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

Article history

The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 07/19/01. The protocol was agreed in April 2007. The assessment report began editorial review in May 2008 and was accepted for publication in December 2008. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

None

Copyright statement

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

2009 Queen’s Printer and Controller of HMSO

Description of health problem

Current service provision

For patients with confirmed NSTE-ACS, UK guidelines recommend early treatment with antiplatelets,12 which have been shown to be effective in preventing ischaemic vascular events in patients at increased risk. 13 They work by inhibiting platelet thrombus formation and by protecting the distal tissues through inhibiting microembolisation. 12 Aspirin is the ‘gold standard’ antiplatelet therapy for the long-term treatment and prevention of ischaemic vascular events. It was the only antiplatelet drug recommended by the National Service Framework for Coronary Heart Disease in 20005 and accounts for 86% of all prescribed antiplatelet drugs. 10 It prevents platelet aggregation by deactivating the enzyme cyclo-oxygenase (COX) which, in turn, blocks the production of thromboxane A2. Newer thienopyridine derivative drugs, which include clopidogrel, ticlopidine and prasugrel, inhibit the P2Y₁₂ADP receptor, which interferes with the function of the platelet membrane and inhibits both platelet aggregation and the release of platelet granule constituents. 14 Clopidogrel is said to be six times more effective than its predecessor, ticlopidine, with fewer haematological side effects. 15 Clopidogrel is the second-most commonly prescribed antiplatelet drug, accounting for nearly 10% of all antiplatelet drug prescriptions. 10

Definition of problem

Guidance by the National Institute for Health and Clinical Excellence (NICE) in 2004 recommended that clopidogrel be taken in combination with aspirin in the management of NSTE-ACS for people at moderate to high risk of ischaemic events. 16 This guidance was based in part on a Technology Assessment Report undertaken by the Centre for Reviews and Dissemination (CRD) and the Centre for Health Economics (CHE) in 2004 and published as a Health Technology Assessment (HTA) report. 12 The report presented the results of a systematic review assessing the clinical effectiveness and cost-effectiveness of clopidogrel in combination with aspirin for people with NSTE-ACS. It also included an economic model of the cost-effectiveness of clopidogrel in combination with aspirin from a National Health Service (NHS) perspective.

Only one relevant trial was identified for inclusion in the systematic review. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, was a large multicentre, randomised, double-blind, placebo-controlled trial of 12,562 patients who presented at one of 482 hospital centres in 28 countries within 24 hours of experiencing an NSTE-ACS event. The trial compared clopidogrel (300 mg initially followed by 75 mg each day) in combination with aspirin (75–325 mg/day) with aspirin alone (75–325 mg/day). 17–22 The trial reported that the proportion of patients experiencing cardiovascular death, MI or stroke was greater in the aspirin-only group at 30 days [relative risk (RR) 0.79; 95% confidence interval (CI) 0.67–0.92) and from 30 days to 12 months (RR 0.82; 95% CI 0.70–0.95). 18 Clopidogrel also reduced the overall incidence of Q-wave MI (RR 0.60; 95% CI 0.48–0.76). 21 In terms of adverse effects, clopidogrel increased the risk of major bleeding (RR 1.38; 95% CI 1.13–1.67), but not of life-threatening bleeds. 18,21 The economic model was developed to assess the short- and long-term cost-effectiveness of 12 months’ treatment with clopidogrel in addition to aspirin, compared with aspirin alone in the UK. The model estimated the short-term costs over a period of 12 months following NSTE-ACS and the long-term costs over a patient’s lifetime, conditional on surviving the first 12 months. The incremental cost-effectiveness ratio (ICER) of clopidogrel plus aspirin compared with treatment with aspirin alone was estimated to be £6078 per quality-adjusted life-year (QALY) gained. At a threshold willingness to pay of £30,000 per QALY, the probability that clopidogrel in combination with aspirin was cost-effective was 0.79. As the absolute benefit of clopidogrel, relative to standard care, appeared to decline over the course of the initial 12-month period, the incremental cost-effectiveness of providing clopidogrel for a range of durations was evaluated. In addition to the base-case analysis, which evaluated a strategy of 12 months’ treatment with clopidogrel, a series of sensitivity analysis were undertaken to explore the potential cost-effectiveness of shorter treatment durations, on the basis that cost-effectiveness may be sensitive to the absolute risk at different follow-up periods. This analysis comprised five strategies: lifetime treatment with aspirin, or clopidogrel as an adjunct to aspirin for 1 month, 3 months, 6 months or 12 months. While treatment with clopidogrel for 12 months appeared to remain cost-effective for the overall cohort, the provisional findings indicated that the shorter treatment durations may be more cost-effective in patients at lower risk at the start of treatment (defined as < 70 years of age, with an absence of ST depression and diabetes). For lower-risk patients, the ICER of providing treatment with clopidogrel for 6 months compared with only 3 months was approximately £30,786 per QALY. The ICER of providing clopidogrel for 12 months compared with only 6 months was £34,629 per QALY. These results indicated that the optimal duration of clopidogrel, based on cost-effectiveness considerations, appeared potentially sensitive to the risk stratification applied. However, the authors also concluded that these results should be seen as provisional for a number of reasons. Firstly, in the absence of appropriate RR data for these separate risk groups, and for the separate time periods, a common RR was applied throughout the model. In other words, the cost-effectiveness of alternative durations was evaluated by varying the baseline risk itself. Secondly, the effect of withdrawing from clopidogrel treatment was not formally considered (aside from reverting back to the risk associated with standard care) and the possibility of a ‘rebound’ effect following early discontinuation of treatment with clopidogrel was not systematically evaluated.

There are a number of generic definitions of the rebound effect:

• ‘A spontaneous reaction, especially a return to a previous state or condition following removal of a stimulus or cessation of treatment’23

• ‘The return of original symptoms when treatment stops’24

• ‘The characteristic of a drug to produce reverse effects when the effect of the drug has passed or the patient no longer responds to it’25

• ‘A reactivation of a condition or concentration of adverse events after withdrawal of a treatment’. 26

There is thought to be a rebound response in platelet activity with the withdrawal of aspirin,27–32 heparin,26,33–36 and non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors. 37 A recent systematic review reported a statistically significant (almost twofold) increase in the incidence of major adverse cardiovascular events (MACEs) in patients with ACS or those being treated for secondary prevention of coronary artery disease who did not adhere to aspirin therapy [odds ratio (OR) 1.82; 95% CI 1.52–2.18; p < 0.00001; 3 studies]. 32 Interestingly, the mean time from discontinuation of aspirin and the MACEs was 10.66 days (95% CI 10.25–11.07), a similar time to the half-life of platelets. 32 One study reported significant median increases in the production of 12-l-hydroxy-5,8,10-hepatadecatrienoic acid (which can be indicative of increased thromboxane A2) in angina patients 1 week (from 40 to 240 g/750 × 10⁶ platelets; p < 0.001) and 2 weeks (to 390 g/750 × 10⁶ platelets) after withdrawal of aspirin. 29 Withdrawal from aspirin has also reportedly increased the risk of stroke or transient ischaemic attack (TIA) (OR 3.4; 95% CI 1.08–10.63; p < 0.05)30 and lower limb ischaemia in patients with stable peripheral artery disease (PAD). 31

There is some evidence from biochemical markers for rebound platelet activity after withdrawal from heparin,33,34,36 and NSAIDs and COX-2 inhibitors. 37 This response tended to occur within hours of discontinuing heparin,33,34,36 and was still evident at least 14 days after withdrawal of NSAIDs and COX-2 inhibitors. 37

It is unclear whether a similar rebound response occurs after clopidogrel withdrawal, and if so, what the time lapse would be from withdrawal to maximum platelet activity. The authors of the previous HTA report12 recommended a prospective trial that would randomise patients to various durations of clopidogrel therapy to estimate its optimum duration of use for patients with NSTE-ACS. Such a trial would also confirm the existence or not of a rebound phenomenon in patients following withdrawal of clopidogrel. However, no formal consideration was made as to the potential value and/or feasibility of conducting such a trial. The present work was undertaken, therefore, to update the previous model and to formally assess the potential value and feasibility of further research to address the optimal duration of clopidogrel treatment.

