Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Cost-effectiveness of the National Health Service Abdominal Aortic Aneurysm Screening Programme in England.

BACKGROUND: Implementation of the National Health Service abdominal aortic aneurysm (AAA) screening programme (NAAASP) for men aged 65 years began in England in 2009. An important element of the evidence base supporting its introduction was the economic modelling of the long-term cost-effectiveness of screening, which was based mainly on 4-year follow-up data from the Multicentre Aneurysm Screening Study (MASS) randomized trial. Concern has been expressed about whether this conclusion of cost-effectiveness still holds, given the early performance parameters, particularly the lower prevalence of AAA observed in NAAASP. METHODS: The existing published model was adjusted and updated to reflect the current best evidence. It was recalibrated to mirror the 10-year follow-up data from MASS; the main cost parameters were re-estimated to reflect current practice; and more robust estimates of AAA growth and rupture rates from recent meta-analyses were incorporated, as were key parameters as observed in NAAASP (attendance rates, AAA prevalence and size distributions). RESULTS: The revised and updated model produced estimates of the long-term incremental cost-effectiveness of £5758 (95 per cent confidence interval £4285 to £7410) per life-year gained, or £7370 (£5467 to £9443) per quality-adjusted life-year (QALY) gained. CONCLUSION: Although the updated parameters, particularly the increased costs and lower AAA prevalence, have increased the cost per QALY, the latest modelling provides evidence that AAA screening as now being implemented in England is still highly cost-effective.

Final follow-up of the Multicentre Aneurysm Screening Study (MASS) randomized trial of abdominal aortic aneurysm screening.

BACKGROUND: The long-term effects of abdominal aortic aneurysm (AAA) screening were investigated in extended follow-up from the UK Multicentre Aneurysm Screening Study (MASS) randomized trial. METHODS: A population-based sample of men aged 65-74 years were randomized individually to invitation to ultrasound screening (invited group) or to a control group not offered screening. Patients with an AAA (3·0 cm or larger) detected at screening underwent surveillance and were offered surgery after predefined criteria had been met. Cause-specific mortality data were analysed using Cox regression. RESULTS: Some 67 770 men were enrolled in the study. Over 13 years, there were 224 AAA-related deaths in the invited group and 381 in the control group, a 42 (95 per cent confidence interval 31 to 51) per cent reduction. There was no evidence of effect on other causes of death, but there was an overall reduction in all-cause mortality of 3 (1 to 5) per cent. The degree of benefit seen in earlier years of follow-up was slightly diminished by the occurrence of AAA ruptures in those with an aorta originally screened normal. About half of these ruptures had a baseline aortic diameter in the range 2·5-2·9 cm. It was estimated that 216 men need to be invited to screening to save one death over the next 13 years. CONCLUSION: Screening resulted in a reduction in all-cause mortality, and the benefit in AAA-related mortality continued to accumulate throughout follow-up. REGISTRATION NUMBER: ISRCTN37381646 (http://www.controlled-trials.com).

The economic consequences of non-adherence to lipid-lowering therapy: results from the Anglo-Scandinavian-Cardiac Outcomes Trial.

BACKGROUND: Adherence to lipid-lowering therapy in clinical practice is less than ideal. Analysis of registry data has indicated that this is associated with poor outcomes. The objective of the present analysis was to assess the impact of high adherence to drug (defined as > 80% of days covered), compared with low adherence to drug (< 50% of days covered) in terms of risk of events and long-term economic consequences. DESIGN: Open-label follow up of a randomised placebo-controlled trial in hypertensive patients. METHODS: Cox proportional hazards and Poisson regression models were used to assess the hazard ratio of patients with high adherence compared with low adherence while controlling for cardiovascular risk. A Markov model was used to predict the long-term costs and health outcomes associated with poor adherence during the follow-up period. RESULTS: Both statistical models indicated that high adherence is associated with improved prognosis [Cox model: 0.75; 95% confidence interval (CI): 0.56-0.98, Poisson model hazard ratio: 0.73; 95% CI: 0.58-0.98]. Discounted at 3.5% per year, the Markov model predicts that as a consequence of higher adherence during the follow-up period, costs would be higher (1689 pounds per patient compared with 1323 pounds per patient) because of higher drug costs, but the projected survival and quality-adjusted survival (QALY) would also be longer (10.83 compared with 10.81 life years and 8.13 compared with 8.11 QALYs). CONCLUSION: Given the higher risk of cardiovascular events associated with low adherence shown here, measures to improve adherence are an important part of the prevention of cardiovascular disease.

