Psychological interventions improve quality of life despite persistent pain in endometriosis: results of a 3-armed randomized controlled trial.

PURPOSE: Despite standard medical treatment endometriosis is often associated with disabling pain and poor quality of life (QoL). Studies indicate that psychological interventions (PIs) may improve pain and QoL, yet studies on the effects of PIs for women with endometriosis are sparse and limited by low-quality study designs. Therefore, this study aimed, in a rigorous three-armed design, to evaluate the effect of PIs on chronic pelvic pain (CPP) and QoL in women with endometriosis. METHODS: This three-armed parallel, multi-center randomized controlled trial included fifty-eight endometriosis patients reporting severe CPP [≥ 5 for pain intensity measured on a 0-10-point numeric rating scale (NRS)]. Patients were randomly assigned to (1) Specific mindfulness- and acceptance-based psychological intervention (MY-ENDO), (2) Carefully matched non-specific psychological intervention (Non-specific), or (3) A wait-list control group (WL). The primary outcome was pelvic pain intensity/unpleasantness measured on NRS. Secondary outcomes included endometriosis-related quality of life, workability, pain acceptance, and endometriosis-related symptoms. Differences in outcomes between groups at post-treatment follow-up were analyzed using mixed linear models. Analyses were performed on an intention-to-treat basis. RESULTS: Compared to WL, psychological intervention (MY-ENDO + Non-specific) did not significantly reduce pain. However, psychological intervention did significantly improve the QoL-subscales 'control and powerlessness', 'emotional well-being', and 'social support' as well as the endometriosis-related symptoms 'dyschezia' and 'constipation'. MY-ENDO was not superior to Non-specific. CONCLUSIONS: Women with endometriosis may have significant and large effects of psychological intervention on QoL despite an ongoing experience of severe CPP. TRIAL REGISTRATION: 12 April 2016, clinicaltrials.gov (NCT02761382), retrospectively registered.

Bowel Endometriosis Syndrome: a new scoring system for pelvic organ dysfunction and quality of life.

STUDY QUESTION: Is it possible to develop a validated score that can identify women with Bowel Endometriosis Syndrome (BENS) and be used to monitor the effect of medical and surgical treatment? SUMMARY ANSWER: The BENS score can be used to identify women with BENS and to monitor the effect of medical and surgical treatment of women suffering from bowel endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is a heterogeneous disease with extensive variation in anatomical and clinical presentation, and symptoms do not always correspond to the disease burden. Current endometriosis scoring systems are mainly based on anatomical and surgical findings. STUDY DESIGN, SIZE, DURATION: The score was developed and validated from a cohort of 525 women with medically or surgically treated bowel endometriosis from Aarhus and Copenhagen University Hospitals, Denmark. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Patients filled in questionnaires on pelvic pain, quality of life (QoL) and urinary, sexual and bowel function. Items were selected for the final score using clinical and statistical criteria. The chosen variables were included in a multivariate analysis. Individual score values were designated items to form the BENS score, which was divided into 'no BENS', 'minor BENS' and 'major BENS.' Internal and external validations were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The six most important items were 'pelvic pain', 'use of analgesics', 'dyschezia', 'straining to urinate', 'fecal urgency' and 'satisfaction with sexual life'. The range of the BENS score (0-28) was divided into 0-8 (no BENS), 9-16 (minor BENS) and 17-28 (major BENS). External validation showed a significant association between BENS score and QoL (P = 0.0001). LIMITATIONS, REASONS FOR CAUTION: The BENS scoring system is limited by the fact that it was developed from a single endometriosis unit in Denmark, making it susceptible to social, cultural and demographic bias. WIDER IMPLICATIONS OF THE FINDINGS: It is the first endometriosis classification system to be based directly on the symptomatology of the patient. Validation in other languages will promote comparison of treatments and results across borders. STUDY FUNDING/COMPETING INTEREST(S): No external funding was either sought or obtained for this study. A.F. is an investigator for Bayer, outside this work.

Low-cost high-fidelity anaesthetic simulation.

Simulation has been advocated as a useful training tool, and specific manikin simulators have been developed for use in this role. Debriefing and repetition have been identified as key to achieving educational goals and, while the technical features of manikin simulators can influence simulation outcomes, their cost and infrastructure requirements reduce their suitability for smaller healthcare facilities. We describe a local solution using biomedical calibration machines and modified basic manikins already available in our institution to form a high-fidelity anaesthetic simulator at minimal cost. This was effective in running high-fidelity, team-based in situ simulations and 'can't intubate, can't oxygenate' assessments for anaesthetic trainees. Though equipment in other centres may differ both in availability or suitability for simulation, the option we describe or similar may offer a low-cost solution for peripheral centres to run limited high-fidelity scenarios on a regular basis.

Using process data to understand outcomes in sexual health promotion: an example from a review of school-based programmes to prevent sexually transmitted infections.