Methods for reviewing clinical effectiveness

Results of the clinical evaluation

Discussion of the clinical evaluation

Effectiveness and safety

Since the previous HTA report,12 only one RCT has been conducted in the patients with NSTE-ACS for whom data are available. 39 This RCT recruited only 43 patients per treatment arm and therefore was likely to be underpowered. Furthermore, it reported a limited number of outcomes, and results were primarily extrapolated from a Kaplan–Meier graph. Data from this trial show that the rate of non-fatal MI, recurrent ischaemia and cardiovascular-related death over a 12-month period was nearly twice as high for patients on placebo (16 patients; 37.2%) as for patients on clopidogrel (9 patients; 20.9%). However, the CURE trial is still the primary source of data in the NSTE-ACS population. Results from the CURE trial show clopidogrel to be significantly more effective than placebo at reducing the risk of the composite outcome, cardiovascular death, non-fatal MI or stroke, for a treatment duration of 1 month (and possibly treatment durations of up to 3 months) and across the whole 12-month follow-up period.

Previous systematic reviews evaluating clopidogrel included trials conducted in various patient populations: patients with ischaemic stroke, MI or symptomatic atherosclerotic PAD;87–92 stable coronary heart disease (CHD);93 planned PCI or coronary angiogram;43–46 documented MI, with or without ST elevation;94 acute STEMI, left bundle branch block or ST depression;95,96 and multiple atherothrombotic risk factors or documented coronary, cerebrovascular or symptomatic PAD disease. 97–99 In our review of clopidogrel plus aspirin in NSTE-ACS, these trials did not meet our inclusion criteria, and the results of these other systematic reviews are not comparable with those of our review. Given that there are so few data to inform our review, it might be argued that a broader range of trials ought to be drawn upon. However, a comparison between these other studies and the CURE trial found that, in addition to being conducted in non-ACS populations, the trials were not comparable with the CURE trial in terms of study size, treatment regimen, time to follow-up and outcomes reported. Where similar outcomes were measured across the trials, results varied greatly in magnitude and sometimes direction of effect. This reflects the clinical heterogeneity between the trials, and demonstrates that results from these populations are not generalisable to the NSTE-ACS population. The details of these trials and their results, on which this comparison was made, are provided in Appendix 3.

Duration of treatment and rebound

There were no studies that directly compared different durations of clopidogrel treatment. There was some evidence from the CURE trial that benefits of clopidogrel treatment, such as a reduction in MI, stroke and death, may be most apparent within the first 3 months of treatment. An exhaustive search for evidence to support the suggestion that clopidogrel withdrawal is associated with a rebound effect in patients with NSTE-ACS yielded few studies. One retrospective cohort study reported an increased risk of adverse events within the first 90 days post withdrawal of clopidogrel. However, the cohort was obtained from Veterans Affairs hospital discharges, consisting predominantly of male veterans (99%; mean age 66 years), and the generalisability of these results to a wider population is uncertain. 38 Furthermore, even if reliable, these data cannot confirm whether the risk of acute MI or mortality following clopidogrel withdrawal is higher or lower than that in patients not treated with clopidogrel. Much of the evidence available showed that, as expected, the time lag between withdrawal and increases in biomarkers reflects the lifespan of platelets, which is approximately 10 days. 100 This would reflect the expected physiological process rather than any adverse effect of clopidogrel therapy.

Changes in service provision

Since the CURE trial was conducted, there has been a substantial increase in the use of PCI in the UK. This rise in PCI use over 16 years is demonstrated in Figure 1, constructed from data from the British Cardiac Intervention Society (BCIS) audit reports. 101 According to the BCIS audit reports, 73,612 PCI procedures were undertaken across 91 UK centres (1216 per million) in 2006, compared with 20,511 PCI procedures across 53 UK centres in 1996 (359 per million). Of those undertaken in 2006, 94.4% involved stent placement, compared with approximately 45% in 1996. 101 It is likely that many of the higher-risk patients included in the CURE trial would now undergo an early PCI rather than prolonged medical management or a late PCI procedure. Given this, it seems appropriate to determine the effectiveness of clopidogrel treatment in patients at intermediate risk of ACS, rather than in the entire ACS population. Results from the CURE trial show that patients with intermediate risk do benefit from clopidogrel treatment in terms of cardiovascular death, MI or stroke, but that they have an increased risk of major bleeding. 19

FIGURE 1.

Increase in the number of PCIs conducted per million population between 1991 and 2006, using data from the British Cardiac Intervention Society audit reports. 101

Further factors for consideration regarding future service provision are the expiry of the patent for clopidogrel in 2013, the associated availability of cheaper generic brands and the emergence of new, possibly more effective, drugs such as prasugrel. It may be argued that if clopidogrel is to be superseded by a more effective or safer drug in the near future, a trial of clopidogrel may not be advisable or cost-effective. However, if the cost of clopidogrel is likely to decrease markedly, this will make its use in both a future trial and clinical practice more cost-effective.

Summary of approach

The search strategy outlined in Chapter 3 was used to identify published cost-effectiveness studies, in order to assist in updating an existing decision model evaluating alternative durations of clopidogrel treatment in patients with NSTE-ACS. 12 The objective was to examine other published decision models evaluating the cost-effectiveness of clopidogrel in NSTE-ACS, with the aim of identifying alternative structural assumptions, parameter estimates and key areas of uncertainty. These studies were not subject to a formal review, but were used to inform the overall development of the existing model in relation to structural assumptions and parameter estimates. These findings were used in conjunction with the results of the clinical effectiveness review to provide a basis for updating the existing decision model and the assumptions and parameter inputs applied therein.

The assessment of cost-effectiveness evidence starts with an overview of the existing decision model,12 in order to highlight the main issues and the assumptions adopted in the existing approach used to evaluate the cost-effectiveness of alternative durations of clopidogrel. The wider cost-effectiveness evidence is then considered in more detail. This provides the context for the updated cost-effectiveness model and the VOI analysis presented in Chapter 5.

Overview of existing decision model

Main and colleagues12 developed a decision model to assess the long-term cost-effectiveness of 12 months of treatment with clopidogrel in addition to aspirin in comparison with aspirin alone in the UK NHS. This model forms the basis of the updated analyses presented in Chapter 5. The model comprised two parts: a short-term element, which relates to a period of 12 months after a patient presents with NSTE-ACS, and a long-term element which extrapolates a patient’s lifetime costs and outcomes conditional on surviving the first 12 months after the acute episode. It was developed to estimate costs from the perspective of the NHS and health outcomes in terms of QALYs. For the base-case analysis, a lifetime time horizon was used.

To avoid excessive duplication, only a brief overview of the data sources and input parameters is reported here. Full details are published elsewhere. 12 The model is probabilistic in that all input parameters are entered as probability distributions to reflect their imprecision, and Monte Carlo simulation is used to reflect this uncertainty in the model’s results. A 2001–2 price base was used, and annual discount rates of 6% for costs and 1.5% for benefits were applied.

