS trial confirmed that between 500 and 800 patients were admitted per annum at each centre, 91% within 24 hours.

After the trial began, significant problems were encountered with the screening and identification of eligible patients, and these are addressed in Chapter 4. After discussion with the Trial Steering Committee, various amendments were made to the original protocol to try and improve recruitment (see Changes to protocol); these are also considered in Chapter 3 (Recruitment).

There were initial difficulties in obtaining phenylephrine in 2004 because of manufacturing problems, there being no supplies in the UK for 2 months, which delayed the start of the pressor arm until March 2004. Subsequently, in line with the recommendation of the Trial Steering Committee and HTA, following significant problems recruiting hypotensive patients in the hyperacute post-stroke period amongst all centres it was agreed to close the pressor arm to recruitment in April 2005. This allowed time and resources to be concentrated on improving recruitment into the depressor arm and ensuring complete data collection.

Statistical analysis

Systolic and diastolic blood pressure levels at randomisation were calculated as the average of six readings. Stroke was classified as ischaemic (evidence of an infarct or haemorrhagic transformation of infarct in keeping with the physical signs at presentation), PICH or no relevant abnormality on neuroimaging [standard computerised tomography (CT) scanning in all centres]. Patients were excluded from the intention to treat analysis if imaging confirmed a diagnosis other than acute stroke. The primary end point was death and dependency at 2 weeks, with dependency defined as an mRS score of greater than 3.

All continuous measures are approximately normally distributed. Binary outcomes – death and dependency at 2 weeks, or change in NIHSS score at 72 hours greater than 3 points – were analysed by logistic regression. Regression analysis was used to compare continuous outcomes by and across treatment groups. Repeated measures analysis of SBP at baseline and at 4, 8 and 24 hours was carried out using generalised estimating equations (GEE) modelling with unstructured correlation. The model included time, treatment and time by treatment interaction terms. Analyses were first undertaken of active treatment compared with placebo, followed by comparisons across the three treatment groups when appropriate. To protect the results from multiple tests, Fisher’s protected least square difference (LSD) method was used. Statistical significance was set at 5% and, if no significant difference was found across the three groups for a particular outcome measure, no further subgroup analysis was performed. Survival data were analysed by Cox’s proportional hazards model with non-parametric Kaplan–Meier plots. Significance levels were set at 5%.

Health economic analysis

Economic analyses of the CHHIPS study data were carried out to determine the cost-effectiveness of active treatment versus placebo.

The primary outcomes were incremental cost per incremental survivor at 3 months of active treatment versus placebo, and incremental cost per incremental QALY gained at 14 days and 3 months. Additional analyses comparing death and dependency at 14 days and death at 14 days were performed. Date of death was collected for each patient. An mRS score of 6 was given to those patients who had died.

As baseline EQ-5D data were not available and limited observations were available at 3 months, it was not possible to directly calculate QALYs gained from EQ-5D scores. Therefore, utilities were mapped to mRS scores calculated from a previous study. 84 In this study, 459 individuals completed a number of outcome measures at 6 months post stroke, and the utility of the mRS scores was estimated using the time trade-off approach (Table 1).

These utility scores were compared with utility scores estimated by converting the EQ-5D profiles reported in the trial using the standard UK valuation set. 85 QALYs gained were subsequently estimated based on the mRS-based utilities.

Our original intention was to perform the analyses from a societal perspective. However, because of small sample sizes, the perspective was limited to that of the acute hospital admitting the stroke patient. Drug acquisition costs were used to represent the cost of study drugs. Intravenous labetalol was administered as a bolus over 1 minute and so any additional cost incurred by this route of administration would be small. All patients who received intravenous agents were hospital inpatients and therefore no additional cost was incurred for home administration or district nurse or GP time. The number of tablets or vials used was averaged over the intervention period of 14 days. Hospital length of stay (LoS) was used to measure the hospitalisation cost.

The price year was 2006. Sources other than 2006 were converted to 2006 prices using the Consumer Prices Index (CPI). LoS was calculated as (date of discharge or date of death) – date of randomisation. For patients not yet discharged, LoS was truncated at 14 or 84 days as follows. When date of discharge was recorded as more than 3 months post randomisation, LoS was set to a maximum of 84 days. When date of discharge was not recorded, but it was known that patients were still in hospital at day 14, the observations were used in the 14-day analysis but counted as missing in the 3-month analysis.

To calculate the cost of a hospital admission the National Schedule of Reference Costs86 was used, which calculated the mean cost of a stroke admission to be £2462, based on a mean LoS of 11 days. The daily cost of excess bed-days is £176. Inpatient costs tend to be skewed towards the first few days of admission. Therefore, to allow for this, cost of admission is calculated as £2462 + (LoS – 11) × 176.

The results are presented as quantities of resource use and total cost by treatment group [labetalol, lisinopril, active treatment (labetalol and lisinopril combined) and placebo]. Quantities of resource use and costs are compared using t-tests and analysis of variance (ANOVA) as appropriate. Incremental cost-effectiveness ratios (ICERs) are calculated as:

where C₂ and E₂ are the cost of and QALYs gained from active treatment respectively and C₁ and E₁ are the cost of and QALYs gained from placebo. This expresses the extra cost to generate one extra unit of outcome (e.g. extra survivor).

Confidence intervals around incremental costs and outcomes, and cost-effectiveness acceptability curves (CEACs) are generated using a non-parametric bootstrap with 1000 replications. The CEAC shows the strategy with the highest probability of being cost-effective at varying thresholds of willingness to pay for a unit of outcome. We also present results as incremental net benefit (INB) curves, in which:

where λ is the willingness to pay for a unit of outcome and INB can be interpreted as the monetary value of the benefits less the value of the costs. A value greater than zero implies that the added benefits are valued more highly than the added costs; therefore the intervention would be deemed cost-effective. As the value of λ is unknown, the curve plots for a range of values (a value of λ of between £20,000 and £30,000 per QALY gained or £1m per premature death averted is thought to be a ‘reasonable’ willingness to pay for a unit of health outcome). As baseline characteristics of treatment groups are similar, no adjustment for baseline differences was carried out.

Screening data

Local trial co-ordinators at the four centres participating in both the pressor and the depressor limbs of the CHHIPS study kept a record of patients screened during set periods of the trial. It was not possible to keep a complete 24-hour analysis of all stroke admissions for the whole trial period because of staffing levels. In total, 2361 patients were screened during periods lasting between 14 and 19 months in the four centres; 94 had been discharged or had died before the researcher could review them, leaving a total of 2267 patients with a clinical presentation of stroke (Table 2). Non-stroke patients (i.e. those with stroke mimics) and those with transient ischaemic attacks (TIAs; symptoms and signs having resolved by the time the patient was reviewed by a researcher) have been excluded from this analysis as they were ineligible for the trial.

Those who were on antihypertensive medication and able to swallow were excluded as per protocol and considered for another clinical trial. The remaining patients were split into three groups based on systolic blood pressure: SBP > 160 mmHg (depressor group); SBP 141–160 mmHg (excluded from CHHIPS); and SBP ≤ 140 mmHg (pressor group). A schematic breakdown of the patients is depicted in the flowchart in Figure 1.

FIGURE 1.

Schematic breakdown of patients screened and randomised for the CHHIPS study from the log. Anti-HT, antihypertensive treatment; COSSACS, Continue Or Stop post-Stroke Antihypertensives Collaborative Study; SBP, systolic blood pressure; TIA, transient ischaemic attack.

Depressor arm

Of the patients with a SBP of > 160 mmHg, i.e. ‘potential CHHIPS depressor group’ (n = 578), 396 had exclusion criteria, specified in the protocol, and 182 (8.1%) were eligible at the time of hospital presentation. A total of 66 (2.9% of all screened but 36.3% of all eligible patients at hospital presentation) were randomised to the CHHIPS depressor arm. The reasons for ineligibility of patients at hospital admission screening are given in Figure 2 and Table 3, and the reasons for non-recruitment of patients initially eligible are given in Figure 3 and Table 4.

FIGURE 2.

Pie chart illustrating reasons for patient ineligibility (n = 1936) at hospital admission for revised CHHIPS depressor protocol. CI, contraindication; DN, not dysphagic; HT, on antihypertensives; NIH, NIHSS Section 1a score of > 1, i.e. depressed consciousness level.

FIGURE 3.

Pie chart illustrating reasons for entry or non-entry of eligible patients (n = 182) at the time of hospital admission to revised CHHIPS depressor protocol. BP, blood pressure.

TABLE 3 - Reasons for patient ineligibility at hospital admission for revised CHHIPS depressor protocol

BP, blood pressure; mRS, modified Rankin Scale.

Unclear about antihypertensive drug therapy at time of admission and/or dysphagia status, but with other exclusion criteria for the depressor arm of the study.