This article discusses how process indicators can complement outcomes as part of a comprehensive explanatory evaluation framework, using the example of skills-based behavioural interventions to prevent sexually transmitted infections and promote sexual health among young people in schools. A systematic review was conducted, yielding 12 eligible outcome evaluations, 9 of which included a process evaluation. There were few statistically significant effects in terms of changes in sexual behaviour outcomes, but statistically significant effects were more common for knowledge and self-efficacy. Synthesis of the findings of the process evaluations identified a range of factors that might explain outcomes, and these were organized into two overarching categories: the implementation of interventions, and student engagement and intervention acceptability. Factors which supported implementation and engagement and acceptability included good quality teacher training, involvement and motivation of key school stakeholders and relevance and appeal to young people. Factors which had a negative impact included teachers' failure to comprehend the theoretical basis for behaviour change, school logistical problems and omission of topics that young people considered important. It is recommended that process indicators such as these be assessed in future evaluations of school-based sexual health behavioural interventions, as part of a logic model.

Reproductive prognosis in daughters of women with and without endometriosis.

STUDY QUESTION: Do daughters of women with endometriosis exhibit an increased risk of endometriosis and impaired long-term reproductive prognosis when compared with daughters of women without endometriosis? SUMMARY ANSWER: Daughters of women with endometriosis have over a 2-fold higher risk of endometriosis but no difference in long-term reproductive prognosis compared with controls. WHAT IS KNOWN ALREADY: Several studies have found an increased prevalence of endometriosis in sisters and mothers of women with endometriosis, but none have examined the long-term reproductive prognosis in daughters of these patients. STUDY DESIGN, SIZE, DURATION: A controlled historical cohort study with a 33-year follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among women 15-49 years old during the period 1977-1982, 24 691 were diagnosed with endometriosis during the study period. These women were age matched to 98 764 women without endometriosis. Daughters of these two groups were followed until 31 December 2009 for an endometriosis diagnosis and reproductive outcomes. Women were excluded from the study at death or if they emigrated. MAIN RESULTS AND THE ROLE OF CHANCE: Except for 4-6% of emigrated women, the follow-up rate of the study was almost 100%. Daughters of women with endometriosis (n = 12 389) had a 2.12-fold (95% confidence interval 1.89-2.37, P < 0.0001) increased risk of being diagnosed with endometriosis, compared with daughters of women without endometriosis (n = 52 371). Delivery rate, risk of spontaneous abortions and ectopic pregnancies were similar for the two cohorts, whereas induced abortions were slightly more frequent in the exposed cohort. LIMITATIONS, REASONS FOR CAUTION: The most important limitation of the study was the lack of data concerning the attempt to become pregnant. Also, some women with endometriosis might never be diagnosed with the condition. This applies to both the control mothers and the control daughters, but also the daughters of mothers with endometriosis. Other limitations are lack of accounting for potential confounders and the lack of data on preterm birth. However, the influence of most confounding factors was expected to be minimal because of the close matching by age of controls. WIDER IMPLICATIONS OF THE FINDINGS: The external validity of the study is expected to be high owing to the unselected inclusion criteria. The encouraging finding was that despite the increased risk of being diagnosed with endometriosis, daughters of women with endometriosis have a reproductive prognosis comparable with that of daughters of women without endometriosis. STUDY FUNDING/COMPETING INTEREST(S): The Department of Gynaecology at Rigshospitalet University Hospital, Copenhagen, covered all expenses of the study. Ø.L. has, within the last 3 years, received honoraria for speeches in pharmacoepidemiological issues and has been expert witness in a legal US case in 2011-2012. None of the other authors have any conflicts of interest.

The effectiveness of interventions to treat severe acute malnutrition in young children: a systematic review.