In the base-case analysis, two alternative strategies were considered:

• Strategy 1: Treatment with clopidogrel as an adjunct to standard therapy (including aspirin) for 12 months, followed by standard therapy for the remainder of a patient’s lifetime

• Strategy 2: Lifetime treatment with standard therapy (including aspirin) alone.

A range of sensitivity analyses were also undertaken to assess the robustness of the results of the base-case model to the use of alternative assumptions and parameter inputs. Two of these analyses have particular relevance to the question being addessed within this review. The first element is related to risk stratification, exploring the impact of heterogeneity in baseline event data between higher-risk (defined as the presence of one or more of the following characteristics: age 70 years or more; ST depression and diabetes) and lower-risk patients (absence of all of these). The second element considered a range of alternative strategies representing shorter durations of clopidogrel, in addition to the two main strategies included in the base-case analysis.

The following section summarises the main structural issues and assumptions related to the short- and long-term models.

Short-term model

The short-term model was developed using a decision tree and characterised the period up to 12 months following an episode of ACS. The structure of this model is outlined in Figure 2. Baseline probabilities of death, non-fatal MI and revascularisation as well as resource use data were taken from the Prospective Registry of Acute Ischaemic Syndrome in the UK (PRAIS-UK). 102 This is an observational cohort registry of 1046 patients admitted to 56 UK hospitals with ACS between 23 May 1998 and 3 February 1999. Baseline data reported in PRAIS-UK were only reported at 6 months’ follow-up. In order to provide input parameters for the short-term model, these data were extrapolated to 12 months to reflect the follow-up period reported in the CURE trial. These data were used to represent the probabilities of these events associated with Strategy 2.

FIGURE 2.

Structure of the short-term model. ACS, acute coronary syndrome; CABG, coronary artery bypass graft; MI, myocardial infarction; PCI, percutaneous coronary intervention.

For patients who experience a non-fatal MI during the 6-month period, resource use and cost were based on costs estimated in NHS hospitals in England. 102 In addition, the costs of adverse events related to major bleeding and stroke were incorporated into the short-term model with the respective probabilities of incurring these events taken from PRAIS-UK. The drug costs were based on undiscounted prices from the British National Formulary. Other data used to evaluate resource use were taken from the literature.

Three mutually exclusive outcomes were modelled: non-fatal MI, death (cardiovascular and non-cardiovascular) and IHD without non-fatal MI during the 12-month period. These outcomes also represented the starting health states for the long-term model. The RRs for the use of clopidogrel in addition to aspirin compared with aspirin alone were taken from the CURE trial. Separate RRs for each of the major end points in the short-term model (as well as those for the adverse events) were modelled as log-normal distributions. These RRs were applied to the baseline probabilities to estimate the respective probabilities of the outcomes (and adverse events) associated with Strategy 1 (12 months of clopidogrel treatment).

Long-term model

A long-term (extrapolation) model estimated the subsequent prognosis for patients who finished the short-term (12-month) model in one of two disease states: those having experienced a non-fatal MI and those who have not (well but with IHD and hereafter referred to as IHD). This was used to quantify the remaining quality-adjusted life expectancy and costs of patients exiting the short-term model in the two non-fatal states. It took the form of a four-state Markov process as illustrated in Figure 3.

FIGURE 3.

Structure of the long-term model. MI, myocardial infarction.

Depending on progress through the short-term model, patients entered the long-term model in either the IHD state or the non-fatal MI state. Patients entering the IHD state could subsequently experience a non-fatal MI, in which case they moved to the non-fatal MI state for 1 year, after which they could die or move to the post-MI state. Patients experiencing any subsequent non-fatal MIs remained in the post-MI state, although the costs of such events were reflected in the model. The transitions from the IHD, non-fatal MI and post-MI states to death reflected the all-cause mortality risk (including both cardiovascular and non-cardiovascular mortality). These transitions were estimated from data on two cohorts from the Nottingham Heart Attack Register (NHAR) from 1992 (n = 979) and 1998 (n = 300).

Based on a cycle of 1 year, the annual percentage probability of non-fatal MI and death for IHD patients was estimated to be 1.8% and 7.2% respectively. The probability of death in the first year following non-fatal MI was 19%, and for subsequent years was 7%. The uncertainty associated with each transition probability was characterised by assigning a normal distribution to the (log) hazard.

Health-state costs were incorporated into the Markov model by attaching a mean annual cost to the IHD, non-fatal MI and post-MI states. An additional (one-off) transition cost was also added when a patient died, based on resource data obtained from the NHAR. These state and transition costs related to hospital resource use only, and were based on data collected as part of the 1998 cohort of the NHAR. Average annual health-state costs were calculated by aggregating the resources consumed by each patient in the 1998 NHAR cohort according to whether they would have fallen into the three non-dead states in the model: IHD, non-fatal MI or post-MI. As in the short-term model, the uncertainty in resource use in the long-term model was characterised by beta distributions (to reflect the proportion of patients utilising a particular resource item) and log-normal distributions (to reflect the intensity of use).

In order to quality-adjust survival (and hence to estimate QALYs), it was assumed that the health states of all patients who were alive were valued, on average, at the same utility, regardless of which health state they were in. For the base-case analysis, this was assumed to be 0.8 with a standard deviation (SD) of 0.09. A range of alternative estimates were considered in the sensitivity analysis.

The overall model was run for a period of 40 cycles (equivalent to 40 years), after which the vast majority of patients had died. The model was developed in excel with the Crystal Ball ‘add-on’. The Monte Carlo simulation was run for 1000 iterations. The model was run several times – once for a base-case analysis and then for a number of alternative sensitivity analyses.

Review of published cost-effectiveness analyses

The following section provides an overview of published studies on the cost-effectiveness of clopidogrel in patients with NSTE-ACS. The searches identified two economic models analysing cost per life-year gained104,105 and three additional cost–utility models. 106–108 The studies were also included in a recent comprehensive pharmacoeconomic review that was identified during the search process. 109

The models were reviewed in relation to the assumptions and parameter inputs applied. In particular, close attention was paid to aspects related to the assumption of a constant RR or to issues that may be related to a rebound effect.

Introduction

The existing economic model was revised, based on the updated review of clinical effectiveness data reported in Chapter 3 and the review of economic studies in Chapter 4. The changes made to the original model are reported in the following sections. The objective was to update the model inputs and assumptions, and to extend the previous work to address two related analyses concerning the optimal duration of clopidogrel treatment:

1. A revised assessment of the relative cost-effectiveness of alternative treatment durations based on the updated reviews of clinical effectiveness and cost-effectiveness data. This requires an estimation of mean lifetime costs and QALYs of the different strategies and their cost-effectiveness to be compared using ICERs as appropriate. Uncertainty in the cost-effectiveness of the alternative strategies will be reflected by means of cost-effectiveness acceptability curves (CEACs). These show the probability that each strategy is cost-effective, using alternative values for the maximum (or threshold) value the health service is willing to pay for an additional QALY in these patients.

2. A formal assessment of the potential value of further research using VOI analyses. Bayesian VOI analysis is used to estimate the expected costs of decision uncertainty predicted by the model and the maximum value that can be placed on additional research aimed at reducing this uncertainty. This analysis will be used as the basis for identifying research priorities in this area and to establish an upper bound on the value of a future trial in this area. This will provide a necessary condition for establishing whether a trial is likely to provide value for money for the HTA programme.