Exclusion criterion	Number
On antihypertensive therapy	727
BP ≤ 140 mmHg	451
BP 140–160 mmHg	362
mRS score > 2/3 (too dependent)	104
Admission > trial window	80
NIHSS Section 1a score > 1 (too drowsy)	67
Contraindication to drug	43
Others	102
Total	1936
Unclassifieda	149

TABLE 4 - Reasons for entry or non-entry of eligible patients at the time of hospital admission to revised CHHIPS depressor protocol

SBP, systolic blood pressure.

Outcome	Number
Randomised	66
Within time window at presentation but outside by the time reviewed by researcher	64
Declined participation/unable to consent/no relative assent feasible	26
SBP > 160 mmHg documented at admission but lower (< 160 mmHg) when reviewed by researcher, therefore not eligible	25
Reason for exclusion unknown	1
Total eligible	182

Pressor arm

The reasons for patient ineligibility at hospital admission for the revised CHHIPS pressor protocol are given in Figure 4 and Table 5. In total, 11.4% were excluded because they were reviewed outside the trial eligibility window (180 admitted > 11.5 hours from onset plus 77 reviewed outside the 12-hour window). Patients presenting with a SBP of ≤ 140 mmHg and not on antihypertensive medication were categorised as ‘potential CHHIPS pressor group’. The outcomes of potentially suitable CHHIPS pressor patients are presented in Table 6; among the 10 patients who were potentially suitable at hospital admission (0.4% of all screened), in three cases no clear reason for non-recruitment was found. The one patient recruited into the pressor arm was not recruited during the screening period.

FIGURE 4.

Pie chart illustrating reasons for patient ineligibility at hospital admission (n = 226) for revised CHHIPS pressor protocol. HT, antihypertensive therapy; OS, onset to screening time; SBP, systolic blood pressure.

TABLE 5 - Reasons for patient ineligibility at hospital admission for revised CHHIPS pressor protocol

CT, computerised tomography; mRS, modified Rankin Scale; OA, onset to admission.

Assumes that unknown onset to admission delay equates to > 12 hours, i.e. ineligible.

Reason for exclusion	Number
On antihypertensive treatment	1302
Antihypertensive status not known	112
SBP > 140 mmHg	570
OA delay unknown or > 12 hours	180
Screened > 12 hours from symptom onseta	77
mRS score > 2/3 (too dependent)	5
Thrombolysed (exclusion)	3
Uncertain diagnosis (exclusion)	3
Contraindication to drug	2
Non-consent	2
CT not performed	1
Potentially eligible	10 (0.4%)
Total	2267

TABLE 6 - Outcome of potentially suitable CHHIPS pressor patients

Outcome	Number	Location
No clear reason for non-recruitment	3	Exeter, Leicester, Newcastle (one each)
Presented after pressor arm of trial discontinued	7
Total	10

Recruitment

The CHHIPS study recruited 180 patients who had persistent neurological symptoms lasting more than 60 minutes from the six active recruiting centres over the course of the study, with 179 in the depressor arm and one in the pressor arm. Reasons why centres did not recruit to the numbers originally proposed included concerns about the intensity of monitoring required and suitable facilities, patients receiving thrombolysis and thus requiring open-label blood pressure control, decreasing numbers of potentially eligible patients (this was particularly true in terms of increasing numbers of patients being on antihypertensive medication on admission), and ongoing conflicting trials at the time that CHHIPS started recruiting. In addition to these considerations, each site had a dedicated research fellow or nurse and there was no provision for cover during periods of absence for study or annual leave (statutory holiday leave of 30 working days per annum) and weekend cover was ad hoc.

Seven patients were entered into the study but were subsequently withdrawn because of non-stroke diagnoses [one Bell’s palsy, one subdural haematoma, one subarachnoid haemorrhage, one unspecified, one withdrawal of consent and two protocol violations (one on antihypertensive therapy and dysphagic before approval of protocol amendment 6 allowing inclusion of these patients and one intracerebral haemorrhage with systolic blood pressure > 200 mmHg)]. The primary end point was recorded for all 172 patients; thus, the retention rate was 96.7%. The patient in the pressor arm is not included in the analysis below as he or she was randomised to placebo.

The protocol amendments were effective at increasing recruitment. Of the total of 180 patients recruited, six (3%) had an mRS score of 3, 10 (5%) were receiving prior antihypertensive therapy but were dysphagic at entry, and 25 were recruited between 24 and 36 hours from stroke onset (13.9%).

Compliance with randomised treatment

Out of 179 patients randomised in the depressor arm, seven were withdrawn for non-stroke diagnosis and 126 (73%) completed the full 14-day trial treatment as specified in the CHHIPS protocol; one patient was withdrawn before receiving any allocated treatment and a further 45 discontinued study medication at some point during the first 2 weeks. Figure 5a and b shows the timing of treatment discontinuation in days from randomisation. The total number of discontinuations by group [16 (28%) in the labetalol group, 18 (32%) in the lisinopril group and 11 (21%) in the placebo group] are shown in Figure 5c, and discontinuations by treatment group and dysphagia status are illustrated in Figure 6a–e. There was no significant difference between labetalol, lisinopril and placebo in the number of discontinuations (p = 0.44). Discontinuations because of SAEs are considered in more detail in the section on causality. A full list of medication discontinuations can be found in Appendix 1. The allocation of patients randomised in the depressor arm and the distribution of trial withdrawals is shown in the CONSORT diagram in Figure 7.

FIGURE 5.

(a) Trial medication discontinuations by time for active and placebo groups combined. (b) Cumulative trial medication discontinuations for active and placebo groups combined. (c) Total medication discontinuations by group.

FIGURE 6.

(a) Trial medication discontinuations by treatment group by time. (b) Cumulative trial medication discontinuations by treatment group. (c) Trial medication discontinuations by dysphagia status. (d) Cumulative trial medication discontinuations by dysphagia status. (e) Cumulative trial medication discontinuations by group and dysphagia status. i.v., intravenous; p.o., oral; s.l., sublingual.

FIGURE 7.

Randomisation and intention to treat groups. Anti-HT, antihypertensive therapy; PICH, primary intracerebral haemorrhage; SAH, subarachnoid haemorrhage; SBP, systolic blood pressure; SDH, subdural haemorrhage.

Baseline characteristics

The labetalol, lisinopril and placebo groups were well matched for gender, age, systolic and diastolic BP, mRS score, NIHSS score and dysphagia at randomisation (Table 7). Mean age (SD) for all of the trial patients was 74 (11) years, mean SBP and DBP were 181 (16) mmHg and 95 (13) mmHg, respectively, and mean NIHSS score was 11 (7).

Outcomes

All analyses were on an intention to treat basis.

Secondary outcomes

Safety: early neurological deterioration

Early neurological deterioration at 72 hours, defined as an increase in NIHSS score of more than 3 points from baseline, occurred in seven (6%) people in the active treatment group and three (5%) in the placebo group (RR 1.22, 95% CI 0.33–4.54; p = 0.76; Table 9). There was one death at 72 hours in the active treatment group compared with three in the placebo group.

TABLE 9 - Change in neurological status at 72 hours

NIHSS, National Institutes of Health Stroke Scale.

	Treatment group
	Labetalol (n = 56)	Lisinopril (n = 57)	Active (labetalol + lisinopril) (n = 113)	Placebo (n = 59)
An increase in NIHSS score of ≥ 4 or dead at 72 hours, n (%)	1 (2)	7 (12)	8 (7)	6 (10)
Active vs placebo	p = 0.56
Across three groups	p = 0.09
An increase in NIHSS score of ≥ 4 at 72 hours, n (%)	1 (2)	6 (10)	7 (6)	3 (5)
A decrease in NIHSS score of ≥ 4 at 72 hours, n (%)	51 (91)	48 (84)	99 (88)	52 (88)
NIHSS score not significantly changed (change ≤ 3 from baseline) at 72 hours, n (%)	4 (7)	2 (4)	6 (5)	1 (2)
Dead at 72 hours, n (%)	0 (0)	1 (2)	1 (1)	3 (5)

Stroke subtype

The effect of stroke subtype [classified as CT-/magnetic resonance imaging-confirmed relevant infarct including haemorrhagic transformation of infarct, PICH or other (this group includes those whose neuroimaging was reported as normal)] on outcome was also studied. Two patients randomised to the placebo arm died before neuroimaging and therefore are not included in the figures as stroke subtype was classified as ‘unknown’. The numbers in each group were too small to allow further useful analysis (Table 10).

TABLE 10 - Neurological deterioration, systolic and diastolic blood pressure change and death and dependency at 2 weeks by stroke subtype

DBP, diastolic blood pressure; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; SBP, systolic blood pressure.

Minus sign indicates a fall from baseline.