BACKGROUND: Severe acute malnutrition (SAM) arises as a consequence of a sudden period of food shortage and is associated with loss of a person's body fat and wasting of their skeletal muscle. Many of those affected are already undernourished and are often susceptible to disease. Infants and young children are the most vulnerable as they require extra nutrition for growth and development, have comparatively limited energy reserves and depend on others. Undernutrition can have drastic and wide-ranging consequences for the child's development and survival in the short and long term. Despite efforts made to treat SAM through different interventions and programmes, it continues to cause unacceptably high levels of mortality and morbidity. Uncertainty remains as to the most effective methods to treat severe acute malnutrition in young children. OBJECTIVES: To evaluate the effectiveness of interventions to treat infants and children aged < 5 years who have SAM. DATA SOURCES: Eight databases (MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, CAB Abstracts Ovid, Bioline, Centre for Reviews and Dissemination, EconLit EBSCO and The Cochrane Library) were searched to 2010. Bibliographies of included articles and grey literature sources were also searched. The project expert advisory group was asked to identify additional published and unpublished references. REVIEW METHODS: Prior to the systematic review, a Delphi process involving international experts prioritised the research questions. Searches were conducted and two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full texts of retrieved papers by one reviewer and checked independently by a second. Included studies were mapped to the research questions. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Differences in opinion were resolved through discussion at each stage. Studies were synthesised through a narrative review with tabulation of the results. RESULTS: A total of 8954 records were screened, 224 full-text articles were retrieved, and 74 articles (describing 68 studies) met the inclusion criteria and were mapped. No evidence focused on treatment of children with SAM who were human immunodeficiency virus sero-positive, and no good-quality or adequately reported studies assessed treatments for SAM among infants < 6 months old. One randomised controlled trial investigated fluid resuscitation solutions for shock, with none adequately treating shock. Children with acute diarrhoea benefited from the use of hypo-osmolar oral rehydration solution (H-ORS) compared with the standard World Health Organization-oral rehydration solution (WHO-ORS). WHO-ORS was not significantly different from rehydration solution for malnutrition (ReSoMal), but the safety of ReSoMal was uncertain. A rice-based ORS was more beneficial than glucose-based ORSs, and provision of zinc plus a WHO-ORS had a favourable impact on diarrhoea and need for ORS. Comparisons of different diets in children with persistent diarrhoea produced conflicting findings. For treating infection, comparison of amoxicillin with ceftriaxone during inpatient therapy, and routine provision of antibiotics for 7 days versus no antibiotics during outpatient therapy of uncomplicated SAM, found that neither had a significant effect on recovery at the end of follow-up. No evidence mapped to the next three questions on factors that affect sustainability of programmes, long-term survival and readmission rates, the clinical effectiveness of management strategies for treating children with comorbidities such as tuberculosis and Helicobacter pylori infection and the factors that limit the full implementation of treatment programmes. Comparison of treatment for SAM in different settings showed that children receiving inpatient care appear to do as well as those in ambulatory or home settings on anthropometric measures and response time to treatment. Longer-term follow-up showed limited differences between the different settings. The majority of evidence on methods for correcting micronutrient deficiencies considered zinc supplements; however, trials were heterogeneous and a firm conclusion about zinc was not reached. There was limited evidence on either supplementary potassium or nicotinic acid (each produced some benefits), and nucleotides (not associated with benefits). Evidence was identified for four of the five remaining questions, but not assessed because of resource limitation. LIMITATIONS: The systematic review focused on key questions prioritised through a Delphi study and, as a consequence, did not encompass all elements in the management of SAM. In focusing on evidence from controlled studies with the most rigorous designs that were published in the English language, the systematic review may have excluded other forms of evidence. The systematic review identified several limitations in the evidence base for assessing the effectiveness of interventions for treating young children with severe acute malnutrition, including a lack of studies assessing the different interventions; limited details of study methods used; short follow-up post intervention or discharge; and heterogeneity in participants, interventions, settings, and outcome measures affecting generalisability. CONCLUSIONS: For many of the most highly ranked questions evidence was lacking or inconclusive. More research is needed on a range of topic areas concerning the treatment of infants and children with SAM. Further research is required on most aspects of the management of SAM in children < 5 years, including intravenous resuscitation regimens for shock, management of subgroups (e.g. infants < 6 months old, infants and children with SAM who are human immunodeficiency virus sero-positive) and on the use of antibiotics.

Peginterferon alfa and ribavirin for chronic hepatitis C in patients eligible for shortened treatment, re-treatment or in HCV/HIV co-infection: a systematic review and economic evaluation.