Methods

The existing decision model was updated and extended, based on the clinical and cost-effectiveness reviews, to provide the vehicle for the revised cost-effectiveness estimates and the VOI analysis.

Assumptions and data inputs

Scenarios

Cost-effectiveness and VOI estimates are presented for a number of scenarios. All scenarios consider a cohort of non-ST-elevation ACS patients (at a starting age of 60) over a time horizon of 40 years. The base-case analysis (Scenario 1) assumes a constant treatment for the different durations of clopidogrel. Separate analyses are presented for all patients and also for high- and low-risk groups. Two further individual scenarios are then considered:

• Scenario 2: Applying separate treatment effects for the different durations of clopidogrel based on the data reported in the SIGN guidelines. As in Scenario 1, results are presented for all patients and for the high- and low-risk groups.

• Scenario 3: Investigating the impact of the introduction of generic clopidogrel. This scenario is undertaken only for the VOI analysis, as the implementation decision about the cost-effectiveness of clopidogrel should be based on prevailing prices, and a separate decision should be taken following the emergence of generic clopidogrel. However, while the decision about a potential trial can be made on the basis of current information, given that the delay in the arrival of this information is likely to be after the introduction to the market of a generic version of clopidogrel, it seems pertinent to consider the potential implications of this future change.

Results

Cost-effectiveness of different treatment durations of clopidogrel assuming constant effects

Base-case scenario (Scenario 1)

Table 19 presents the analysis of the ICER for the base-case scenario assuming constant relative treatment effects for clopidogrel in all patients. Where more than two programmes are being compared, the ICERs are calculated using the following process:

• The strategies are ranked in terms of cost (from the least expensive to the most costly).

• If a strategy is more expensive and less effective than the previous strategy, then this strategy is said to be dominated and is excluded from the calculation of the ICERs.

• The ICERs are calculated for each successive alternative, from the cheapest to the most costly. If the ICER for a given strategy is higher than that of the next most effective strategy, then this strategy is ruled out on the basis of extended dominance.

• Finally, the ICERs are recalculated, excluding any strategies that are ruled out using the notions of dominance and extended dominance.

TABLE 19 - Cost-effectiveness results for all patients (Scenario 1)

ICER, incremental cost-effectiveness ratio; NA, not applicable; QALYs, quality-adjusted life-years.

Mean values from simulation				% of results cost-effective at threshold
Strategy	QALYs	Cost (£)	ICER (£)	£20,000	£30,000	£40,000
1: Clopidogrel – 12 months	8.1236	19,758	18,712	51.7	67.5	73.8
2: Clopidogrel – 6 months	8.1094	19,493	10,482	18.9	9.9	6.4
3: Clopidogrel – 3 months	8.0954	19,347	9489	2.0	0.7	0.2
4: Clopidogrel – 1 month	8.0835	19,233	4790	7.5	5.0	4.0
5: Standard therapy	8.0642	19,141	NA	15.7	16.8	15.7

In this scenario, none of the 5 strategies is ruled out on the grounds of dominance/extended dominance. The use of clopidogrel over longer periods is associated with both increased costs and increased QALYs in comparison with shorter durations, such that the ICER rises as the duration of treatment with clopidogrel increases. The ICER of Strategy 4 (1-month treatment with clopidogrel) compared with Strategy 5 (standard care alone) is £4790 per QALY. The ICER of Strategy 3 compared with Strategy 4 is £9489. The ICER of Strategy 2 compared with Strategy 3 is £10,482. The ICER of Strategy 1 compared with Strategy 2 is £18,712. Hence, the results of this analysis indicate that a decision concerning the optimal duration of treatment with clopidogrel is dependent upon the amount the NHS is prepared to pay per additional QALY. As the amount the NHS is prepared to pay increases, the more cost-effective treatment with clopidogrel for longer durations becomes. At conventional thresholds of between £20,000 and £30,000 per QALY, the optimal duration of clopidogrel appears to be 12 months.

In comparison with the earlier model, the ICERs associated with the clopidogrel strategies are higher in the updated model. The reasons for this are: (1) the increase in costs due to applying current prices, and (2) the changes to the discount rates, employing 3.5% for both costs and outcomes (as opposed to 1.5% for outcomes and 6% for costs in the previous model). However, despite the less favourable ICERs, the conclusions arising from the updated model are consistent with those reported previously.

Figures 4 and 5 present the CEACs and associated frontier for Scenario 1. The CEACs demonstrate that the probability that Strategy 1 is cost-effective increases as the maximum willingness to pay increases: if society is prepared to pay £20,000 for an additional QALY, the probability that Strategy 1 is cost-effective is approximately 52%, increasing to 74% if the maximum willingness to pay is £40,000.

FIGURE 4.

CEAC of different clopidogrel strategies (Scenario 1, all patients). QALY, quality-adjusted life-year; WTP, willingness to pay.

FIGURE 5.

Cost-effectiveness frontier for the different strategies (Scenario 1, all patients). QALY, quality-adjusted life-year; WTP, willingness to pay.

Although the CEAC provides a useful graphical representation of the uncertainty associated with the probability that individual strategies are cost-effective over a range of threshold values, the results of the CEAC can only be used to identify the optimal implementation decision under a restrictive set of assumptions. This is because the strategy with the highest probability of being cost-effective does not necessarily have the highest expected pay-off (i.e. net benefit), and will only have this when the distribution of these pay-offs is symmetrical. This limitation can be overcome by using a cost-effectiveness frontier to indicate which strategy is optimal (and the associated probability that this strategy is the most cost-effective) across the range of values representing the maximum amount the NHS is prepared to pay for an additional QALY. The frontier for this analysis is provided in Figure 5.

The expected costs and QALYs and the ICER of the alternative strategies based on the high-risk and low-risk groups are reported in Tables 20 and 21 respectively. In both risk groups, none of the five strategies were ruled out on the grounds of dominance/extended dominance. As before, the use of clopidogrel over longer periods was associated with both increased costs and increased QALYs in comparison with shorter durations. However, the ICER between the various strategies was markedly different between the two risk groups.

TABLE 20 - Cost-effectiveness in high-risk patients (Scenario 1)

ICER, incremental cost-effectiveness ratio; NA, not applicable; QALYs, quality-adjusted life-years.

Mean values from simulation				% of results cost-effective at threshold
Strategy	QALYs	Cost (£)	ICER (£)	£20,000	£30,000	£40,000
1: Clopidogrel – 12 months	7.7710	19,187	13,380	65.8	75.1	78.9
2: Clopidogrel – 6 months	7.7496	18,900	7971	9.3	4.2	2.1
3: Clopidogrel – 3 months	7.7300	18,744	7930	0.7	0.2	0.0
4: Clopidogrel – 1 month	7.7123	18,604	4846	4.8	3.2	2.5
5: Standard therapy	7.6882	18,487	NA	16.5	17.3	16.5

TABLE 21 - Cost-effectiveness in low-risk patients (Scenario 1)

ICER, incremental cost-effectiveness ratio; NA, not applicable; QALYs, quality-adjusted life-years.