Treatment group (n)	Increase in NIHSS score ≥ 4 at 72 hours, n (%)	SBP change at 24 hours (mmHg), mean (SE)a	SBP change at 2 weeks (mmHg), mean (SE)a	DBP change at 2 weeks (mmHg), mean (SE)a	Death and dependency at 2 weeks (mRS score> 3), n (%)
Ischaemic (99)
Active (64)	4 (6.2)	–23 (3)	–30 (3)	–14 (2)	44 (68)
Placebo (35)	2 (5.7)	–9 (3)	–25 (5)	–10 (3)	19 (54)
Haemorrhage (25)
Active (18)	2 (11)	–18 (5)	–31 (6)	–9 (3)	14 (77)
Placebo (7)	0 (0)	–17 (10)	–34 (8)	–12 (5)	3 (43)
Other (46)
Active (31)	1 (3.2)	–20 (3)	–24 (3)	–13 (2)	11 (35)
Placebo (15)	0 (0)	–17 (5)	–15 (7)	–5 (4)	11 (73)

Change in blood pressure

Blood pressure values fell from randomisation to 24 hours in each of the three groups and remained lower at 2 weeks (Tables 11 and 12; Figure 8). There was a statistically significant reduction in SBP from baseline to 24 hours in the combined active treatment group compared with the placebo group (mean reduction 10 mmHg, 95% CI 17–3; p = 0.004) (Table 11). Analysis across the three treatment groups showed the presence of an overall difference between the groups (p = 0.005). This difference could be seen to arise from the significant reduction in SBP with lisinopril compared with placebo (mean reduction 14 mmHg, 95% CI 22–5; p = 0.001) but not with labetalol compared with placebo (mean reduction 7 mmHg, 95% CI 15 to –1; p = 0.096).

TABLE 11 - Change in systolic blood pressure (SBP) from randomisation by time and by group (dysphagic and non-dysphagic groups combined)

Minus sign indicates a fall from baseline.

	Treatment group
	Labetalol	Lisinopril	Active (labetalol + lisinopril)	Placebo
SBP change at 4 hours (mmHg), mean (SE)a	–22 (2)	–16 (2)	–19 (2)	–9 (2)
SBP change at 8 hours (mmHg), mean (SE)a	–20 (3)	–29 (3)	–25 (3)	–14 (3)
SBP change at 24 hours (mmHg), mean (SE)a	–18 (3)	–25 (3)	–21 (2)	–11 (3)
Active vs placebo	p = 0.004
Across three groups	p = 0.005
Labetalol vs placebo	p = 0.096
Lisinopril vs placebo	p = 0.001
SBP change at 2 weeks (mmHg), mean (SE)a	–31 (3)	–32 (3)	–31 (2)	–24 (3)
Active vs placebo	p = 0.045
Across three groups	p = 0.13

TABLE 12 - Change in diastolic blood pressure (DBP) from randomisation by time and by group (dysphagic and non-dysphagic groups combined)

DBP, diastolic blood pressure.

Minus sign indicates a fall from baseline.

	Treatment group
	Labetalol	Lisinopril	Active (labetalol + lisinopril)	Placebo
DBP change at 4 hours (mmHg), mean (SE)a	–10 (1.3)	–9 (1.4)	–5 (1.7)	–5 (1.4)
DBP change at 8 hours (mmHg), mean (SE)a	–13 (2.2)	–18 (2.3)	–10 (2.7)	–6 (2.2)
DBP change at 24 hours (mmHg), mean (SE)a	–6 (2.1)	–13 (2.1)	–3 (2.6)	–6 (2.1)
Active vs placebo	p = 0.189
Across three groups	p = 0.021
Labetalol vs placebo	p = 0.909
Lisinopril vs placebo	p = 0.019
DBP change at 2 weeks (mmHg), mean (SE)a	–11 (2)	–15 (2)	–13 (1)	–9 (2)
Active vs placebo	p = 0.10
Across three groups	p = 0.12

FIGURE 8.

(a) Systolic blood pressure (SBP) changes for the active treatment group (labetalol and lisinopril groups combined) and the labetalol and lisinopril groups separately vs placebo following randomisation. Standard error bars are omitted for clarity. (b) SBP changes by group following randomisation. Standard error bars are omitted for clarity. The sample sizes for the blood pressure trends shown in (b) are shown in Table 13. i.v., intravenous; p.o., oral; s.l., sublingual.

TABLE 13 - Sample sizes for the blood pressure trends shown in Figure 8b

i.v., intravenous; p.o., oral; s.l., sublingual.

	0 hours	4 hours	8 hours	24 hours	2 weeks
Systolic blood pressure
Labetalol i.v.	27	27	27	27	26
Labetalol p.o.	29	29	29	29	29
Lisinopril s.l.	28	28	27	28	23
Lisinopril p.o.	29	29	28	29	28
Placebo i.v./s.l.	28	28	27	28	23
Placebo p.o.	31	29	30	30	30
Diastolic blood pressure
Labetalol i.v.	27	23	18	19	26
Labetalol p.o.	29	26	23	21	29
Lisinopril s.l.	28	21	17	21	23
Lisinopril p.o.	29	26	22	22	28
Placebo i.v./s.l.	28	22	22	18	23
Placebo p.o.	31	25	21	23	30

SBP change at 2 weeks showed a difference in the combined active treatment arm compared with the placebo group (mean reduction 8 mmHg, 95% CI 16–0.2; p = 0.045). When analysed across the three groups, no statistically significant difference in SBP change at 2 weeks between groups was found. DBP change at 2 weeks did not show any statistically significant differences either in the combined active group compared with the placebo group (mean reduction 4 mmHg, 95% CI 9 to –0.8; p = 0.10) or across the three groups (p = 0.12) (Table 12).

Dysphagic group

Mean SBP changes over the first 24 hours and 2 weeks and mean DBP changes at 2 weeks in dysphagic and non-dysphagic patients by treatment group are shown in Table 14. Repeated measures analysis for SBP at 4, 8 and 24 hours in the dysphagic group for the three treatment arms (Table 15) showed an overall significant difference between treatments with time (p = 0.0001; Figure 9). There was a borderline significant reduction in SBP in the lisinopril group compared with placebo at 8 hours (mean reduction 10 mmHg, 95% CI 21 to –1; p = 0.07) and a significant reduction at 24 hours (mean reduction 12 mmHg, 95% CI 23–2; p = 0.024), but not at 4 hours. In contrast, the labetalol dysphagic group had a significant reduction in SBP compared with placebo at 4 hours (mean reduction 16 mmHg, 95% CI 26–5; p = 0.005), but not at 8 hours and 24 hours (Table 15).

TABLE 14 - Changes in systolic blood pressure (SBP) at 24 hours and 2 weeks and diastolic blood pressure (DBP) at 2 weeks (dysphagic and non-dysphagic groups)

Treatment group (n)	Baseline SBP (mmHg), mean (SD)	Baseline DBP (mmHg), mean (SD)	SBP change at 24 hours (mmHg), mean (SE)	SBP change at 2 weeks (mmHg), mean (SE)	DBP change at 2 weeks (mmHg), mean (SE)
Dysphagic (83)
Labetalol (27)	179 (15)	91 (12)	–11 (4)	–34 (5)	–11 (3)
Lisinopril (28)	184 (18)	96 (12)	–23 (4)	–27 (6)	–12 (3)
Placebo (28)	180 (18)	95 (14)	–7 (4)	–25 (6)	–9 (4)
Non-dysphagic (89)
Labetalol (29)	183 (16)	95 (16)	–24 (4)	–28 (3)	–11 (2)
Lisinopril (29)	181 (18)	97 (13)	–26 (4)	–36 (3)	–17 (2)
Placebo (31)	182 (13)	96 (11)	–15 (4)	–22 (4)	–9 (2)

TABLE 15 - Repeated measures analysis for systolic blood pressure (SBP) changes in the dysphagic group

p-Value is given for active treatment at each time point compared with placebo, adjusted for baseline values. Overall for the model, p < 0.0001.

Treatment group (n)	SBP at randomisation (mmHg), mean (SD),	SBP at 4 hours (mmHg), mean (95% CI)	SBP at 8 hours (mmHg), mean (95% CI)	SBP at 24 hours (mmHg), mean (95% CI)
Labetalol (27)	179 (15)	155 (148–163)	164 (156–171)	167 (159–175)
p-Valuea		0.005	0.62	0.26
Lisinopril (28)	184 (18)	169 (162–177)	156 (149–164)	161 (153–169)
p-Valuea		0.77	0.07	0.024
Placebo (28)	180 (18)	171 (163–178)	166 (159–174)	173 (166–181)

FIGURE 9.

Mean systolic blood pressure (SBP) values by treatment group over the 2-week period in dysphagic patients. Standard error bars omitted for clarity. i.v., intravenous; s.l., sublingual.

Achievement of target blood pressure

As per protocol, patients not achieving the target SBP at 4 hours (a fall of 15 mmHg from baseline or SBP 145–155 mmHg) received a second test dose of medication. If the BP target was not achieved at 8 hours, a further dose was given, up to a maximum of three doses (i.e. three doses of lisinopril 5 mg or labetalol 50 mg or equivalent placebo, up to a maximum of 15 mg lisinopril or 150 mg labetalol).