OBJECTIVE: to assess the clinical effectiveness and cost-effectiveness of peginterferon alfa and ribavirin for the treatment of chronic hepatitis c virus (HCV) in three specific patient subgroups affected by recent licence changes: those eligible for shortened treatment courses [i.e. those with low viral load (LVL) and who attained a rapid virological response (RVR) at 4 weeks of treatment], those eligible for re-treatment following previous non-response or relapse, and those co-infected with human immunodeficiency virus (HIV). DATA SOURCES: Fourteen electronic bibliographic databases, including the Cochrane Library, MEDLINE and EMBASE, were searched up to October 2009. Key hepatitis C resources and symposia, bibliographies of related papers and manufacturer submissions to the National Institute for Health and Clinical Excellence were also searched and clinical experts were contacted. REVIEW METHODS: A systematic review and economic evaluation were carried out. Titles and abstracts were screened for eligibility by one reviewer. Inclusion criteria were defined a priori and applied independently by two reviewers to the full text of retrieved references. For the clinical effectiveness review, studies were included if they were randomised controlled trials (RCTs) of adults with chronic HCV, restricted to the patient groups described above. The intervention was standard peginterferon and ribavirin combination therapy compared with shortened duration courses (24 weeks for genotype 1, 16 weeks for genotype 2/3) or best supportive care (BSC). Outcomes included sustained virological response (SVR), relapse rate and adverse events. In addition, full economic evaluations and studies of health-related quality of life were sought for this subgroup of patients. Data extraction and quality assessment were undertaken by two reviewers independently. Studies were synthesised through a narrative review with tabulation of results. Our previously published Markov state-transition model was adapted to estimate the cost-effectiveness of treatment strategies in subgroups of adults with chronic HCV who were eligible for shortened treatment and re-treatment and those with HCV/HIV co-infection. The model extrapolated the impact of SVR on life expectancy, quality-adjusted life expectancy and lifetime costs for each subgroup of patients with HCV. Categories of costs included in the model were drug acquisition, patient management, on-treatment monitoring, management of adverse events, and health-state costs for disease progression. RESULTS: In total, 2400 references were identified. Six RCTs were included in the review of clinical effectiveness, all reporting peginterferon alfa and ribavirin therapy in patients eligible for shortened treatment. In general, these RCTs were of good quality. No RCTs comparing peginterferon and ribavirin with BSC were identified for the re-treatment or co-infection populations. The results suggest that chronic HCV patients who have LVL at baseline and who achieve an RVR can be treated with shortened courses of therapy (24 weeks for genotype 1, 16 weeks for genotype 2/3) and achieve SVR rates that are comparable to those who receive the standard duration of treatment (ranges 84%-96% vs 83%-100%, respectively). However, patient numbers in the LVL/RVR subgroups were small and none of the trials was powered for this subgroup analysis, so results should be interpreted with caution. In the one trial reporting virological relapse rates in the subgroup of patients with LVL/RVR, rates were low and not statistically significantly different between those treated for 24 versus 48 weeks [3.6% vs 0%, respectively, difference 3.6%, 95% confidence interval (CI) -7.2% to 6.6%, p = 1.000]. In the cost-effectiveness analysis of shortened treatment with peginterferon alfa-2a, incremental cost-effectiveness ratios (ICERs) ranged from £35,000 to £65,000 for patients with genotype 1, whereas in patients with genotypes 2 and 3 shortened treatment dominated standard treatment. For patients with genotype 1 with LVL/RVR, shortened treatment with peginterferon alfa-2b dominated standard treatment. In patients with genotype 1 and those with genotype non-1 who were re-treated with peginterferon alfa-2a, the ICERs were £9169 and £2294, respectively. In patients with genotypes 1 and 4, who were re-treated with peginterferon alfa-2b, the ICER was £7681, whereas re-treatment dominated BSC for patients with genotypes 2 and 3. In patients co-infected with HCV/HIV, who were receiving peginterferon alfa-2a, the ICER was £7941 per quality-adjusted life-year (QALY) gained in patients with genotypes 1 and 4, whereas in patients with genotypes 2 and 3 peginterferon alfa-2a dominated BSC. In co-infected patients receiving peginterferon alfa-2b the ICER was £11,806 in genotypes 1 and 4, and £2161 in genotypes 2 and 3. CONCLUSIONS: The clinical trial evidence indicates that patients may be successfully treated with a shorter course of peginterferon combination therapy without compromising the likelihood of achieving an SVR. The economic evaluation shows that treatment with peginterferon alfa in the specified subgroups of patients with LVL/RVR will yield QALY gains, without excessive increases in costs, and may be cost saving in some situations. However, a judgement is required on the value of the QALY loss that may result from adopting a shorter treatment regimen, if shorter treatment is associated with a lower SVR than standard treatment duration. There is a need for further RCT evidence, particularly in people who have not responded to, or relapsed following, treatment. Phase II and Phase III trials are currently in progress, evaluating the safety and efficacy of protease inhibitors and nucleoside analogues for treatment-naive and treatment-experienced people with chronic HCV. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of topotecan as second-line treatment for small cell lung cancer (SCLC). DATA SOURCES: Bibliographic databases were searched from 1990 to February 2009, including the Cochrane library, MEDLINE (Ovid), EMBASE (Ovid), PREMEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were assessed and experts were contacted to identify additional references and the manufacturer's submission to NICE was also searched. REVIEW METHODS: Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text of retrieved papers using a standard form. For the clinical effectiveness review, the studies were randomised controlled trials (RCTs), which included adult participants with relapsed SCLC who responded to first-line treatment and for whom re-treatment with first-line therapy was inappropriate. The treatment was topotecan (oral or intravenous, i.v.) compared with one another, best supportive care (BSC) or other chemotherapy regimens. Outcomes included measures of response or disease progression and measures of survival. For the cost-effectiveness review studies were eligible for inclusion if they reported cost-effectiveness, cost-utility, cost-benefit or cost-consequence analyses. Data extraction and quality assessment of included studies was undertaken by one reviewer and checked by a second. Studies were synthesised through a narrative review with full tabulation of results. An independent economic model estimated the cost-effectiveness of topotecan (oral or i.v.) compared with BSC. The model used survival analysis methods to derive estimates of mean survival for patients treated with topotecan or receiving BSC alone. These were combined with quality of life (QoL) weights to derive estimates of mean quality-adjusted life expectancy for patients receiving BSC alone or topotecan plus BSC. Categories of costs included in the model included drug use, chemotherapy administration and on-treatment monitoring, management of adverse events, monitoring for disease progression and palliative care. RESULTS: A total of 434 references were identified of which five were included in the clinical effectiveness review. In these trials topotecan was compared with BSC, CAV [cyclophosphamide, Adriamycin (doxorubicin) and vincristine] or amrubicin, or oral topotecan was compared with i.v. topotecan. No economic evaluations were identified. There were no statistically significant differences between groups when i.v. topotecan was compared with either CAV or oral topotecan for overall response rate (ORR). Response rate was significantly better in participants receiving i.v. amrubicin than in those receiving a low dose of i.v. topotecan (38% versus 13%, respectively, p = 0.039). There was a statistically significant benefit in favour of oral topotecan compared with BSC (HR 0.61, 95% CI 0.43 to 0.87, p = 0.01). Drug acquisition costs for four cycles of treatment were estimated at 2550 pounds for oral topotecan and 5979 pounds for i.v. topotecan. Non-drug treatment costs accounted for an additional 1097 pounds for oral topotecan and 4289 pounds for i.v. topotecan. Total costs for the modelled time horizon of 5 years were 4854 pounds for BSC, 11,048 pounds for oral topotecan and between 16,914 pounds and 17,369 pounds for i.v. topotecan (depending on assumptions regarding time progression). Life expectancy was 0.4735, 0.7984 and 0.7784 years for BSC, oral topotecan and i.v. topotecan respectively. Total quality-adjusted life-years (QALYs) were 0.2247 and 0.4077, for BSC and oral topotecan respectively, resulting in an incremental cost-effectiveness ratio (ICER) of 33,851 pounds per QALY gained. Total QALYs for i.v. topotecan were between 0.3875 and 0.4157 (depending on assumptions regarding time progression) resulting in an ICER between 74,074 pounds and 65,507 pounds per QALY gained. CONCLUSIONS: Topotecan appeared to be better than BSC alone in terms of improved survival, and was as effective as CAV and less favourable than i.v. amrubicin in terms of response. Oral topotecan and i.v. topotecan were similar in efficacy. Topotecan offers additional benefit over BSC, but at increased cost. ICERs for i.v. topotecan, compared with BSC, were high and suggest that it is unlikely to be a cost-effective option. The ICER for oral topotecan is at the upper extreme of the range conventionally regarded as cost-effective from an NHS decision-making perspective. Further research into the QoL of patients with relapsed SCLC could identify the impacts of disease progression and treatment response.