Mean values from simulation				% of results cost-effective at threshold
	QALYs	Cost (£)	ICER (£)	£20,000	£30,000	£40,000
1: Clopidogrel – 12 months	8.6850	21,244	49,436	4.9	16.7	28.7
2: Clopidogrel – 6 months	8.6802	21,005	36,226	14.8	20.2	22.8
3: Clopidogrel – 3 months	8.6769	20,886	17,826	31.3	30.0	23.7
4: Clopidogrel – 1 month	8.6713	20,786	4891	31.6	20.2	13.7
5: Standard therapy	8.6600	20,731	NA	11.1	13.0	11.1

In high-risk patients, the ICER of Strategy 1 (12-month duration of clopidogrel) was more favourable than in the combined analysis of all patients. This was to be expected as the number of events represented by the baseline was higher, and as such the application of the same treatment effect would result in proportionally more absolute benefit. Hence, the ICER was decreased to £13,380 per QALY and, at conventional thresholds, Strategy 1 appears cost-effective. In turn, the lower number of baseline events in low-risk patients had a less favourable effect on the cost-effectiveness of longer durations of clopidogrel. At conventional thresholds of cost-effectiveness, Strategy 3 (3 months of clopidogrel) appears to be the optimal decision and longer durations do not appear cost-effective.

Cost-effectiveness of different durations of clopidogrel treatment assuming varying treatment effects

Scenario 2

Table 22 reports the ICER estimates employing the composite outcome based on the data reported in the SIGN guidelines. As shown in Table 17, the RRs assigned in this analysis do not assume a constant treatment effect, with more favourable estimates assigned to months 0–1 and 1–3 compared with periods beyond 3 months’ duration. The results show less favourable ICER estimates, although these do not vary significantly from those reported in Scenario 1. The resulting ICER increased marginally to £20,661 per QALY (compared with £18,712 in Scenario 1). As expected, the associated ICERs of the shorter durations (Strategy 3 = 3 months, Strategy 4 = 1 month) improved markedly owing to the more favourable RR estimates applied to the earlier periods of treatment with clopidogrel. However, assuming a threshold of between £20,000 and £30,000 per QALY, Strategy 1 appeared to remain the optimal strategy in all patients.

TABLE 22 - Cost-effectiveness estimates for all patients (Scenario 2)

ICER, incremental cost-effectiveness ratio; NA, not applicable; QALYs, quality-adjusted life-years.

Mean values from simulation				% of results cost-effective at threshold
Strategy	QALYs	Cost (£)	ICER (£)	£20,000	£30,000	£40,000
1: Clopidogrel – 12 months	8.2019	20,094	20,661	42.9	56.3	62.6
2: Clopidogrel – 6 months	8.1887	19,820	11,917	32.5	26.6	23.0
3: Clopidogrel – 3 months	8.1753	19,661	4095	24.6	17.1	14.4
4: Clopidogrel – 1 month	8.1236	19,449	3632	0.1	0.0	0.0
5: Standard therapy	8.0686	19,250	NA	0.0	0.0	0.0

It should be recognised that the structural alterations required to model the composite end point, will have a potentially important effect on the results if there are differences between the effect of clopidogrel on the composite end point and its effect on individual end points. The constant effects model assumes a larger treatment effect for non-fatal MI (RR 0.70) and stroke (RR 0.73), while the effect on mortality was comparatively low (RR 0.93). In contrast, the use of the composite end point assumes that the effects on mortality, non-fatal MI and stroke are equal (although these vary with time), with RRs of 0.78 (0–1 month), 0.69 (months 1–3) and 0.92 (after month 3). Consequently, while the impact of applying the composite end points results in less favourable RRs across each of the time intervals beyond 1 month for stroke and non-fatal MI, the estimate for mortality remains higher at each interval. While these two effects are likely to counter each other to some degree, the impact of assuming a higher treatment effect on mortality could be important. However, it is unclear whether this was sufficient to markedly bias the results.

Figures 6 and 7 report the CEACs and associated frontier for Scenario 2 and demonstrate that there is higher decision uncertainty related to the use of clopidogrel over 12 months compared with Scenario 1. This may have important implications for the VOI estimates reported separately, as while Strategy 1 appears to remain cost-effective in this scenario, the uncertainty surrounding this was no higher and, assuming all other things remain equal, should result in a higher value associated with obtaining further information.

FIGURE 6.

CEAC for clopidogrel strategies (Scenario 2, all patients). QALY, quality-adjusted life-year; WTP, willingness to pay.

FIGURE 7.

Cost-effectiveness frontier for clopidogrel strategies (Scenario 2, all patients). QALY, quality-adjusted life-year; WTP, willingness to pay.

The expected costs and QALYs and the ICER of the alternative strategies based on the high-risk and low-risk groups are reported in Tables 23 and 24 respectively. In the high-risk group, none of the five strategies were ruled out on the grounds of dominance/extended dominance. As before, the use of clopidogrel over longer periods was associated with both increased costs and increased QALYs in comparison with shorter durations. Similarly, the ICERs for longer durations of clopidogrel were less favourable for durations of longer than 3 months (and vice versa for durations of 3 months or less), although the ICER for Strategy 1 was below conventional thresholds.

TABLE 23 - Cost-effectiveness based on Scenario 2, high-risk patients

ICER, incremental cost-effectiveness ratio; NA, not applicable; QALYs, quality-adjusted life-years.

Mean values from simulation				% of results cost-effective at threshold
Strategy	QALYs	Cost (£)	ICER (£)	£20,000	£30,000	£40,000
1: Clopidogrel – 12 months	7.8783	19.664	15,063	59.3	69.2	73.0
2: Clopidogrel – 6 months	7.8586	19.368	9144	11.9	6.4	4.3
3: Clopidogrel – 3 months	7.8400	19.197	3809	28.7	24.4	22.6
4: Clopidogrel – 1 month	7.7653	18.913	3615	0.1	0.1	0.1
5: Standard therapy	7.6906	18.643	NA	0.0	0.0	0.0

TABLE 24 - Cost-effectiveness based on Scenario 2, low-risk patients

ED, extendedly dominated; ICER, incremental cost-effectiveness ratio; NA, not applicable; QALYs, quality-adjusted life-years.

Mean values from simulation				% of results cost-effective at threshold
Strategy	QALYs	Cost (£)	ICER (£)	£20,000	£30,000	£40,000
1: Clopidogrel – 12 months	8.7079	21,065	58,691	4.6	13.8	23.5
2: Clopidogrel – 6 months	8.7037	20,821	ED	6.0	8.7	10.1
3: Clopidogrel – 3 months	8.7018	20,695	6780	81.9	74.8	65.2
4: Clopidogrel – 1 month	8.6825	20,564	3936	6.1	2.3	1.1
5: Standard therapy	8.6589	20,471	NA	0.2	0.4	0.2

In contrast, in the low-risk group, Strategy 2 was ruled out by extended dominance by Strategy 1. The ICER for Strategy 1 was considerably higher (£58,691 per QALY) than conventional thresholds. The results reinforced the findings from Scenario 1 in low-risk patients, that durations of clopidogrel treatment of longer than 3 months do not appear to be cost-effective.

Value of information associated with the decision problem

Separate estimates of total EVPI and EVPPI were estimated for Scenarios 1 and 2. A third scenario was considered based on the VOI following patent expiry. As the patent of clopidogrel is due to expire in 2011,115 a price reduction of 75% was assumed, which corresponds with the average price of a generic compared with a branded drug in the UK. Rather than reporting the results of the third scenario separately, EVPI results are presented for Scenarios 1 and 2, applying the current price of clopidogrel (‘on patent’ results) and applying the potential generic price of clopidogrel (‘off patent’ results). These results are reported across a range of potential thresholds of cost-effectiveness.