The numbers of patients who reached the SBP reduction target at 4, 8 and 24 hours are shown in Table 16 and the numbers of patients who reached the SBP reduction target at 4 hours and maintained it at 8 hours are shown in Table 17. The percentages of patients who received additional doses at 4 hours were labetalol 23%, lisinopril 39% and placebo 63%; the percentages who received additional doses again at 8 hours were 7%, 12% and 39% respectively.

TABLE 16 - Numbers and percentages of patients in whom SBP targets were achieved at various time points by treatment arm for dysphagic and non-dysphagic groups combined

	Treatment group
	Labetalol (n = 56)	Lisinopril (n = 57)	Active (labetalol + lisinopril) (n = 113)	Placebo (n = 59)
Target achieved at
4 hours, n (%)	43 (77)	35 (61)	78 (69)	22 (37)
8 hours, n (%)	37 (66)	47 (82)	84 (74)	27 (46)
24 hours, n (%)	32 (57)	37 (65)	69 (61)	27 (46)

TABLE 17 - Numbers and percentages of patients in whom SBP targets were maintained at 4 and 8 hours by treatment arm for dysphagic and non-dysphagic groups combined

Note: Because of death or missing values, numbers presented in the total column may not add up to 100%.

Treatment group (n)	4 hours, n (%)	8 hours, n (%)
Labetalol (56)	Yes: 43 (77)	Yes: 28 (50)
		No: 15 (27)
	No: 13 (23)	Yes: 9 (16)
		No: 4 (7)
Lisinopril (57)	Yes: 35 (61)	Yes: 32 (56)
		No: 1 (2)
	No: 22 (39)	Yes: 15 (26)
		No: 7 (12)
Labetalol + lisinopril (113)	Yes: 78 (69)	Yes: 60 (53)
		No: 16 (14)
	No: 35 (31)	Yes: 24 (21)
		No: 11 (10)
Placebo (59)	Yes: 22 (37)	Yes: 15 (25)
		No: 7 (12)
	No: 36 (63)	Yes: 12 (20)
		No: 23 (39)

Those reaching and not reaching the target BP were further split by treatment type and group to assess whether any differences found were an effect of the route of administration (Table 18). In total, 50% of those receiving intravenous labetalol had reached the target SBP at 4 hours, but by 8 hours 50% of this group were again above the target SBP level and did not receive further treatment until 24 hours after the initial test dose. In contrast, 87% of those receiving sublingual lisinopril who had achieved the target SBP at 4 hours had maintained the target SBP at 8 hours.

TABLE 18 - Numbers and percentages of patients reaching and maintaining the systolic blood pressure (SBP) target in the dysphagic and non-dysphagic groups

Treatment group (n)	4 hours, n (%)	8 hours, n (%)
Labetalol dysphagic (27)	Yes: 22 (81)	Yes: 11 (41)
		No: 11 (41)
	No: 5 (19)	Yes: 3 (11)
		No: 2 (7)
Labetalol non-dysphagic (29)	Yes: 21 (72)	Yes: 17 (58)
		No: 4 (14)
	No: 8 (28)	Yes: 6 (21)
		No: 2 (7)
Lisinopril dysphagic (28)	Yes: 16 (57)	Yes: 14 (50)
		No: 2 (7)
	No: 12 (43)	Yes: 9 (32)
		No: 3 (11)
Lisinopril non-dysphagic (29)	Yes: 19 (66)	Yes: 19 (65)
		No: 0 (0)
	No: 10 (34)	Yes: 6 (21)
		No: 4 (14)
Labetalol + lisinopril dysphagic (55)	Yes: 38 (69)	Yes: 25 (45)
		No: 13 (24)
	No: 17 (31)	Yes: 12 (22)
		No: 5 (9)
Labetalol + lisinopril non-dysphagic (58)	Yes: 40 (69)	Yes: 36 (62)
		No: 4 (7)
	No: 18 (31)	Yes: 12 (21)
		No: 6 (10)
Placebo dysphagic (28)	Yes: 9 (32)	Yes: 6 (21)
		No: 3 (11)
	No: 19 (68)	Yes: 6 (22)
		No: 13 (46)
Placebo non-dysphagic (30)	Yes: 13 (43)	Yes: 9 (31)
		No: 4 (13)
	No: 17 (57)	Yes: 7 (23)
		No: 10 (33)

Time to treat

The minimum time to treatment was 6.8 hours in the labetalol group,7.0 hours in the lisinopril group and 5.5 hours in the placebo group (Figure 10a–c). No difference was found in the primary outcome of death and dependency at 2 weeks when adjusted for time to treatment. All patients were randomised within 36 hours of stroke onset, although for a few patients there was a further delay between randomisation and first treatment dose, explaining the observed differences in time to treatment (Figure 10a–c). None of the patients received treatment within 5 hours of stroke onset.

FIGURE 10.

(a) Time to treatment (labetalol). (b) Time to treatment (lisinopril). (c) Time to treatment (placebo).

Serious adverse events

Description

SAEs were categorised as advised by the Medicines and Healthcare Products Regulatory Agency (MHRA) in terms of commonly occurring adverse events following a stroke (Appendix 2 of this report contains the SAE reporting form used). In total, 96 SAEs were reported in 58 patients. Twenty-three patients had multiple SAEs: 17 patients had two, two patients had three, three patients had four, and one patient had five. There was no significant difference in the number of SAEs reported in the three intervention groups, with 28 SAEs being reported in the labetalol group, 33 in the lisinopril group and 35 in the placebo group. In each group there were more SAEs reported in the dysphagic than in the non-dysphagic arm labetalol group: 18 dysphagic versus 10 non-dysphagic; placebo group: 25 dysphagic versus 10 non-dysphagic; lisinopril group: 17 dysphagic versus 16 non-dysphagic) (Figure 11).

FIGURE 11.

Serious adverse events by treatment group and method of drug administration. i.v., intravenous; s.l., sublingual.

Severity

There were fatal SAEs in each of the treatment groups: one in the labetalol group, six in the placebo group and five in the lisinopril group. One patient in the placebo group had two fatal events reported. The cause of death as reported by local investigators is presented in Table 19. All fatal SAEs up to 2 weeks were classified as either respiratory or neurological. The numbers are too small to identify any statistically significant trends. Figure 12 illustrates the severity of the SAEs by treatment group for the non-dysphagic and dysphagic groups combined, and Figure 13 shows the severity of the SAEs by treatment group in the dysphagic versus the non-dysphagic groups.

TABLE 19 - Cause of death by treatment group at 2 weeks for dysphagic and non-dysphagic groups combined

Cause of death	Treatment group
	Labetalol, n	Lisinopril, n	Placebo, n
Neurological (stroke)	1	4	2
Respiratory (pneumonia)	0	1	4
Total	1	5	6

FIGURE 12.

Severity of the serious adverse events (SAEs) by treatment group for the dysphagic and non-dysphagic groups combined.

FIGURE 13.

Severity of the serious adverse events by treatment group in the dysphagic vs the non-dysphagic groups. Note: Includes two fatal SAEs for one patient in the dysphagic placebo group.

Causality

There was thought to be a causal relationship between study medication and SAE by the local investigators in two patients in the labetalol group and two patients in the lisinopril group (Figure 14); these are described below. There was no unblinding of treatment allocation in these patients until the end of the trial.

FIGURE 14.

Causality of serious adverse events according to treatment type as assessed by investigators.

Of those in whom a causal relationship was reported, one patient in the labetalol group and one in the lisinopril group developed bronchospasm, requiring nebulised bronchodilators; both events were reported to be of moderate severity. The patient in the labetalol group continued with the study medication; the patient in the lisinopril group did not at the discretion of the local investigators. One patient in the labetalol group had an extension of the presenting intracerebral haemorrhage, evidenced on repeat CT scan, without further neurological deterioration; this was graded as a severe SAE and led to interruption of study medication. One patient in the lisinopril group became hypotensive (BP 82/42 mmHg); this was again felt to be caused by the study drug and led to discontinuation.

There was uncertainty regarding causality in nine patients in the labetalol group, four in the lisinopril group and four in the placebo group.

Discontinuations

There were 18 discontinuations of study medication because of SAEs (six labetalol, eight lisinopril, four placebo), and five of these patients (one labetalol, two lisinopril, two placebo) subsequently suffered a fatal event.

System affected

The majority of SAEs and deaths recorded within the first 14 days of treatment were related to the neurological and respiratory systems. There were 32 neurological SAEs, of which seven were fatal; these events included deterioration in NIHSS score, recurrent stroke and seizure. There were 28 respiratory SAEs, of which five were fatal; events in this group included bronchopneumonia, bronchospasm and low oxygen saturations. One patient was reported as having two fatal SAEs, one of which was neurological (deterioration in NIHSS score ≥ 4) and the other respiratory (bronchopneumonia) – both are included. The cause of death is that recorded by the local investigator. Figure 15 illustrates the SAEs by system affected.