Modelling the long-term cost-effectiveness of endovascular or open repair for abdominal aortic aneurysm.

BACKGROUND: Recent randomized trials have shown that endovascular abdominal aortic aneurysm repair (EVAR) has a 3 per cent aneurysm-related survival benefit in patients fit for open surgery, but it also has uncertain long-term outcomes and higher costs. This study assessed the cost-effectiveness of EVAR. METHODS: A decision model was constructed to estimate the lifetime costs and quality-adjusted life years (QALYs) with EVAR and open repair in men aged 74 years. The model includes the risks of death from aneurysm, other cardiovascular and non-cardiovascular causes, secondary reinterventions and non-fatal cardiovascular events. Data were taken largely from the EVAR trial 1 and supplemented from other sources. RESULTS: Under the base-case (primary) assumptions, EVAR cost 3800 pounds sterling (95 per cent confidence interval (c.i.) 2400 pounds sterling to 5200 pounds sterling) more per patient than open repair but produced fewer lifetime QALYs (mean -0.020 (95 per cent c.i. -0.189 to 0.165)). These results were sensitive to alternative model assumptions. CONCLUSION: EVAR is unlikely to be cost-effective on the basis of existing devices, costs and evidence, but there remains considerable uncertainty.

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

OBJECTIVES: To consider how the impact of the NHS Health Technology Assessment (HTA) Programme should be measured. To determine what models are available and their strengths and weaknesses. To assess the impact of the first 10 years of the NHS HTA programme from its inception in 1993 to June 2003 and to identify the factors associated with HTA research that are making an impact. DATA SOURCES: Main electronic databases from 1990 to June 2005. The documentation of the National Coordinating Centre for Health Technology Assessment (NCCHTA). Questionnaires to eligible researchers. Interviews with lead investigators. Case study documentation. REVIEW METHODS: A literature review of research programmes was carried out, the work of the NCCHTA was reviewed, lead researchers were surveyed and 16 detailed case studies were undertaken. Each case study was written up using the payback framework. A cross-case analysis informed the analysis of factors associated with achieving payback. Each case study was scored for impact before and after the interview to assess the gain in information due to the interview. The draft write-up of each study was checked with each respondent for accuracy and changed if necessary. RESULTS: The literature review identified a highly diverse literature but confirmed that the 'payback' framework pioneered by Buxton and Hanney was the most widely used and most appropriate model available. The review also confirmed that impact on knowledge generation was more easily quantified than that on policy, behaviour or especially health gain. The review of the included studies indicated a higher level of impact on policy than is often assumed to occur. The survey showed that data pertinent to payback exist and can be collected. The completed questionnaires showed that the HTA Programme had considerable impact in terms of publications, dissemination, policy and behaviour. It also showed, as expected, that different parts of the Programme had different impacts. The Technology Assessment Reports (TARs) for the National Institute for Health and Clinical Excellence (NICE) had the clearest impact on policy in the form of NICE guidance. Mean publications per project were 2.93 (1.98 excluding the monographs), above the level reported for other programmes. The case studies revealed the large diversity in the levels and forms of impacts and the ways in which they arise. All the NICE TARs and more than half of the other case studies had some impact on policy making at the national level whether through NICE, the National Screening Committee, the National Service Frameworks, professional bodies or the Department of Health. This underlines the importance of having a customer or 'receptor' body. A few case studies had very considerable impact in terms of knowledge production and in informing national and international policies. In some of these the principal investigator had prior expertise and/or a research record in the topic. The case studies confirmed the questionnaire responses but also showed how some projects led to further research. CONCLUSIONS: This study concluded that the HTA Programme has had considerable impact in terms of knowledge generation and perceived impact on policy and to some extent on practice. This high impact may have resulted partly from the HTA Programme's objectives, in that topics tend to be of relevance to the NHS and have policy customers. The required use of scientific methods, notably systematic reviews and trials, coupled with strict peer reviewing, may have helped projects publish in high-quality peer-reviewed journals. Further research should cover more detailed, comprehensive case studies, as well as enhancement of the 'payback framework'. A project that collated health research impact studies in an ongoing manner and analysed them in a consistent fashion would also be valuable.