Total EVPI

Tables 25 and 26 report the total population EVPI for a range of cost-effectiveness thresholds for Scenarios 1 and 2 respectively. Estimates of total EVPI ranged between £3.27 million and £123.17 million across the different scenarios, risk groups and range of thresholds. The calculation demonstrates that there was significant variability in the potential value of research, depending upon the scenario (and risk group) or threshold considered most relevant to the particular decision-maker. At a more conventional threshold of cost-effectiveness between £20,000 and £30,000 per QALY, the range was reduced to between £3.27 million and £108.45 million. However, the potential value of a trial to address the current decision problem clearly remains highly uncertain and may be considered to be potentially worthwhile at the top end of the scale and not at the lower end.

TABLE 25 - Total EVPI for Scenario 1 (constant treatment effects)

EVPI, expected value of perfect information; QALY, quality-adjusted life-year.

	EVPI at a willingness to pay per QALY (£)
	£20,000	£30,000	£40,000
EVPI while on patent
All patients	102,442,841	108,454,348	123,171,826
High-risk patients	65,803,244	77,100,300	92,043,666
Low-risk patients	15,007,631	20,376,578	28,264,558
EVPI while off patent
All patients	50,691,302	66,929,942	84,945,937
High-risk patients	42,274,257	57,936,239	74,972,484
Low-risk patients	11,597,014	10,762,438	11,385,255

TABLE 26 - Total EVPI for Scenario 2 (varying treatment effects)

EVPI, expected value of perfect information; QALY, quality-adjusted life-year.

	EVPI at a willingness to pay per QALY (£)
	£20,000	£30,000	£40,000
EVPI while on patent
All patients	77,630,538	84,699,365	92,810,082
High-risk patients	57,425,624	68,493,740	82,069,534
Low-risk patients	3,265,709	7,917,239	16,148,398
EVPI while off patent
All patients	50,413,420	69,988,782	90,072,197
High-risk patients	34,107,321	48,687,162	63,485,715
Low-risk patients	11,903,071	11,705,540	12,525,800

The estimates of total EVPI for the high- and low-risk groups differed markedly. At a threshold of cost-effectiveness between £20,000 and £30,000 per QALY, total EVPI ranged from £34.11 million to £77.10 million in high-risk patients (and from £3.27 million to £20.38 million in low-risk patients). As expected, for the majority of analyses, estimates of total EVPI based on the scenario of generic clopidogrel (EVPI while off patent) reduced the total EVPI range to between £50.41 million and £69.99 million in all patients (and between £34.11 million and £57.94 million in high-risk patients and £10.76 million and £11.90 million in low-risk patients).

The separation of the results according to different risk groups, and the subsequent variability in the total EVPI estimates, may have important policy implications, particularly in relation to a future trial. As the cost-effectiveness estimates have demonstrated, the cost-effectiveness of alternative durations of clopidogrel differed markedly between the risk groups. While a strategy of 12 months of clopidogrel treatment appeared potentially cost-effective compared with shorter durations in all patients and in the subgroup of patients at high risk, strategies of treating beyond 3 months were not considered cost-effective for patients at low risk. It should also be recognised that since the CURE trial has been published, routine clinical practice has shifted towards greater use of invasive investigation in medium- to high-risk patients. 85 Given this, recent guidance from SIGN has suggested that the benefits of clopidogrel are likely to be overestimated in the case of more widespread application invasive investigation. The implications of this remain somewhat unclear. While, it is apparent that this may have an effect on the cost-effectiveness of longer treatment durations and potentially alter the conclusions based on cost-effectiveness regarding the optimal duration of clopidogrel in high-risk patients, it is also possible that this in itself could increase the decision uncertainty and hence the associated VOI. However, if routine clinical practice has shifted markedly in the UK to the extent that the CURE trial itself (or the model presented here) is no longer considered to be representative of current practice, then the results for this group of patients may be misleading.

Given the uncertainty surrounding changing practice, the result for the lower-risk group may be considered more reliable in terms of informing a future trial on the basis of the current model and the data inputs. At a threshold of £20,000–£30,000 per QALY, total EVPI ranged between £3.27 million and £20.38 million. These results are considerably lower than the EVPI results for all patients or the high-risk group. A separate analysis of EVPI in low-risk patients was also undertaken that looked at various combinations of strategies. This may assist in informing the potential design of any future trial, as it may not be feasible to run a trial with the five strategies outlined.

Figure 8 reports the EVPI estimates for different combinations of strategies in low-risk patients. The combinations of strategies with the highest EVPI were Strategies 1 (12 months of clopidogrel) versus 5 (standard care alone) and Strategies 1 (12 months of clopidogrel) versus 4 (1 month of clopidogrel). While the results of the cost-effectiveness analysis suggest that the question of most apparent interest would be a comparison of Strategies 1 (12 months of treatment based on current NICE guidelines) and 3 (3 months of treatment based on the results of the cost-effectiveness analysis and the recent SIGN guidelines), the value of a trial to inform this question appears to be markedly lower than other combinations (£8.13 million).

FIGURE 8.

Expected value of perfect information (EVPI) for different combinations of strategies, low-risk patients, on patent.

EVPPI

Although estimates of the total EVPI provide a useful global estimate of the uncertainty surrounding the adoption decision, they do not provide an indication of where further research would be of most value. EVPPI can be used to consider particular elements of the decision problem in order to direct and focus research towards the specific areas where the elimination of uncertainty has the most value. The EVPPI can be calculated for individual or subsets of parameters. This can be particularly relevant to the design of any future research, as subsets of parameters can be grouped according to related areas, and may also be used to separate out parameters for which a randomised design is necessary and those where this may not be essential (e.g. effectiveness parameters are likely to need a randomised design to minimise bias; however, issues of bias are likely to be less critical for obtaining epidemiological or cost data and observational design may be more appropriate). Given the computational time required to perform these calculations, they were undertaken using an assumption of constant relative effect (Scenario 1) at a threshold of £30,000 per QALY.

Parameters in the model were separated into three distinct areas:

1. effectiveness parameters – comprising the RR estimates applied in the model

2. epidemiology – comprising the baseline events and long-term prognosis parameters

3. costs – comprising the short- and longer-term cost inputs applied in the model.

Table 27 reports the results for EVPPI (also represented graphically in Figure 9). The results indicate the uncertainty surrounding the effectiveness parameters (hence the requirement for a randomised trial) contribute much more significantly to all patients and the high-risk group. In both of these groups, the effectiveness parameters account for the majority of the uncertainty surrounding the total EVPI estimates. However, for the low-risk group, the effectiveness parameters constitute less than 50% of the total EVPI estimates. Consequently, while the total EVPI (Scenario 1) ranges between £10.76 million and £20.38 million for the low-risk group, the VOI associated with the effectiveness parameters ranges between £4.25 million and £8.80 million.

TABLE 27 - EVPPI results (at a threshold of £30,000 per QALY) (£)

EVPI, expected value of perfect information.

	All patients, on patent	All patients, off patent	High risk, on patent	High risk, off patent	Low risk, on patent	Low risk, off patent
Total EVPI	108,454,348	66,929,942	77,100,300	57,936,239	20,376,578	10,762,438
Effectiveness	89,113,472	62,599,024	77,346,725	52,717,491	8,795,492	4,246,111
Epidemiology	1,326,024	0	25,558	0	7,112,372	1,129,651
Cost	3,269,190	477,875	498,879	228,462	3,097,121	1,046,485

FIGURE 9.

Partial expected value of perfect information (EVPI) results (at a threshold of £30,000 per QALY).