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

OBJECTIVES: To assess the effectiveness and cost-effectiveness of schools-based skills-building behavioural interventions to encourage young people to adopt and maintain safer sexual behaviour and to prevent them from acquiring sexually transmitted infections (STIs). DATA SOURCES: Electronic bibliographic databases (e.g. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, PsycINFO, CCRCT, NHS EED and DARE) were searched for the period 1985 to March 2008. Bibliographies of systematic reviews and related papers were screened and experts contacted to identify additional published and unpublished references. REVIEW METHODS: A systematic review of effectiveness and economic evaluation of cost-effectiveness were carried out. A descriptive map of studies that met inclusion criteria was produced, and keywords were developed and systematically applied to these studies to identify a policy-relevant subset of studies for the systematic review. Outcome data for variables including sexual behaviour were extracted. An economic model was developed to compare the costs and consequences of the behavioural interventions. A Bernoulli statistical model was constructed to describe the probability of STI infection. RESULTS: There were few significant differences between the interventions and comparators in terms of changes in sexual behaviour outcomes, although there were some significant differences for knowledge and some measures of self-efficacy. The studies included in this review conducted relatively short follow-up assessments at a time when many young people were becoming sexually active. It is therefore possible that favourable behaviour change may have occurred, and become more cost-effective, with time, as sexual activity becomes more routine in young people's lives. The quality of the intervention provider influenced whether or not young people found the interventions to be acceptable and engaging; enthusiasm and considerable expertise were important for effective class management and delivery of skills-building activities, and a supportive school culture was also helpful. Recognition of young people's individual needs in relation to sexual health was another important factor. No conclusions could be drawn on the impact of the interventions on sexual health inequalities due to a lack of relevant data on socioeconomic status, gender and ethnicity. The results of the economic evaluation were considered to be illustrative, mainly due to the uncertainty of the effect of intervention on behavioural outcomes. The results were most sensitive to changes in parameter values for the intervention effect, the transmission probability of STIs and the number of sexual partners. The costs of teacher-led and peer-led behavioural interventions, based on the resources estimated from the relevant randomised controlled trials in our systematic review, were 4.30 pounds and 15 pounds per pupil, respectively. Teacher-led interventions were more cost-effective than peer-led interventions due to the less frequent need for training. The incremental cost-effectiveness of the teacher-led and peer-led interventions was 20,223 pounds and 80,782 pounds per quality-adjusted life-year gained, respectively. An analysis of individual parameters revealed that future research funding should focus on assessing the intervention effect for condom use from a school-based intervention. CONCLUSIONS: School-based behavioural interventions for the prevention of STIs in young people can bring about improvements in knowledge and increased self-efficacy, but the interventions did not significantly influence sexual risk-taking behaviour or infection rates. Future investigation should include long-term follow-up to assess the extent to which safer sexual behaviour is adopted and maintained into adulthood, and prospective cohort studies are needed to look at the parameters that describe the transmission of STIs between partners. Funding should focus on the effectiveness of the interventions on influencing behaviour.