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

OBJECTIVES: To assess the acceptability and feasibility of functional tests as a gateway to angiography for management of coronary artery disease (CAD), the ability of diagnostic strategies to identify patients who should undergo revascularisation, patient outcomes in each diagnostic strategy, and the most cost-effective diagnostic strategy for patients with suspected or known CAD. DESIGN: A rapid systematic review of economic evaluations of alternative diagnostic strategies for CAD was carried out. A pragmatic and generalisable randomised controlled trial was undertaken to assess the use of the functional cardiac tests: angiography (controls); single photon emission computed tomography (SPECT); magnetic resonance imaging (MRI); stress echocardiography. SETTING: The setting was Papworth Hospital NHS Foundation Trust, a tertiary cardiothoracic referral centre. PARTICIPANTS: Patients with suspected or known CAD and an exercise test result that required non-urgent angiography. INTERVENTIONS: Patients were randomised to one of the four initial diagnostic tests. MAIN OUTCOME MEASURES: Eighteen months post-randomisation: exercise time (modified Bruce protocol); cost-effectiveness compared with angiography (diagnosis, treatment and follow-up costs). The aim was to demonstrate equivalence in exercise time between those randomised to functional tests and those randomised to angiography [defined as the confidence interval (CI) for mean difference from angiography within 1 minute]. RESULTS: The 898 patients were randomised to angiography (n = 222), SPECT (n = 224), MRI (n = 226) or stress echo (n = 226). Initial diagnostic tests were completed successfully with unequivocal results for 98% of angiography, 94% of SPECT (p = 0.05), 78% of MRI (p < 0.001) and 90% of stress echocardiography patients (p < 0.001). Some 22% of SPECT patients, 20% of MRI patients and 25% of stress echo patients were not subsequently referred for an angiogram. Positive functional tests were confirmed by positive angiography in 83% of SPECT patients, 89% of MRI patients and 84% of stress echo patients. Negative functional tests were followed by positive angiograms in 31% of SPECT patients, 52% of MRI patients and 48% of stress echo patients tested. The proportions that had coronary artery bypass graft surgery were 10% (angiography), 11% (MRI) and 13% (SPECT and stress echo) and percutaneous coronary intervention 25% (angiography), 18% (SPECT) and 23% (MRI and stress echo). At 18 months, comparing SPECT and stress echo with angiography, a clinically significant difference in total exercise time can be ruled out. The MRI group had significantly shorter mean total exercise time of 35 seconds and the upper limit of the CI was 1.14 minutes less than in the angiography group, so a difference of at least 1 minute cannot be ruled out. At 6 months post-treatment, SPECT and angiography had equivalent mean exercise time. Compared with angiography, the MRI and stress echo groups had significantly shorter mean total exercise time of 37 and 38 seconds, respectively, and the upper limit of both CIs was 1.16 minutes, so a difference of at least 1 minute cannot be ruled out. The differences were mainly attributable to revascularised patients. There were significantly more non-fatal adverse events in the stress echo group, mostly admissions for chest pain, but no significant difference in the number of patients reporting events. Mean (95% CI) total additional costs over 18 months, compared with angiography, were 415 pounds (-310 pounds to 1084 pounds) for SPECT, 426 pounds (-247 pounds to 1088 pounds) for MRI and 821 pounds (10 pounds to 1715 pounds) for stress echocardiography, with very little difference in quality-adjusted life-years (QALYs) amongst the groups (less than 0.04 QALYs over 18 months). Cost-effectiveness was mainly influenced by test costs, clinicians' willingness to trust negative functional tests and by a small number of patients who had a particularly difficult clinical course. CONCLUSIONS: Between 20 and 25% of patients can avoid invasive testing using functional testing as a gateway to angiography, without substantial effects on outcomes. The SPECT strategy was as useful as angiography in identifying patients who should undergo revascularisation and the additional cost was not significant, in fact it would be reduced further by restricting the rest test to patients who have a positive stress test. MRI had the largest number of test failures and, in this study, had the least practical use in screening patients with suspected CAD, although it had similar outcomes to stress echo and is still an evolving technology. Stress echo patients had a 10% test failure rate, significantly shorter total exercise time and time to angina at 6 months post-treatment, and a greater number of adverse events, leading to significantly higher costs. Given the level of skill required for stress echo, it may be best to reserve this test for those who have a contraindication to SPECT and are unable or unwilling to have MRI. Further research, using blinded reassessment of functional test results and angiograms, is required to formally assess diagnostic accuracy. Longer-term cost-effectiveness analysis, and further studies of MRI and new generation computed tomography are also required.