FIGURE 15.

Fatal and non-fatal serious adverse events during the 14-day treatment period by system affected. Includes two fatal events for one patient (one respiratory and one neurological). Cardio, cardiological; DVT, deep vein thrombosis; GU, genitourinary; haem, haematological; neuro, neurological; resp, respiratory.

Three-month mortality

The co-ordinating centre established patient survival at 3 months after randomisation, and deaths were recorded from the NHS register, cause of death being taken from death certificates (Table 20). Mortality at 3 months was reduced in the active treatment group compared with the placebo group [11/113 (9.7%) vs 12/59 (20.3%); p = 0.05; Figure 16, Table 21] with a hazard ratio of 2.2, (95% CI 1.0–5.0) for death in the placebo group compared with the active treatment group. No comparative analysis between the labetalol and lisinopril groups was undertaken because of the small numbers involved and insufficient data were available on disability at 3 months for adequate analysis of the combined end point of death or disability.

TABLE 20 - Recorded cause of death by treatment group at 3 months

Cause of death	Treatment group
	Labetalol	Lisinopril	Placebo
Cardiac	1 (heart failure)	1 (myocardial infarction)	0
Neurological	3 (stroke)	5 (stroke)	6 (stroke)
Respiratory	0	1	6 (pneumonia)
Total	4	7	12

TABLE 21 - Mortality at 3 months’ follow-up

	Treatment group		Total
	Active	Placebo
Dead, n	11	12	23
Alive, n	102	47	149
Total, n	113	59	172

FIGURE 16.

Kaplan–Meier plot for 90-day survival estimates for active treatment versus placebo.

Utility and quality-adjusted life-years

Comparison of point estimate utilities derived from the EQ-5D and mRS scores84 shows utility scores based on the mRS to be significantly higher than those based on the EQ-5D (p = 0.002) (Figure 17). For consistency, mRS-based utilities were used to estimate utility and QALYs.

FIGURE 17.

Modifed Rankin Scale (mRS) vs EQ-5D utility estimates.

On average, patients on active treatment gained 0.043 QALYs over 3 months compared with those on placebo, although we were unable to detect any statistically significant difference (p = 0.074; Table 22). These results must be interpreted with caution as they are based on small sample sizes and are likely to suffer from selection bias because of the mortality rate (23 of 33 observations).

TABLE 22 - Mean (SD) modified Rankin Scale (mRS)-based utility at baseline, 14 days and 3 months

	n (labetalol, lisinopril, placebo)	Labetalol	Lisinopril	Active (labetalol + lisinopril)	Placebo	p-Value (active vs placebo)
Baseline	(56, 57, 59)	0.895 (0.070)	0.890 (0.071)	0.892 (0.070)	0.899 (0.063)
14 days	(56, 57, 59)	0.576 (0.216)	0.517 (0.255)	0.546 (0.237)	0.526 (0.271)
3 months	(8, 11, 14)	0.403 (0.437)	0.306 (0.426)	0.346 (0.421)	0.088 (0.225)
QALYs gained (14 days)	(56, 59, 57)	0.028 (0.004)	0.027 (0.005)	0.028 (0.005)	0.027 (0.005)	0.732
QALYs gained (3 months)	(8, 14, 11)	0.111 (0.074)	0.087 (0.084)	0.097 (0.079)	0.054 (0.044)	0.074

Resource use and cost

Length of stay (LoS) and hospitalisation costs at 14 days and 3 months are presented in Tables 23 and 24. There was no difference in median LoS between active treatment and placebo at 14 days, and very little at 3 months. Drug costs were negligible for each of the three groups. There was no difference in the mean cost per patient for the first 14 days following stroke for active treatment versus placebo. At 3 months active treatment patients cost £1071 less on average than placebo patients, although this difference was not statistically significant. For details of costings used see Appendix 3.

TABLE 23 - Resource use and costs at 14 days by treatment type (intention to treat analysis)

IQR, interquartile range; LoS, length of stay.

	n (labetalol, lisinopril, placebo)	Labetalol	Lisinopril	Active (labetalol + lisinopril)	Placebo
Mean (SD) LoS (days)	(56, 57, 59)	11.57 (4.263)	11.23 (4.464)	11.40 (4.35)	11.36 (4.429)
Median (IQR) LoS (days)	(56, 57, 59)	14 (11.25–14)	14 (8–14)	14 (9–14)	14 (10–14)
Patients still hospitalised, n (%)	(56, 57, 59)	40 (71)	36 (63)	76 (67)	36 (61)
Cost of hospitalisation (£), mean (SD)	(56, 57, 59)	2563 (750)	2502 (786)	2532 (766)	2525 (779)
Cost of study drugs (£), mean (SD)	(56, 57, 59)	7 (8)	1 (1)	4 (6)	0 (0)
Total cost (£), mean (SD)	(56, 57, 59)	2569 (752)	2504 (786)	2536 (767)	2525 (779)
Student’s t-test of total cost (active vs placebo)		t = 0.093, p = 0.92
Mann–Whitney test of median LoS (active vs placebo)		p = 0.88

TABLE 24 - Resource use and costs at 3 months by treatment type (intention to treat analysis)

IQR, interquartile range; LoS, length of stay.

	n (labetalol, lisinopril, placebo)	Labetalol	Lisinopril	Active (labetalol + lisinopril)	Placebo
Mean (SD) LoS (days)	(53, 57, 53)	45.75 (34.66)	40.98 (34.87)	43.37 (34.68)	49.47 (54.98)
Median (IQR) LoS (days)	(56, 57, 59)	38 (7–84)	30 (7–84)	36.5 (7–84)	36 (10–84)
Patients still hospitalised, n (%)	(55, 59, 57)	17 (31)	12 (20)	29 (25)	16 (28)
Cost of hospitalisation (£), mean (SD)	(53, 57, 53)	8579 (6100)	7739 (6137)	8159 (6104)	9233 (9676)
Cost of study drugs (£), mean (SD)	(56, 57, 59)	7 (8)	1 (1)	4 (6)	0 (0)
Total cost (£), mean (SD)	(53, 57, 53)	8586 (6103)	7740 (6137)	8163 (6106)	9233 (9676)
Student’s t-test of total cost (active vs placebo)		t = 0.864, p = 0.38
Mann–Whitney test of median LoS (active vs placebo)		p = 0.84

Cost-effectiveness

The primary analysis was incremental cost per incremental survivor at 3 months. Active treatment was compared with placebo (Table 25).

TABLE 25 - Cost-effectiveness, active treatment vs placebo, based on mortality at 3 months

ICER, incremental cost-effectiveness ratio.

Treatment group (n)	£ per patient	Survival (proportion)
Active treatment (106)	8163	0.896
Placebo (57)	9233	0.789
Increment (95% CI)	–1071 (–3817 to 1633)	0.107 (–0.015 to 0.239)
ICER	(active treatment dominates)

On average, active treatment was £1071 cheaper than placebo and resulted in a higher survival probability than placebo at 3 months, although these differences were not statistically significant. However, the scatter plot of bootstrapped cost and outcome pairs (Figure 18) suggests that there is a preponderance of points in the southeast quadrant of the cost-effectiveness plane, implying that, in the majority of cases, active treatment is likely to be both more effective and less costly than placebo.

FIGURE 18.

Scatter plot of cost and outcome pairs.

The CEAC shows the proportion of the 1000 bootstrapped points with an ICER below a given threshold willingness to pay for a unit of outcome (Figure 19). A typical willingness to pay for a life saved is approximately £1 m (Green Book,87 paragraph 31, HM Treasury). In total, 96.3% of the bootstrapped re-samples resulted in an ICER of below £1m per life saved. This is interpreted as a 96.3% probability that the incremental cost per life saved from active treatment compared with placebo is less than £1m. Even if the willingness to pay for a fatality avoided is £0, there is a 75.5% probability that active treatment is the ‘cost-effective’ treatment.

FIGURE 19.

Cost-effectiveness acceptability curve.

An alternative presentation of these data is in the form of an incremental net benefit chart, and this is illustrated in Figure 20. At a willingness to pay of £1 m the mean incremental net benefit is £110,000 (95% CI –£12,500 to £238,000). This means that, given a willingness to pay for a life saved of £1 m, on average the added benefits of active treatment are valued more highly than any added costs. However, we did not detect a statistically significant result.

FIGURE 20.

Mean values and 95% confidence intervals of the net monetary benefit of active treatment over placebo at 3 months.