Telbivudine for the treatment of chronic hepatitis B infection.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of telbivudine for the treatment of chronic hepatitis B (CHB) in adults based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's evidence came from one randomised controlled trial (RCT) (GLOBE) of reasonable methodological quality comparing telbivudine with lamivudine. One other RCT that appeared to meet the inclusion criteria was excluded from the submission. For the primary outcome of therapeutic response telbivudine was statistically superior to lamivudine at weeks 52 and 104 for hepatitis B e antigen (HBeAg)-positive patients, and at week 104 for HBeAg-negative patients. There were statistically significant differences in favour of telbivudine for some secondary outcomes at 2 years including hepatitis B virus (HBV) DNA reduction, HBV DNA non-detectability and alanine aminotransferase normalisation though not for HBeAg-positive patients. In HBeAg-positive patients there was no significant difference between treatment groups for HBeAg loss or seroconversion at any time point. The incidence of adverse events was similar between treatments. Two RCTs comparing entecavir with lamivudine were included in the indirect comparison; however, this was poorly conducted and the results should be treated with caution. The manufacturer developed two economic models to determine the cost-effectiveness of telbivudine. Evidence on the efficacy of telbivudine and lamivudine was taken from the GLOBE trial; efficacy of adefovir was based on assumption. There was a lack of critical assessment and assurance of the quality of the data used to populate the models. The manufacturer concluded that telbivudine is a cost-effective option compared with lamivudine using evidence from the viral load model [HBeAg-positive patients/HBeAg-negative patients: mean incremental cost 19,087 pounds/49,003 pounds, mean quality-adjusted life-year (QALY) gain 1.30/4.67, incremental cost-effectiveness ratio (ICER) 14,665 pounds/10,497 pounds per QALY]. Resubmitted results after a request for clarification by the ERG gave less favourable ICERs (HBeAg-positive patients/HBeAg-negative patients: mean incremental cost 23,983 pounds/41,910 pounds, mean QALY gain 1.56/2.07, ICER 15,377 pounds/20,256 pounds per QALY). The manufacturer concluded that telbivudine is a cost-effective option (on its own or followed by adefovir) for patients who have developed resistance to first-line telbivudine treatment; however, the presentation of the results was not ideal. In conclusion, although telbivudine was statistically superior to lamivudine for most antiviral outcomes, the difference was not clinically significant; in addition, the cost-effectiveness evidence for telbivudine presented in the manufacturer's submission was limited. The NICE guidance issued as a result of the STA states that telbivudine is not recommended for the treatment of chronic hepatitis B and that people currently receiving telbivudine should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

Omalizumab for the treatment of severe persistent allergic asthma.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of omalizumab for the treatment of chronic severe persistent allergic asthma, in accordance with the licensed indication, based upon the evidence submission from Novartis to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The clinical evidence comes from a randomised controlled trial comparing omalizumab as an add-on to standard therapy with placebo and standard therapy over a 28-week treatment period. For the primary outcome of the rate of clinically significant asthma exacerbations, there was no statistically significant difference between treatment groups. However, after making a post hoc adjustment for a suggested 'clinically relevant' imbalance between trial arms in baseline exacerbation rate, the difference became marginally statistically significant. In terms of secondary outcomes, there were statistically significant differences favouring omalizumab over placebo in total emergency visits, Asthma Quality of Life Questionnaire scores, total symptom scores and lung function. Adverse events appeared to be similar between the trial arms. Results from three other publications are included in the manufacturer's submission as supporting evidence for the effectiveness of omalizumab, despite not meeting the inclusion criteria which adhere strictly to the licensed indication. The ERG checked and provided commentary on the manufacturer's model using standard checklists as well as undertook one-way sensitivity analysis, scenario analysis and a probabilistic sensitivity analysis. The cost-effectiveness analysis estimates the incremental costs and consequences of omalizumab as an add-on to standard therapy. The base-case analysis of the trial's primary intention-to-treat population estimates a cost per quality-adjusted life-year of 30,647 pounds. The ERG conducted one-way sensitivity analyses for parameters omitted from the manufacturer's submission sensitivity analysis. The results were most sensitive to variation in the utility values for omalizumab responders, and the unit cost of omalizumab. The guidance issued by NICE in November 2007 as a result of the STA states that omalizumab is recommended as a possible treatment for adults and young people over 12 years with severe persistent allergic asthma when their asthma meets certain conditions. Omalizumab treatment should be given along with the person's current asthma medicines. It should be prescribed by a doctor who is experienced in asthma and allergy medicine at a specialist centre. If omalizumab does not control the asthma after 16 weeks, treatment should be stopped.