How cost-effective is screening for abdominal aortic aneurysms?

OBJECTIVE: To provide reliable estimates of the long-term cost-effectiveness of abdominal aortic aneurysm screening in men. METHODS: A Markov health economic decision model for screening is described and extrapolated to 30 years. The strategy modelled involves a one-off scan at age 65 years, with annual and three-monthly follow-up scans for small and medium aneurysms, respectively. Referral for elective surgery occurs at an aortic diameter of 5.5 cm. Model parameters are estimated from patient-level data from the UK Multi-centre Aneurysm Screening Study. Model structure is validated on this trial's data, and input parameter uncertainty is addressed by probabilistic sensitivity analysis. Costs and life-years gained are obtained for both screening and no systematic screening strategies. RESULTS: Cost-effectiveness improves dramatically when considered over longer timescales. Taking a 30-year perspective, screening for abdominal aortic aneurysms in men is highly cost-effective at 2320 pounds per life-year gained (95% uncertainty interval: 1600 pounds to 4240 pounds). Adjusting life-years for the age-specific health-related quality of life experienced in this population gave a figure of 2970 pounds (95% uncertainty interval: 2030 pounds to 5430 pounds) per quality-adjusted life-year gained. The additional cost of screening the UK male population is estimated to be 19 m pounds per year. CONCLUSIONS: The long-term cost-effectiveness of screening for abdominal aortic aneurysms in men is highly attractive and this evidence provides further support for a national screening programme in the UK.

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.