Cost–utility analysis

We present here cost–utility ratios evaluated at 14 days and 3 months. Over 14 days there is very little difference in costs or outcomes, and mean figures suggest a point estimate ICER of £41,500, with only a 48% probability that the ICER is under £30,000 per QALY gained (Table 26, Figure 21). At the same £30,000 threshold this corresponds to a mean incremental net monetary benefit of –£8 (not statistically significant). Mean results over 3 months suggest that active treatment results in lower costs (–£5768, or 47% less than placebo; not statistically significant) and a better quality of life (0.039 QALYs, 95% CI 0.001–0.081). This results in active treatment dominating placebo, with a 97.5% probability of the ICER being below £30,000 per QALY gained. These results must be interpreted with caution because of the high risk of selection bias as stated in the section on utility and quality-adjusted life-years.

TABLE 26 - Cost–utility analyses

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

		14 days	3 months
n	Active	113	18
	Placebo	59	14
Cost	Active	£2536	£5067
	Placebo	£2525	£10,835
Increment (95% CI)		£12 (–231 to 265)	–£5768 (–15,118 to 975)
QALY	Active	0.028	0.094
	Placebo	0.027	0.054
Increment (95% CI)		0 (–0.001 to 0.002)	0.039 (0.001–0.081)
ICER		£41,471	–£146,608
Probability (£30,000)		48.00%	97.50%
INB (£30,000) (95% CI)		–8 (–270 to 258)	7119 (17–16489)

FIGURE 21.

Cost-effectiveness acceptability curves at 14 days and 3 months.

Recruitment

The recruitment to the CHHIPS trial was less than had been initially planned; only 11% of the numbers projected for the depressor limb were enrolled during the 30 months of the trial in the five active centres and the pressor limb was terminated early as it became evident that even meaningful numbers allowing a proof of concept analysis would not be obtained. Originally the trial was powered on a recruitment rate of 1650 patients over a 30-month period for 10 centres (approximately five to six patients per month per centre); however, for the depressor arm only 1.2 patients per month per centre were recruited by the five participating units. The reasons for this disparity can be explained by analysis of the screening data, an area that has not been reported on by any other BP trial in acute stroke. Although the screening data from each site do not cover the entire study period, it is clear that there were a number of major reasons why patients were excluded from the study. A large proportion of patients were ineligible for the depressor arm because, although they were hypertensive, they were on antihypertensive treatment at the time of their stroke. There is an increasing body of evidence indicating a rise in the use of antihypertensives in the UK for both primary and secondary stroke prevention. The OXVASC study88 has shown an increase in the use of antihypertensives, with 25% of patients in the 1980s being on antihypertensive medication at the time of their first incident stroke compared with 42% in 2002–4; in terms of secondary prevention, 35% were on depressor therapy at the time of stroke recurrence in the 1980s compared with 58% in 2002–4, with a reduction in primary stroke incidence from 1.65 to 1.45 per 1000 population. This increased prescribing of antihypertensive agents has recently been enhanced by the introduction of the Quality and Outcomes Framework targets for general practitioners, which has stimulated better control of blood pressure in the community. Data from hospital sources also suggest that more stroke patients are now being admitted on antihypertensive therapy than even 5 years ago.

It is clear that one-third of potentially eligible patients were excluded because they were not assessed by the trial staff sufficiently early. They were thus excluded because they were outside the time window, an area that could be potentially improved upon if more personnel were available to aid recruitment. Another large group of patients that may have been initially eligible, having a SBP > 160 mmHg, could not be included as, by the time of screening, BP values had fallen to within the normal range as defined by the study protocol; earlier assessment again may have potentially enhanced recruitment.

Of those eligible, over one-third were recruited to the trial, which is in keeping with, or better than, other intensive acute stroke trials. 89,90 The question of whether antihypertensive therapy should be continued or stopped in stroke patients already on such therapy at the time of their stroke is currently being addressed by other ongoing trials (COSSACS,91 ENOS92) and therefore these patients were excluded from the CHHIPS study (see below).

As previously stated, five sites failed to take up the offer of funding for a research nurse to run the trial, despite expressing a strong interest during the initial stages of the application. Most of these centres considered on reflection that the study was too intensive, in terms of drug preparation, administration and monitoring, to participate and to be nurse led. This may now be overcome to some extent by the data presented here showing the safety of the drugs used and that intensive monitoring after administration as performed in CHHIPS is not necessary. Three of the four main recruiting centres were offering thrombolysis for acute ischaemic stroke, but this had a minimal effect on recruitment into the CHHIPS study. Other reasons for non-participation are given in the results section on screening data. A series of protocol amendments were made to try and improve recruitment, such as extending the depressor recruitment window by 12 hours and including dysphagic patients previously receiving antihypertensives; however, the effects of these changes on recruitment were somewhat disappointing. Possible ways of increasing future recruitment could include a much shorter admission to assessment time, which would be helped by nurse screening (the screening in CHHIPS was performed in the vast majority of cases by the one clinical research fellow per centre); a simpler protocol (a single antihypertensive agent versus placebo, although dysphagic and non-dysphagic limbs would still be required); lower BP entry criteria and less requirement for intensive BP monitoring; a significantly increased number of participating centres; the non-dysphagic arms being nurse led; and more staff able to screen and randomise patients (which would help for those patients admitted outside normal working hours and at weekends). The last factor in particular would be helped by using the support provided by the recently established Stroke Research Network. The trial was adopted by the Stroke Research Network, but the setting up of this probably came too late to aid participation and recruitment.

As regards recruitment to the pressor arm of the trial, this was undertaken only by the four centres that were allocated clinical research fellows as it was considered inappropriate for this limb of the trial to be conducted by a research nurse in view of the potential clinical risks. As can be seen from the screening data, less than 0.5% of all stroke admissions were potentially eligible for the pressor arm using the CHHIPS criteria. Only one patient was recruited, who received placebo, and this limb of the trial was stopped after 14 months after consultation with the HTA when it became evident that insufficient numbers would be recruited during the time frame of the trial. The reasons for failure to recruit to this limb of the trial have already been outlined. Access to rapid neuroradiology before randomisation did not appear to be a major factor in the failure to enter such patients as it has in some other acute stroke trials. Failure was more closely related to the other entry criteria, in particular the previous use of antihypertensive medication. If a pressor study is to be contemplated in the future, major changes to the inclusion and exclusion criteria that CHHIPS employed will have to be made, in particular the upper limit of entry BP could perhaps be raised.

Compliance and adverse events associated with randomised treatment

As might be expected, the greatest number of treatment discontinuations came within the first 72 hours following randomisation, although treatment was generally well tolerated, with nearly three-quarters of all patients completing the 14-day schedule, and treatment allocation was never broken during trial progress. This percentage of patients continuing treatment until the end of the trial period (73%) was greater than the 64% reported in the similarly sized BEST trial,53 in which beta-blockers were used but with a comparable treatment period. The few other BP-lowering trials in acute stroke were either of considerably shorter duration,93 did not report data on discontinuation rates58 or were not placebo controlled. Overall there was no significant difference in the number of withdrawals between either the labetalol or lisinopril groups and the placebo group, but small numbers limit the power of the study to detect small differences. There were more discontinuations in the dysphagic group than in the non-dysphagic group for all three treatments arms, but again active treatment was not associated with an increase in SAEs. In fact, the largest number of SAEs was seen in the placebo dysphagic arm of the trial and the fewest was in the oral labetalol group. Discontinuation of treatment because of an SAE was reported in 10% of the total trial population, with slightly more SAEs in the active treatment than in the placebo group, although this difference was not statistically significant. Of the fatal events that occurred during the first 14 days, more were seen in the placebo group than in either active treatment arms combined, although the number of events was too small to draw any firm conclusions.

Primary outcome measure and early neurological deterioration

The three arms of the study were well matched in terms of known baseline prognostic indicators, for example age, stroke severity and type, BP levels and degree of premorbid disability, although nearly half were dysphagic at randomisation in each group compared with the expected 25%. Death and dependency in the placebo group at 2 weeks was 59%, which was exactly as predicted, the power calculations being based on a 60% level. This degree of dependency and death may appear high but, given the severity of stroke in those enrolled (about two-thirds of those recruited having a partial or total anterior cerebral circulation event), it is to be expected and is in keeping with observational data. 94 Active treatment, however, had no effect on this primary short-term outcome measure (OR 1.03, 95% CI 0.80–1.33), but the confidence intervals were wide, with the possibility of a 20% benefit of treatment or a 33% deterioration with active blood pressure lowering; however, the numbers in the trial did not allow the detection of smaller but still clinically significant changes. Similarly, it was not possible to assess if there was any heterogeneity in the effects according to stroke subtype of additional BP lowering (e.g. cerebral infarct from haemorrhage). From a trial safety point of view the greater BP reduction seen with lisinopril or labetalol compared with placebo over the first 24 hours did not result in any evidence of neurological deterioration at 72 hours.