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

OBJECTIVE: To update and extend a 2006 report on the clinical effectiveness and cost-effectiveness of adefovir dipivoxil (ADV) and pegylated interferon alpha (PEG-alpha) for the treatment of chronic hepatitis B (CHB). DATA SOURCES: Thirteen bibliographic databases were searched including MEDLINE, EMBASE and the Cochrane Library. Searches were run from the beginning of 2005 to September 2007. REVIEW METHODS: For the clinical effectiveness review, randomised controlled trials (RCTs) comparing ADV, PEG-alpha-2a and PEG-alpha-2b with currently licensed treatments for CHB, including non-pegylated interferon alpha (IFN-alpha) and lamivudine (LAM), were included. Outcomes included biochemical, histological and virological response to treatment, drug resistance and adverse effects. A systematic review of economic evaluations of antiviral treatments for CHB was conducted. The economic Markov model used in the 2006 report was updated in terms of utility values, discount rates and costs. RESULTS: Of the 82 papers retrieved for detailed screening, eight RCTs were included. Three evaluated ADV, four evaluated PEG-alpha-2b and one (from the original literature search) compared PEG-alpha-2b plus LAM with PEG-alpha-2b monotherapy. No RCTs of PEG-alpha-2a were identified. One ADV trial showed a statistically significant difference between ADV and placebo in terms of ALT response and HBV DNA levels, favouring ADV. Following withdrawal of ADV, levels were similar to those in placebo patients. In the ADV versus ADV plus LAM trial, there was a statistically significant difference in favour of the combination treatment. In the PEG-alpha trials, there were statistically significant differences favouring PEG-alpha-2b plus LAM compared with either one of the drugs given as monotherapy. For the comparison between PEG-alpha-2b and IFN-alpha and the comparison between different staggered regimens of the commencement of PEG-alpha-2b and LAM, there were no statistically significant differences between groups. Four full economic evaluations were identified, in addition to one identified in the original report. Two assessed PEG-alpha-2a; the remainder assessed ADV. PEG-alpha-2a was associated with increased treatment costs and gains in quality-adjusted life expectancy. In a UK study, the incremental cost-effectiveness ratio (ICER) for PEG-alpha-2a was 10,444 pounds per QALY gained compared with LAM. Evaluations of ADV found that LAM monotherapy was dominated; the ICER for ADV monotherapy compared with 'doing nothing' was $19,731. The results of the updated analysis were generally robust to changes in deterministic sensitivity analysis. In a probabilistic sensitivity analysis, the same sequence of treatments was identified as optimal. In a probabilistic sensitivity analysis, PEG-alpha-2b had a probability of being cost-effective of 79% at a willingness-to-pay threshold of 20,000 pounds per QALY, and 86% at a willingness-to-pay threshold of 30,000 pounds per QALY. CONCLUSIONS: Both ADV and PEG-alpha are beneficial for patients with CHB in terms of suppressing viral load, reducing liver damage-associated biochemical activity, inducing HBeAg seroconversion, and reducing liver fibrosis and necroinflammation. The effects of long-term treatment with ADV are generally durable, with relatively low rates of resistance. In most cases, cost-effectiveness estimates were within acceptable ranges. Further research should assess the clinical effectiveness and cost-effectiveness of newer antiviral agents in relation to existing drugs, including the role of initiating treatment with combination therapy.