OBJECTIVES: To update the systematic review evidence on the effectiveness, health-related quality of life (HRQoL) and cost-effectiveness of implantable cardioverter defibrillators (ICDs); compilation of new data on the service provision in the UK; and on the clinical characteristics, survival, quality of life and costs of ICD patients in the UK, and a new cost-effectiveness model using both international RCT and UK-specific data. DATA SOURCES: Electronic databases searched from November 1999 to March 2003, this was supplemented by a systematic review of research published during 2003-5. Survey data. REVIEW METHODS: Studies were selected and assessed. A survey of ICD centres was carried out. Basic data were obtained from two major implanting centres including 535 patients (approximately 10% of overall UK activity) implanted between 1991 and 2002, and retrieval of fuller data, on patient characteristics, management and resource use, from patient notes for a sample of 426 patients was attempted. A cross-sectional survey collected HRQoL data (using the Nottingham Health Profile, Short Form 36, Hospital Anxiety and Depression questionnaire, EuroQoL 5 Dimensions and disease-specific questions) on a sample of 229 patients. A Markov model combined UK patient data with data from published randomised controlled trials (RCTs) to estimate incremental costs per life-year or quality-adjusted life-year (QALY) gained. RESULTS: None of the economic analyses in the studies found could be directly applied to the UK. The multiple sources of routine data available (including the national ICD database) provide an imperfect picture of the need for and use of ICDs. Implantation rates have been rising to a rate of around 20 per million population. Mean age is increasing and most ICDs are implanted into men aged 45-74 years. There is significant geographical variation. A survey of 41 UK centres provided additional evidence, particularly of variation in level of activity and resourcing. Most detailed data were obtained for 380 patients (89%). The postal survey produced a 73% response rate. Demographic characteristics of these patients were similar to ICD recipients in the UK as a whole and patients included in secondary prevention RCTs. Mean actuarial survival at 1, 3 and 5 years was 92%, 86% and 71%, respectively. Patient age at implantation and functional status significantly affected survival. Levels of most of the HRQoL measures were lower than for a UK general population. There was no evidence of a change with time from implantation. Patients who had suffered ICD shocks had significantly poorer HRQoL. Most patients nevertheless expressed a high level of satisfaction with ICD therapy. Mean initial costs of implantation showed little variation between centres (23,300 pounds versus 22,100 pounds) or between earlier and more recent implants. There appeared to be greater variation between patients presenting along different pathways. Postdischarge costs (tests, medications and follow-up consultations) and costs of additional hospitalisations were also calculated. Using the Markov model it was found that over a 20-year horizon, mean discounted incremental costs were 70,900 pounds (35,000-142,400 pounds). Mean discounted gain was 1.24 years (0.29-2.32) or 0.93 QALYs. Cost-effectiveness was most favourable for men aged over 70 years with a left ventricular ejection fraction (LVEF) below 35%. If the treatment effect were to continue, then the cost per life-year over a lifetime might fall to around 32,000 pounds. Five RCTs of ICDs, a meta-analysis and, a cost-effectiveness analysis of ICDs used in primary prevention, and a meta-analysis of ICDs in patients with non-ischaemic cardiomyopathy have been published recently. These trials provide confirmation of survival benefit of ICDs used in primary prevention in both ischaemic and non-ischaemic cardiomyopathy patients. Costs per QALY ranged from US$34,000 in older trials to controls being both less expensive and more effective (CABG Patch, DINAMIT). More recent trials estimated cost per QALY between $50,300 and $70,200. The inconsistency in evidence for a HRQoL benefit has not been resolved and further work on risk stratification is necessary. CONCLUSIONS: The evidence of short- to medium-term patient benefit from ICDs is strong but cost-effectiveness modelling indicates that the extent of that benefit is probably not sufficient to make the technology cost-effective as used currently in the UK. One reason is the high rates of postimplantation hospitalisation. Better patient targeting and efforts to reduce the need for such hospitalisation may improve cost-effectiveness. Further cost-effectiveness modelling, underpinned by an improved ICD database with reliable long-term follow-up, is required. The absence of a robust measure of the incidence of sudden cardiac death is noted and this may be an area where further organisational changes with improved data collection would help.

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

OBJECTIVE: To determine the relative cost-effectiveness of three classes of antidepressants: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and the modified TCA lofepramine, as first choice treatments for depression in primary care. DESIGN: Open, pragmatic, controlled trial with three randomised arms and one preference arm. Patients were followed up for 12 months. SETTING: UK primary care: 73 practices in urban and rural areas in England. PARTICIPANTS: Patients with a new episode of depressive illness according to GP diagnosis. INTERVENTIONS: Patients were randomised to receive a TCA (amitriptyline, dothiepin or imipramine), an SSRI (fluoxetine, sertraline or paroxetine) or lofepramine. Patients or GPs were able to choose an alternative treatment if preferred. MAIN OUTCOME MEASURES: At baseline the Clinical Interview Schedule, Revised (CIS-R PROQSY computerised version) was administered to establish symptom profiles. Outcome measures over the 12-month follow-up included the Hospital Anxiety and Depression Scale self-rating of depression (HAD-D), CIS-R, EuroQol (EQ-5D) for quality of life, Short Form (SF-36) for generic health status, and patient and practice records of use of health and social services. The primary effectiveness outcome was the number of depression-free weeks (HAD-D less than 8, with interpolation of intervening values) and the primary cost outcome total direct NHS costs. Quality-adjusted life-years (QALYs) were used as the outcome measure in a secondary analysis. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were computed. Estimates were bootstrapped with 5000 replications. RESULTS: In total, 327 patients were randomised. Follow-up rates were 68% at 3 months and 52% at 1 year. Linear regression analysis revealed no significant differences between groups in number of depression-free weeks when adjusted for baseline HAD-D. A higher proportion of patients randomised to TCAs entered the preference arm than those allocated to the other choices. Switching to another class of antidepressant in the first few weeks of treatment occurred significantly more often in the lofepramine arm and less in the preference arm. There were no significant differences between arms in mean cost per depression-free week. For values placed on an additional QALY of over 5000 pounds, treatment with SSRIs was likely to be the most cost-effective strategy. TCAs were the least likely to be cost-effective as first choice of antidepressant for most values of a depression-free week or QALY respectively, but these differences were relatively modest. CONCLUSIONS: When comparing the different treatment options, no significant differences were found in outcomes or costs within the sample, but when outcomes and costs were analysed together, the resulting cost-effectiveness acceptability curves suggested that SSRIs were likely to be the most cost-effective option, although the probability of this did not rise above 0.6. Choosing lofepramine is likely to lead to a greater proportion of patients switching treatment in the first few weeks. Further research is still needed on the management of depressive illness in primary care. This should address areas such as the optimum severity threshold at which medication should be used; the feasibility and effectiveness of adopting structured depression management programmes in the UK context; the importance of factors such as physical co-morbidity and recent life events in GPs' prescribing decisions; alternative ways of collecting data; and the factors that give rise to many patients being reluctant to accept medication and discontinue treatment early.