Secondary outcome measures – blood pressure reduction and targets

It is well known that BP tends to fall spontaneously in the first few days after stroke, and the blood pressure changes seen in the placebo group within the first 24 hours and by day 14 in CHHIPS are similar to those reported in observational studies. 27,95 The CHHIPS depressor trial set out to lower BP acutely following ischaemic and haemorrhagic stroke using agents not previously studied in a large number of patients or with a placebo control and using novel methods of administration, i.e. the sublingual route. This is the first study to our knowledge to compare different routes of administration as well as different antihypertensive agents in the acute stroke situation. Until now, the administration of depressor agents to stroke patients who are dysphagic (this group comprising nearly 50% of the trial population) has been difficult and has usually meant using the intravenous route with its associated problems.

The results show that the active treatments chosen in the CHHIPS trial (i.e. lisinopril and labetalol) were more effective than placebo at reducing post-stroke BP within 24 hours of randomisation; this difference was statistically significant for the treatment groups combined and for lisinopril versus placebo, although the differences for labetalol did not reach statistical significance at the 5% level. Intravenous labetalol did, however, produce a significant SBP fall by 4 hours compared with placebo, an earlier SBP reduction than that seen with the oral preparation of labetalol or lisinopril or with sublingual lisinopril. Over 80% of subjects in the intravenous labetalol arm reached the target SBP at 4 hours, meaning that no further drug would have been potentially given until 8 hours post randomisation. This probably explains the subsequent SBP rise at 8 hours in those receiving intravenous labetalol, BP values being only slightly lower than the BP values in those receiving placebo at this time point. The trial therefore emphasises the relatively short duration of action of intravenous labetalol, and future studies would need to administer this agent on a more regular basis than the current CHHIPS protocol allowed for, especially with regard to the 16-hour gap between the potential 8-hour post-randomisation dose and the next dose at 24 hours. The intravenous dose of labetalol used in CHHIPS was larger than the dose that some authorities have suggested for controlling BP before thrombolysis, although the target BP levels before thrombolysis were higher than in this trial. Sublingual lisinopril would appear to be an effective and well-tolerated alternative to the intravenous route of administrating antihypertensive agents in acute stroke, meaning that it could potentially be given by paramedics on initial patient contact or by nurses in the A&E department on patient arrival before a formal swallow assessment has taken place. The BP changes at 24 hours for the active group combined are similar to those obtained using the intravenous calcium channel blocker nimodipine54 or transdermal glyceryl trinitrate. 59 Beta-blocker therapy in the BEST trial53 resulted in half of the depressor effect seen here, whereas other placebo-controlled studies using oral nimodipine93 and oral candesartan70 found no BP-lowering effect of these agents acutely.

Treatment targets were set to an optimum SBP level for decreased death and disability based on observational data,10 with a target SBP of between 145 and 155 mmHg by 4 and 8 hours from randomisation; if the target was not achieved, additional therapy was given. Previous stroke BP trials have not set BP targets or used an incremental dosage approach to achieve goal BP levels. By 4 hours 77% of patients receiving labetalol (oral and intravenous routes combined) had achieved the target SBP reduction, but by 24 hours this had fallen to just over 50% and was not statistically different from the number at the target SBP in the placebo group. This suggests, as previously stated, that the action of labetalol, probably because of the more rapid effects of the intravenous route, is more effective than that of lisinopril initially but that the effect is relatively short-lived and repeated dosing or continuous infusion may be the preferred method to achieve sustained SBP reduction. This would, however, necessitate a longer duration of intensive monitoring, and further work is required to clarify this issue. Lisinopril was able to achieve the target BP in nearly two-thirds of patients by 4 hours and in over half at 8 and 24 hours with little difference in achieved targets between the sublingual and oral routes. From a practical viewpoint, lisinopril, although not achieving rapid BP control in the first 4 hours, did appear to achieve more sustained control over the first 24 hours and is certainly easier to administer than intravenous labetalol for the dysphagic patient. Whether rapid early BP reduction as achieved with labetalol is better in terms of a greater reduction in death and disability than the slower antihypertensive effect achieved with lisinopril cannot be commented on because of the study size.

Compared with the placebo group, SBP, but not DBP, was significantly lower at 2 weeks in the active treatment groups combined by a mean of 7 mmHg. Few other studies have continued antihypertensive treatment for this duration; one study that did59 found no antihypertensive effect comparing glyceryl trinitrate with placebo by day 7. All major secondary prevention trials of blood pressure lowering post stroke (which have shown the effectiveness of ACEIs or angiotensin receptor blockers and/or thiazide-like diuretics) have had a minimum entry criterion from stroke onset of 2 weeks and it was not thought to be ethical to continue trial treatment longer than the 14-day period.

Secondary outcome measures – 3-month mortality

In keeping with many other acute intervention stroke trials, mortality at 3 months was also assessed. Despite the relatively small number of events, a borderline significant reduction in death was found in the actively treated group, with the risk of death being increased over twofold in the placebo group. The death rate at 3 months in the CHHIPS placebo group of 20% was very similar to that seen in other acute stroke trials which have included the same percentage of severe stroke patients as in CHHIPS. For example, the IMAGES trial,96 a randomised placebo-controlled study of intravenous magnesium in acute stroke, found a 90-day mortality rate of 19% in the placebo group, and GIST, a placebo-controlled trial of insulin and potassium in acute stroke patients with mildly raised blood glucose levels, reported a 27% mortality rate at 3 months. 97 We did not assess deaths alone at 2 weeks as this was not the primary outcome measure, but the Kaplan–Meier plot suggests that the divergence in mortality between the active and placebo groups in CHHIPS was evident from very early on following randomisation and increased with time. This could not be explained by baseline differences between the active and placebo groups as they were well balanced. However, care must be taken in interpreting these results in view of the small number of events and the results being possibly due to chance. Interestingly, despite the lack of BP change compared with placebo during the first week of treatment with candesartan, the ACCESS study found a similar level of reduction in cardiovascular events at 12 months to that of CHHIPS. We did not set out to collect dependency data at 3 months in all patients, but a random sample was collected to be used in the cost–benefit analysis. The data we did obtain also suggest a positive benefit for active BP lowering in reducing death and disability at 3 months, but again small numbers preclude any statistically meaningful analysis of the data.

Cost-effectiveness

We were unable to detect any statistically significant differences in costs between the active and placebo treatments, again mainly because of the small numbers and lack of long-term dependency data in all subjects. However, there were trends for active treatment to be both more effective (more survivors) and less expensive than placebo, although further trials with larger sample sizes are required to verify or refute this hypothesis.

The 3-month cost–utility analysis results should be treated with appropriate caution because of the very small sample sizes and the very high risk of selection bias; indeed, at this power we were unable even to detect a mean cost differential of 50% as statistically significant, and 23 of the 33 observations were present by virtue of the patient having passed away and therefore the utility score was by definition zero. The finding of a significant improvement in QALYs in the active treatment group, although consistent with other outcome measures and expectations, may well be spurious.

To our knowledge this is the first study examining the cost-effectiveness of antihypertensive medication immediately post stroke. Previous studies have focused on either primary or secondary prevention of stroke and heart attack in patients with hypertension or other forms of cerebrovascular disease. These studies generally support the use of angiotensin type 2 receptor antagonists98,99 and statins100 for primary or secondary prevention of cardiovascular events in these patients. Our economic evaluation relied almost exclusively on length of stay as the major predictor of cost as the study drugs themselves were a very small component of the total cost and too few data on post-discharge resource use were collected to make a meaningful contribution to the economic evaluation. The perspective of the analysis was therefore limited to the acute hospital admitting the stroke patient. Nevertheless, length of stay is the major determinant of acute care cost in stroke rehabilitation,101,102 and therefore our estimates of cost based on length of stay are likely to be reasonably reliable indicators of the cost of treating patients in the acute setting.

Our original intention was to analyse cost–utility from a societal perspective. Unfortunately, because of the small sample sizes we were unable to make meaningful comparisons of such and therefore the perspective was limited to the acute care setting until first discharge. This excluded readmissions, wider NHS and social services costs, patient out-of-pocket costs and indirect costs. However, based on our small sample of societal costs we estimated the acute care costs to first discharge to represent 66% of the total societal cost [mean acute cost across all patients = £8537 (average across totals from Table 24); mean other NHS, social services, out-of pocket and indirect costs = £4359 (Appendix 3, Table 40)]. This is a substantial proportion of the total societal cost, but inferences as to the impact of active treatment on societal cost-effectiveness must be made with due caution. Additional data are required to determine the cost-effectiveness of lisinopril/labetalol compared with placebo from a societal perspective.

The time horizon for the cost–utility analysis was 3 months. However, at this point approximately one-quarter of patients were yet to be discharged. Caution must therefore be exercised in generalising these results as differences in length of stay between the treatment groups may remain after the 3-month follow-up period.

Ongoing studies

It is important to appreciate that there other ongoing trials assessing the effects of BP lowering after stroke, and these are briefly reviewed below.