Conclusions

From a cost-effectiveness perspective, the optimal duration of clopidogrel is clearly an important consideration, particularly in relation to issues of risk stratification. The updated model reinforced the conclusions from the earlier analysis. That is, a policy of 12 months of clopidogrel for patients with NSTE-ACS appears to be cost-effective both in ‘average’ patients (i.e. based on the average across all patient risks considered) and in the subgroup of higher-risk patients, compared with shorter-term durations. However, for lower-risk patients, treatment with clopidogrel beyond 3 months does not appear to be cost-effective. These conclusions appeared robust to alternative assumptions related to whether the relative effect of clopidogrel was assumed to remain constant over time or whether the treatment effect in the first 3 months was assumed to be greater than in later periods.

The major extension to the earlier work was a formal consideration of the VOI surrounding the decision problem. This was undertaken to assist in identifying future research priorities and, in particular, is used to establish the potential value of a future trial. This was done by estimating the EVPI associated with various scenarios in order to provide an upper bound to the amount a decision-maker should be willing to pay to obtain further information (and also assuming that this information will resolve all remaining uncertainty). Account was also taken of the potential impact when a generic version of clopidogrel becomes available. The analysis revealed considerable variation in the EVPI estimates. Estimates of EVPI were markedly higher for an ‘average’ patient and for high-risk patients compared with those for lower-risk patients. Similarly, consideration of the EVPI for parameter groups revealed that the contribution of the relative effectiveness parameters was less significant in the lower-risk patients. It was also acknowledged that if routine clinical practice has shifted markedly in the UK to the extent that the CURE trial itself (or the model presented here) is no longer considered to be representative of current practice for groups at high risk, then the results for this group of patients may be misleading.

At a threshold of £20,000–£30,000 per QALY, total EVPI ranged from £3.27 million to £20.38 million in the low-risk group. Given that a trial is unlikely to be able to report until after the market entry of generic clopidogrel; equivalent EVPI estimates for this scenario ranged between £10.8 million and £11.9 million. The EVPPI calculations demonstrated that approximately 40–45% of this value related to the relative effectiveness parameters (i.e. those for which an RCT would be required). Given that the estimates of EVPI represent upper bounds to further research and that some uncertainty will remain, then the true economic value will be even lower than those reported here.

Statement of principal findings

Strengths and limitations of the assessment

Uncertainties

There is still a large degree of uncertainty surrounding both the optimal duration of clopidogrel treatment and the impact of withdrawal of clopidogrel treatment, which can only be addressed by further research. The most appropriate study design would be an RCT that directly compared different durations of clopidogrel treatment in patients with NSTE-ACS. Such a trial would compare the effects of 3 months’ and 12 months’ treatment with clopidogrel and would follow patients up after discontinuation of clopidogrel. Ideally, in order to definitively answer the possibility of a rebound effect with clopidogrel, outcomes would include with the measurement of biomarkers for platelet activity before, during and after clopidogrel treatment.

The proportion of patients who would have been treated with thienopyridines at the time of the CURE trial, who would now routinely undergo early PCI, is unclear. Since the completion of the CURE trial in 2000 and 2006, there was over a 100% increase in the number of PCIs conducted in the UK (see Figure 1). 101 It is not unreasonable to presume that many of the higher-risk patients that were included in the CURE trial would undergo an early PCI if treated today, rather than prolonged medical management or a late PCI procedure.

Changes in routine clinical practice (particularly for the high-risk group) may mean that the cost-effectiveness and VOI results may be less generalisable in particular risk groups. The implications of this remain uncertain. While it may clearly impact on the cost-effectiveness of longer-treatment durations and potentially alter the conclusions based on cost-effectiveness regarding the optimal duration of clopidogrel in high-risk patients, it is also possible that this itself could increase the decision uncertainty and hence the associated VOI. However, if routine clinical practice has shifted markedly in the UK to the extent that the CURE trial itself (or the model presented here) is no longer considered to be representative of current practice, then the results for this group of patients may be inaccurate.

Feasibility of further research

Ideally, an adequately powered, well-conducted RCT that directly compares different durations of clopidogrel treatment in patients with NSTE-ACS would be required to provide more robust evidence in relation to the impact of clopidogrel withdrawal. The use of an RCT would minimise possible biases associated with establishing causality of any potential rebound effect, and provide robust estimates of the relative effect of alternative durations of treatment. Such an RCT would also address the question of a possible rebound effect associated with clopidogrel withdrawal. However, the design and cost of this trial need to be evaluated carefully, both in relation to the VOI estimates reported here and to issues that may affect the feasibility of such research.

Clearly, an RCT which was sufficiently powered to address alternative durations of clopidogrel would inevitably have to be at least as large as the CURE study (n = 12,562), if not several times greater in magnitude, owing to the smaller effect sizes that would be predicted between different durations of clopidogrel. The feasibility and timeliness of such a trial would therefore need to be questioned. Even if such a trial could be undertaken, it appears unlikely that such a study would be able to report prior to the market entry of a generic version of clopidogrel. As such, the off-patent results from the VOI analysis suggest that the value of further research would be markedly lower than research which would be available currently. Furthermore, should investigation of the physiological basis of any rebound effect be considered to be warranted, this could be accommodated by including assessment of biomarkers as one of the trial outcomes. Realistically, such additional demands would further militate against the feasibility of such a trial.

In addition to the costs and logistics of undertaking such an RCT, other considerations would also need to be taken into account. Owing to the potential for a lengthy delay between commissioning an RCT and the availability of the results, other factors relevant to the current decision problem may have markedly altered which could further limit the ‘realisable’ value of such research. Clearly, the emergence of alternative treatments which could represent relevant comparators to clopidogrel may significantly alter both the cost-effectiveness and VOI estimates presented here. In addition, practice could also significantly change during this period. Indeed, the use of coronary intervention is increasing markedly. If such a trend continues, then the VOI results presented here could significantly over-estimate the value of research, as these results related primarily to the use of clopidogrel in patients who are managed without coronary intervention. The EVPI estimates are likely to decline as the population multiplier applied in the calculations will become smaller as a higher proportion of patients are managed with coronary interventions. It should also be recognised that the more widespread use of coronary interventions and, in particular, the greater use of drug-eluting stents may mean that patients will not be eligible for earlier clopidogrel withdrawal owing to the risk of stent thrombosis. 119

Implications for service provision

• Clopidogrel combined with aspirin is more effective in reducing adverse cardiovascular events than aspirin alone in patients with NSTE-ACS.

• Clopidogrel combined with aspirin may increase the risk of bleeding compared with aspirin alone.

• The optimal duration of clopidogrel treatment in patients with NSTE-ACS is uncertain.

• There was some evidence that a rebound effect occurs following the withdrawal of clopidogrel, but its clinical significance was unclear.

• Cost-effectiveness results suggest that longer durations of clopidogrel (greater than 3 months) do not appear cost-effective in patients at lower risk. However, for an average-risk patient (and in higher-risk patients), 12 months’ treatment of clopidogrel appears to be more cost-effective than shorter durations.

Recommendations for research

To determine optimal duration of clopidogrel treatment, a large, well-conducted RCT that directly compares different durations of clopidogrel treatment in patients with NSTE-ACS is ideally required. However, both the design and cost of this trial need to be evaluated carefully in relation to the VOI estimates reported here. In lower-risk groups, for which shorter durations of clopidogrel appear more cost-effective, it would seem unlikely that an adequately powered RCT would be considered to provide value for money owing to the significant cost that would be required to undertake such a study and the cost of the uncertainty that such a trial might resolve. In addition, to the potential value of such research, there remains a number of other issues which could affect the feasibility and timeliness of such research.