"Flooding in vivo" during the circadian phase of minimal cortisol secretion: anxiety and therapeutic success without adrenal cortical activation.

Seven patients with maximally severe phobias for physical objects were treated by "flooding in vivo", i.e. live confrontation with the feared object. Each reported to the laboratory for 3 hr on five separate occasions, all in the early evening during the circadian phase of minimal adrenal cortical activity. At 20-min intervals during each session, blood was taken for cortisol assay, and anxiety was self-rated on a scale of 0 to 100. Treatment was carried out during the 2nd hr of the third and fourth sessions. The remaining time provided control observations. By behavioral and subjective criteria, the treatment hours produced very intense anxiety. However, they failed to evaluate plasma cortisol levels. The remission of the phobias was 100%. Anxiety, even when intense and dramatic, does not necessarily activate the adrenal cortex, and an adrenal "stress" response is not necessary for the therapeutic effect.

National Wilms' Tumor Study: economic perspective.

The National Wilms' Tumor Study poses a question of an essentially economic nature: Can the socioeconomic impact of therapy for Wilms' tumor on the patient's family and society be lessened without compromising the efficacy of therapy? But the only proposed measure of socioeconomic impact appears to be the extent of hospitalization. From an economic perspective, more information is ideally needed from the trial to establish the magnitude of any difference in effectiveness and the magnitude of the difference in costs, so that any trade-off between the two can be assessed. In practice, the extent of the economic data needed at the end of the study will depend on the clinical outcome results and, hence, the nature of the trade-off that will have to be made. If the less extensive treatment is found to be ineffective, economic issues will not come into play. Similarly, if the less extensive treatment is clearly superior in every clinical aspect, the argument for it will probably be persuasive. The interesting situation of a trade-off arises if the less extensive treatment offers clear socioeconomic advantages but has some small clinical disadvantage. In that case, the extent and nature of an array of socioeconomic factors will need to have been measured, not just presumed. There are, of course, many problems associated with collecting and analyzing more comprehensive socioeconomic data in a long trial. This article considers a number of these problems and focuses on six important issues in designing the necessary economic components of future trials.

Plasma growth hormone: effect of anxiety during flooding in vivo.

The treatment of phobias by rapid in vivo exposure to the feared situation was accompanied by an increase in plasma growth hormone levels on at least one of two occasions in 8 of 11 subjects. The average growth hormone response was greater on the second occasion, even though subjective anxiety was less. Plasma growth hormone was not elevated during the subjects' adaptation to the laboratory. Strong subjective and behavioral anxiety responses failed to elevate plasma growth hormone levels in some subjects. The probability of a growth hormone response was the same whether or not baseline levels were elevated prior to exposure.

A model for analyzing the cost of main clinical events after cardiac transplantation.