Conclusions

In conclusion, both labetalol and lisinopril lowered BP to a greater degree than placebo in acute stroke patients within 36 hours of symptom onset, without causing adverse side effects or an early increase in stroke severity. Sublingual lisinopril and intravenous labetalol were also effective hypotensive agents in the immediate post-stroke period in dysphagic patients. However, active therapy did not reduce death and dependency at 2 weeks, the primary outcome measure, although the trial was underpowered to detect small, but clinically significant, changes in this and the other main outcome measures. Of interest was the reduction in stroke mortality at 3 months with active therapy, a finding in keeping with one other acute BP-lowering stroke trial, although care must be taken in interpretation of the CHHIPS results in view of the small sample size. Further work is now much needed to confirm these results and to assess if there are differences in the effectiveness, in terms of reducing death or dependency, of labetalol compared with lisinopril after acute stroke and whether the introduction of earlier BP lowering post stroke than was achieved in CHHIPS would be of greater benefit, especially with regard to use before thrombolysis. The role for increasing BP in acute stroke remains unresolved, although the number in whom this therapy could be applied is very small using the CHHIPS trial entry criteria. The fact that we are still uncertain as to the best management of BP in the acute stroke situation is of serious concern, as highlighted in two recent guidelines on acute stroke management. 103,104 The positive findings from the CHHIPS trial need to be taken further in formulating the definitive trial of BP lowering in acute stroke.

Research recommendations

To improve recruitment to acute stroke trials in general:

1. Increase the number of recruiting centres (double the number you first thought of), assessing their ‘real’ ability for recruitment, in terms of number of patients seen, and their suitability, as determined from their local stroke register and their levels of staffing and facilities (not those promised by the time that the trial starts). This may include approaching centres outside the UK, although this has potential problems with regard to provision of the trial drugs and provision of the indemnity.

2. At each proposed recruiting centre assess the number of other potentially conflicting acute stroke trials being undertaken or contemplated and their impact on recruitment potential.

3. Identify a local researcher in each centre who is interested in the specific trial and not just the lead stroke researcher for that centre.

4. Ensure that the trial is suitable to be adopted by the Stroke Research Network or the Local Comprehensive Research Network.

5. Funding bodies should not expect ‘quick’ results; most large trials, even pragmatic ones, take many years to complete and very few large studies have been completed in 36–48 months, even with commercial funding. This should be stated by the funding body so that undue pressure is not put on the researchers to try and reach goal numbers in an unrealistic time frame because long-term funding will not be readily available.

6. Ensure that funding to each centre is adequate and that nursing as well as medical staffing levels and the level of experience are sufficient to be able to run the trial. Also, ensure that suitable monitoring equipment and facilities are available and that no dramatic changes to the stroke services are expected during the course of the proposed trial, for example closure of the unit or transfer of the unit to a different hospital.

7. Make sure that the study is as simple as possible so that non-experienced research staff are able to undertake the protocol; this is especially important when dedicated trial staff are away on holiday or sick leave or because of other routine causes. Dedicated trial staff cannot be present at all times and each centre should have a fallback position for when staff members are away to enable recruiting to be continued.

8. Provide adequate funding for academic trials to match that given by similar commercial studies so that triallists are not penalised for undertaking academic studies.

9. Try and predict how the results of other ongoing trials, changes in medical practice, effects of guidelines, etc. will potentially affect recruitment during the period of the trial.

To improve recruitment to a future acute blood pressure stroke trial:

1. The CHHIPS triallists (and also the referees) believe that, despite the data to date, a clear answer to the problem of how to manage blood pressure immediately post stroke is unclear, although the CHHIPS data do give some leads. Therefore, we subscribe to the need for a revised CHHIPS trial, which should be carried out taking into account the important findings obtained to date but with a simpler methodology. First, the pressor arm should not be contemplated as this limb of the trial appears to be neither logical nor practical. The centres undertaking CHHIPS, and those that contemplated doing so, were concerned with the intensity and duration of monitoring that was put in place by the investigators, who were concerned about patient safety. The data obtained from CHHIPS to date for the depressor arm suggest that, at the dosages used, the two hypotensive agents are safe and therefore the level of monitoring does not have to be as intense as initially set out.

2. We suggest that a single hypotensive agent should be used against matching placebo; from the initial data and considering the practicalities, lisinopril, which can be given orally or sublingually, therefore negating the need for intravenous infusions and intensive monitoring, would seem to be the ideal agent. Investigators were very wary of giving intravenous hypotensive agents without very close monitoring in a high-dependency unit, which would not be necessary with lisinopril. This agent could also be given by trained trial nurses, reducing the need for expensive medical staff.

3. Given the results of the CHHIPS trial we would recommend that the same criteria as originally set out are adopted but that only one hypotensive agent is used, markedly reducing the numbers needed to be recruited from 1650 to 1100. To improve recruitment and increase the applicability of the data to day-to-day practice, we would also recommend that entry SBP be reduced from 160 mmHg to 140 mmHg. We would also consider randomising those patients who were already on antihypertensive medication before their stroke. The primary end point should again be death or dependency, but at 3 months and not 2 weeks as in the original protocol. Adequate funding to match that of similar commercial trials, for example the SCAST trial, should be made available and the study should be allowed to recruit outside the UK with provision for supplying medical indemnity for the trial as required.

Participating centres

Leicester: JF Potter, T Robinson, P Eames, N Shah, A Mistri; Newcastle-upon-Tyne: G Ford, A Dixit, J Davis; Exeter: M James, P Johnson; Bournemouth: D Jenkinson, T Black, A Orpen; Liverpool: A Sharma, E Bacabac, John Jones; Wansbeck: S Huntley, C Price.

CHHIPS committees

Publications

Potter H, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al. CHHIPS (Controlling Hypertension and Hypotension Immediately Post Stroke) pilot trial: rationale and design. J Hypertens 2005;23:649–55.

Mistri AK, Robinson TG, Potter JF. Pressor therapy in acute ischemic stroke: systematic review. Stroke 2006;37:1565–71.

Potter JF, Robinson TG, Ford GA, Mistri A, James M, Chenova J, et al. Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial. Lancet Neurology 2009;u8 (in press).

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.

Serious adverse event form

SAE form initiated by:   NIHSS increase ≥ 4   Other

(Please circle)

Resource use quantities

(a) Modified Rankin Scale

(b) Barthel Index

(c) EQ-5D (EuroQoL)

We are trying to find out what you think about your health. I will ask you a few brief and simple questions about your own health state today. I will explain the task fully as I go along but please interrupt me if you do not understand something or if things are not clear to you. Please also remember that there are no right or wrong answers. We are interested here only in your personal view.

First I am going to read out some questions. Each question has a choice of three answers. Please tell me which answer best describes your own health state today. Do not choose more than one answer in each group of questions.

IF RESPONDENT HAS DIFFICULTY IN ANSWERING THEN REPEAT QUESTION VERBATIM. FOR EACH QUESTION RING APPROPRIATE NUMBER ON ANSWER SHEET.

Question 1: Mobility

First I’d like to ask you about mobility.

Would you say you have:

1. No problems in walking about?

2. Some problems in walking about?

3. Are you confined to bed?

Question 2: Self-care

Next I’d like to ask you about self-care.

Would you say you have:

1. No problems with self-care?

2. Some problems washing or dressing yourself?

3. Are you unable to wash or dress yourself?

Question 3. Usual activities

Next I’d like to ask you about usual activities, for example work, study, housework, family or leisure activities.

Would you say you have:

1. No problems with performing your usual activities?

2. Some problems with performing your usual activities?

3. Are you unable to perform your usual activities?

Question 4: Pain/discomfort

Next I’d like to ask you about pain or discomfort.

Would you say you have:

1. No pain or discomfort?

2. Moderate pain or discomfort?

3. Extreme pain or discomfort?

Question 5: Anxiety/depression

Finally I’d like to ask you about anxiety or depression.

Would you say you are:

1. Not anxious or depressed?

2. Moderately anxious or depressed?

3. Extremely anxious or depressed?

PLEASE REMEMBER IT IS IMPORTANT TO HAVE ONE AND ONLY ONE RESPONSE TO EACH GROUP OF THREE RESPONSES

(d) National Institute of Health Stroke Scale

(e) Oxfordshire Community Stroke Project classification

Patients presenting with a stroke can be classified according to their collection of symptoms and signs. These are:

1. TACS – total anterior circulation stroke

2. PACS – partial anterior circulation stroke

3. LACS – lacunar stroke

4. POCS – posterior circulation stroke.

Classification depends on three main features:

• unilateral motor or sensory involvement (face/arm/leg)

• visual involvement – hemianopia or quadrantanopia or visual neglect

• higher cerebral dysfunction (dysphasia, dyscalculia, visuospatial disorder/inattention/neglect).

This is a clinical classification prior to neuroimaging.

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    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.

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