Contribution of authors

Wolf Rogowski (Visiting Research Fellow) was involved in the cost-effectiveness section, study selection, development of the economic model and report writing. Jane Burch (Research Fellow) was responsible for study selection, data extraction, validity assessment, data analysis and writing the report. Stephen Palmer (Senior Research Fellow) was involved in the cost-effectiveness section, study selection, development of the economic model and report writing and took overall responsibility for the economic component. Cheryl Craigs (Research Fellow) was involved in study selection, data extraction, validity assessment, data analysis and writing of the report. Su Golder (Information Officer) devised the search strategy, carried out the literature searches and wrote the search methodology sections of the report. Nerys Woolacott (Senior Research Fellow) provided input at all stages of the review, commented on drafts of the report and took overall responsibility for the review.

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.

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

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

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

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

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

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

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

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

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

   By Hallam L, Henthorne K.

8. Screening for cystic fibrosis.

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

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

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

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

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

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

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

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

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

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

    By Robert G, Stevens A, Gabbay J.

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

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

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

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

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

    A review by Robert G, Milne R.

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

    By Bradley M, Cullum N, Sheldon T.

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

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

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

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

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

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

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

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

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

    By Glenny AM, Song F.

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

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

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

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

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

   A review by Cairns JA, van der Pol MM.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

   By Clegg A, Bryant J, Milne R.

10. Publication and related biases.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    By Payne N, Chilcott J, McGoogan E.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    By Parkes J, Bryant J, Milne R.

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

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

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

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

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

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

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

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

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

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

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

    By Williams JE, Louw G, Towlerton G.

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

    By Shepherd J, Waugh N, Hewitson P.

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

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

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

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

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

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

37. Systematic review of treatments for atopic eczema.

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

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

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

39. The management of dyspepsia: a systematic review.

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

40. A systematic review of treatments for severe psoriasis.

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

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

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

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

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

3. Equity and the economic evaluation of healthcare.

   By Sassi F, Archard L, Le Grand J.

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

   By Eiser C, Morse R.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

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

    By De Broe S, Christopher F, Waugh N.

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

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

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

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

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

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

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

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

22. The measurement and monitoring of surgical adverse events.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    By David AS, Adams C.

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

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

36. Cost analysis of child health surveillance.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

   By Carroll B, Ali N, Azam N.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

13. A systematic review of atypical antipsychotics in schizophrenia.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    By Townsend J, Buxton M, Harper G.

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

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

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

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

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

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

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

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

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

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

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

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

27. Evaluating non-randomised intervention studies.

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

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

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

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

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

30. The value of digital imaging in diabetic retinopathy.

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

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

    By Law M, Wald N, Morris J.

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

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

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

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

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

    By Royle P, Waugh N.

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

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

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

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

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

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

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

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

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

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

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

    By Beard S, Hunn A, Wight J.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

42. Involving South Asian patients in clinical trials.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    By Raftery J, Roderick P, Stevens A.

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

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

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

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

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

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

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

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

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

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

26. Indirect comparisons of competing interventions.

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

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

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

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

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

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

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

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

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

    By Cochrane T, Davey RC, Matthes Edwards SM.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

22. Pressure relieving support surfaces: a randomised evaluation.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

43. Telemedicine in dermatology: a randomised controlled trial.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

43. Contamination in trials of educational interventions.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

   By Loveman E, Frampton GK, Clegg AJ.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

8. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.

   By Taylor RS, Elston J.

9. Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) – a randomised controlled trial.

   By Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al.

10. Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

    By Pilgrim H, Lloyd-Jones M, Rees A.

11. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

    By Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al.

12. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods.

    By Hobart J, Cano S.

13. Treatment of severe ankle sprain: a pragmatic randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of three types of mechanical ankle support with tubular bandage. The CAST trial.

    By Cooke MW, Marsh JL, Clark M, Nakash R, Jarvis RM, Hutton JL, et al. , on behalf of the CAST trial group.

14. Non-occupational postexposure prophylaxis for HIV: a systematic review.

    By Bryant J, Baxter L, Hird S.

15. Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial.

    By Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, et al.

16. How far does screening women for domestic (partner) violence in different health-care settings meet criteria for a screening programme? Systematic reviews of nine UK National Screening Committee criteria.

    By Feder G, Ramsay J, Dunne D, Rose M, Arsene C, Norman R, et al.

17. Spinal cord stimulation for chronic pain of neuropathic or ischaemic origin: systematic review and economic evaluation.

    By Simpson, EL, Duenas A, Holmes MW, Papaioannou D, Chilcott J.

18. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and costeffectiveness and natural history.

    By Fortnum H, O’Neill C, Taylor R, Lenthall R, Nikolopoulos T, Lightfoot G, et al.

19. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study.

    By Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, et al.

20. Systematic review of respite care in the frail elderly.

    By Shaw C, McNamara R, Abrams K, Cannings-John R, Hood K, Longo M, et al.

21. Neuroleptics in the treatment of aggressive challenging behaviour for people with intellectual disabilities: a randomised controlled trial (NACHBID).

    By Tyrer P, Oliver-Africano P, Romeo R, Knapp M, Dickens S, Bouras N, et al.

22. Randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care: the THREAD (THREshold for AntiDepressant response) study.

    By Kendrick T, Chatwin J, Dowrick C, Tylee A, Morriss R, Peveler R, et al.

23. Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation.

    By Bryant J, Cooper K, Picot J, Clegg A, Roderick P, Rosenberg W, et al.

24. Enhanced external counterpulsation for the treatment of stable angina and heart failure: a systematic review and economic analysis.

    By McKenna C, McDaid C, Suekarran S, Hawkins N, Claxton K, Light K, et al.

25. Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).

    By Donnan PT, McLernon D, Dillon JF, Ryder S, Roderick P, Sullivan F, et al.

26. A systematic review of presumed consent systems for deceased organ donation.

    By Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A.

27. Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial.

    By Hay AD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S, et al.

28. A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the management of insulin-treated diabetes mellitus (MITRE).

    By Newman SP, Cooke D, Casbard A, Walker S, Meredith S, Nunn A, et al.

29. Sensitivity analysis in economic evaluation: an audit of NICE current practice and a review of its use and value in decision-making.

    By Andronis L, Barton P, Bryan S.

30. Trastuzumab for the treatment of primary breast cancer in HER2-positive women: a single technology appraisal.

    By Ward S, Pilgrim H, Hind D.

31. Docetaxel for the adjuvant treatment of early node-positive breast cancer: a single technology appraisal.

    By Chilcott J, Lloyd Jones M, Wilkinson A.

32. The use of paclitaxel in the management of early stage breast cancer.

    By Griffin S, Dunn G, Palmer S, Macfarlane K, Brent S, Dyker A, et al.

33. Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma.

    By Dundar Y, Bagust A, Hounsome J, McLeod C, Boland A, Davis H, et al.

34. Bortezomib for the treatment of multiple myeloma patients.

    By Green C, Bryant J, Takeda A, Cooper K, Clegg A, Smith A, et al.

35. Fludarabine phosphate for the firstline treatment of chronic lymphocytic leukaemia.

    By Walker S, Palmer S, Erhorn S, Brent S, Dyker A, Ferrie L, et al.

36. Erlotinib for the treatment of relapsed non-small cell lung cancer.

    By McLeod C, Bagust A, Boland A, Hockenhull J, Dundar Y, Proudlove C, et al.

37. Cetuximab plus radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck.

    By Griffin S, Walker S, Sculpher M, White S, Erhorn S, Brent S, et al.

38. Infliximab for the treatment of adults with psoriasis.

    By Loveman E, Turner D, Hartwell D, Cooper K, Clegg A

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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