Using information from the Papworth Hospital heart transplant service, a model was developed to link the main clinical events after cardiac transplantation to survival and costs. On the basis of the clinical and survival experience of 387 patients treated with triple-drug immunosuppression between 1986 and 1993, together with protocols for patient management, resource use, and costs, a 5-year Markov model with three time periods was used to simulate survival and estimate costs. The model accurately mirrors observed actuarial survival; 1- and 5-year survival rates were 81% and 65%, respectively. An average cost per patient of 26,000 pounds over 5 years (discounted at a rate of 6%) was estimated. The expense of routine care for patients accounts for the majority of the costs; a patient who remains well throughout the 5-year period would incur costs of 23,000 pounds. The sensitivity of the estimates to alternative assumptions is presented, and the way in which the model can be used to compare alternative future scenarios is explored.

An economic evaluation of transdermal glyceryl trinitrate in the prevention of intravenous infusion failure.

A common cause of peripheral intravenous infusion failure is due to the patient developing phlebitis or extravasation. Recent clinical trials indicate that the use of transdermal glyceryl trinitrate (GTN patches) can reduce the incidence of infusion failure and hence the costs of re-infusion. In this study we conduct an economic evaluation of this new pharmaceutical application to determine whether the use of such patches results in hospital resource cost savings. Time-to-first infusion failure probabilities from a placebo-controlled trial are used to model the sequential failure problem as a Markov process. Using estimated staff and materials costs for first and subsequent infusions, we calculate the expected cost per infused patient to time t for treatment and control groups. Using this simple comparative cost method, results indicate that the net impact on hospital resources from patch usage is dependent upon the total required length of infusion time. Analysis of infusion time thresholds indicates that for patients requiring long-term (t greater than 50 hours) periods of infusion the use of patches is likely to generate resource savings. We conclude that to realize such resource savings clinical decisions to infuse with GTN patches should incorporate the prior probability that the total required length of infusion time exceeds 50 hours.

A model for analyzing the cost of the main clinical events after lung transplantation.

BACKGROUND: The aim of this project was to model clinically important events experienced by lung transplant patients (from the day after transplant to 5 years or death) and costs associated with these events, and to assess the economic impact of different immunosuppression therapies. METHODS: The population comprised 356 lung transplant patients (223 heart-lung, 102 single lung and 31 double lung) transplanted between April 1984 and December 1997. All patients received a cyclosporine-based triple-immunosuppression protocol. We designed a Markov model that included 3 time periods (0 to 6, 7 to 12, and 13 to 60 months), 5 clinical states (well, acute rejection, cytomegalovirus infection, non-cytomegalovirus infection and bronchiolitis obliterans syndrome), and death. For the well state, cost elements were immunosuppression, prophylaxis, and routine clinic visits. For all other states, cost elements were diagnosis, treatment, and bed days/visits. We excluded costs of the procedure. RESULTS: The monthly costs associated with the well state decreased over time, from pound sterlings 1,778 ($2,658) in the first 6 months to pound sterlings 503 ($752) in months 7 to 12 and pound sterlings 350 ($523) after the first 12 months. The cost per event of the acute states remained reasonably constant over the 3 periods: pound sterlings 1,850 ($2,766) for rejection, pound sterlings 3,380 ($5,053) for cytomegalovirus, and pound sterlings 2,790 ($4,171) for other infections. The average cost per patient, discounted at 6%, over 5 years was pound sterlings 35,429 ($52,966) (95% range, pound1,435 [$2,145] to pound67,079 [$100,283]). This estimate is most sensitive to changes in immunosuppression. Substituting tacrolimus for cyclosporine increased 5-year costs by 5%; substituting mycophenolate mofetil for azathioprine increased 5-year costs by 26%. CONCLUSIONS: This model is valuable in estimating the effect of new immunosuppression agents on the costs of follow-up care.

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

OBJECTIVES: To develop a method of economic evaluation and triage for research prioritisation, before the funding decision. DATA SOURCES: Existing models were researched focusing on MEDLINE, HealthSTAR, IBSS and HEED. REVIEW METHODS: Papers of primary relevance that included a proposed model were reviewed in detail, and their models appraised using criteria adapted from the EUR-ASSESS project and the authors' previous experience. From this the PATHS model was developed. It assumes three or more possible alternative outcomes or scenarios in terms of research results: 'favourable' to the technology being assessed, 'unfavourable' or 'inconclusive'. An associated flow of benefits or disbenefits, costs or savings is identified for each potential research outcome depending on the likely implementation of the results as judged by experts. These benefits and costs are weighted and discounted in the model to give an expected incremental cost-effectiveness ratio (EICER). EICERS could be estimated for any number of research areas or proposals to inform funding prioritisation. The model was tested and evaluated on three case studies identified in liaison with the NHS R&D HTA programme and the UK Medical Research Council. These case studies were funded research projects, where full evaluation was underway and where results would be reported during the PATHS project. The studies were selected to include surgery or other invasive procedures, and non-invasive health services projects (a fourth case study did not complete during the course of the study). The three case studies included randomised controlled trials of early surgery or observation for small abdominal aortic aneurysms, infusion protocols for adult pre-hospital care, and postnatal midwifery support. RESULTS: Each of the three assessments indicated net clinical benefit or no clinical loss of benefit, in addition to health service cost savings in excess of the cost of the trial. For two case studies, the value of the proposed trial, as evaluated by the model in the prediction, was consistent with the ex post evaluation, thus providing positive tests of the value of the model. In the third case meaningful ex post analysis was not possible as very poor compliance with the trial protocol (indicated in the ex ante evaluation) seriously undermined its conclusions. During the study, at the request of the UK HTA programme, the model was also applied to a funding request for a large randomised trial of beta-interferon for multiple sclerosis treatment. CONCLUSION: The PATHS model has a useful part to play in the research prioritisation process. Its strengths lie in its emphasis on the impact of research results on policy and practice (the keystone for NHS research) and net effects on health benefits and costs. It assesses the cost-effectiveness of the research and may identify ways to enhance the research design, endpoints relevant to implementation, analytical methods and dissemination. Further research is recommended to investigate the scope for synthesising the strengths of the PATHS model with other approaches including value of information; to compare ex ante and immediate ex post assessments of implementation with long term follow-up of actual implementation; and to assess the robustness of such approaches to the choice and number of experts used.

Will a breast screening programme change the workload and referral practice of general practitioners?

STUDY OBJECTIVE: The aim of the study was to consider possible changes in the clinical activities of general practitioners whose patients are registered in a breast cancer screening programme. DESIGN: The study was a survey based on completion of forms recording breast consultations carried out by participating general practitioners during a four week period. SETTING: One of three intervention centres and one of three comparison centres in the national trial of early detection of breast cancer was selected. The intervention centre was in Guildford; the comparison centre in Stoke on Trent. PARTICIPANTS: The participants were general practitioners in the selected centres. In Guildford, 64 of 99 general practitioners approached took part (65%); in Stoke on Trent, 81 of 177 took part (46%). The proportion of male and female participants in the two centres was similar. Doctors in Stoke on Trent were older and worked in smaller practices than in Guildford. RESULTS: A comparison of workloads showed that in the screening centre there was less demand for doctor consultations from those in the screened age group, but those excluded from screening made more use of the general practitioners' services. A difference in referral practice was also apparent, with doctors in the screening centre referring more frequently for specialist advice. CONCLUSIONS: The evidence suggests that no significant change in the overall use of general practice resources can be expected with the introduction of national screening, but there may be greater pressure on assessment services.

Economic evaluation studies in respiratory medicine.

The need for efficient use of resources in the provision of health care is now an accepted reality. Despite its economic significance, respiratory disease has been the subject of very few examples of the application of techniques of economic evaluation. There are a number of examples of cost-minimization studies, and these serve to emphasize that choices based on drug acquisition costs may be quite different from those based on the total costs of care. The difficulty of defining uni-dimensional measures of health outcome for respiratory disease has hampered the development of cost-effectiveness studies, and the future of these must lie with the efforts to develop measures of quality of life more appropriate to this area of medicine. But the multi-dimensional nature of relevant health outcomes suggests that cost-utility approaches are likely to play an important future role, as off attempts to directly establish patients' monetary valuations of the health benefits offered by new respiratory medicines.