Infliximab for the treatment of adults with psoriasis.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of infliximab for the treatment of moderate to severe plaque psoriasis, in accordance with the licensed indication, based on the evidence submission from Schering-Plough to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes stated in the manufacturer's definition of the decision problem were severity [Psoriasis Area and Severity Index (PASI) score], remission rates, relapse rates and health-related quality of life. The main evidence in the submission comes from four randomised controlled trials (RCT) comparing infliximab with placebo and eight RCTs comparing either etanercept or efalizumab with placebo. At week 10, patients on infliximab had a significantly higher likelihood of attaining a reduction in PASI score than placebo patients. There were also statistically significant differences between infliximab and placebo in the secondary outcomes. In the comparator trials both the efalizumab and etanercept arms included a significantly higher proportion of patients who achieved a reduction in PASI score at week 12 than the placebo arms. No head-to-head studies were identified directly comparing infliximab with etanercept or efalizumab. The manufacturer carried out an indirect comparison, but the ERG had reservations about the comparison because of the lack of information presented and areas of uncertainty in relation to the included data. The economic model presented by the manufacturer was appropriate for the disease area and given the available data. The cost-effectiveness analysis estimates the mean length of time that an individual would respond to infliximab compared with continuous etanercept and the utility gains associated with this response. The base-case incremental cost-effectiveness ratio (ICER) for infliximab compared with continuous etanercept for patients with severe psoriasis was 26,095 pounds per quality-adjusted life-year. A one-way sensitivity analysis, a scenario analysis and a probabilistic sensitivity analysis were undertaken by the ERG. The ICER is highly sensitive to assumptions about the costs and frequency of inpatient stays for non-responders of infliximab. The guidance issued by NICE in August 2007 as a result of the STA states that infliximab within its licensed indication is recommended for the treatment of adults with very severe plaque psoriasis, or with psoriasis that has failed to respond to standard systematic therapies. Infliximab treatment should be continued beyond 10 weeks in people whose psoriasis has shown an adequate response to treatment within 10 weeks. In addition, when using the Dermatology Life Quality Index (DLQI), care should be taken to take into account the patient's disabilities, to ensure DLQI continues to be an accurate measure.

Time to full publication of studies of anti-cancer medicines for breast cancer and the potential for publication bias: a short systematic review.

OBJECTIVES: To identify the expected delay between publication of conference abstracts and full publication of results from trials of new anti-cancer agents for breast cancer and to identify whether there are any apparent biases in publication and reporting. DATA SOURCES: Major electronic databases were searched to identify randomised controlled trials (RCTs) of the selected interventions for the treatment of breast cancer. REVIEW METHODS: A systematic review was conducted according to standard methods. Data were extracted from the included studies using a predesigned and piloted data extraction template. RESULTS: Six anti-cancer treatments for breast cancer were included in the review: docetaxel, paclitaxel, trastuzumab, gemcitabine, lapatinib and bevacizumab. The literature searches generated 1556 references, from which 71 publications were retrieved and screened for inclusion. Screening identified 41 publications of 18 RCTs with at least one arm of treatment meeting the inclusion criteria for the review. Of the 18 included RCTs, only four publications (from three RCTs) reported the same outcomes in both an abstract and a full publication. Time between the abstract and full publication was 5 months in two cases, 7 months in one case and 19 months in one case (overall mean delay = 9 months). Eleven trials were identified that have not currently published in a full publication the data presented in an abstract or conference proceeding. The duration between publication of the abstracts and the end of August 2007 varied from 3 months to 38 months (mean delay 16.5 months). The longest delays in publication were for trials investigating gemcitabine (38 months) or bevacizumab (33 months). Observational analysis of the published and unpublished trials did not indicate any particular biases in terms of whether positive results were more likely to be fully published than non-significant ones. CONCLUSIONS: It was surprising that only three of the 18 relevant RCTs had one or more full papers that reported the same outcome measures (and stage of analysis) as an earlier conference abstract. However, a limitation of this review is the small number of studies included. With a larger sample size than that in the present report, investigation into the effect of publication delay on decision-making might be feasible. Future research should include extension of this work to other anti-cancer drugs and investigation into the reasons for lengthy delays to full publication noted for some trials.

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.

OBJECTIVES: To assess the clinical and cost-effectiveness of inhaled corticosteroids (ICS) alone and ICS used in combination with a long-acting beta2 agonist (LABA) in the treatment of chronic asthma in adults and children aged over 12 years. DATA SOURCES: Major electronic bibliographic databases, e.g. MEDLINE and EMBASE, were searched up to February/March 2006 (and updated again in October 2006). REVIEW METHODS: A systematic review of clinical and cost-effectiveness studies was conducted. Cost comparison and cost-consequence analyses were performed where appropriate. RESULTS: The assessment of clinical effectiveness was based on the 67 randomised controlled trials selected from the 5175 reports identified through the systematic literature search. The most frequently reported relevant outcomes were lung function, symptoms, use of rescue medication and adverse events. The trials varied considerably. In the trials that compared low-dose ICS versus ICS and high-dose ICS versus ICS, there were few significant differences in clinical effectiveness, although a few of the trials had assessed non-inferiority between the comparators rather than superiority. At doses of 400, 800 and 'high-level' doses of 1500 or 1600 microg/day, beclometasone dipropionate (BDP) appears to be the current cheapest ICS product both with the inclusion and exclusion of chlorofluorocarbon (CFC)-propelled products. A significant treatment benefit for combination ICS/LABA therapy across a range of outcomes compared with ICS alone was identified [when the ICS was double the accepted clinically equivalent dose of the ICS in the combination inhaler, and dry powder inhalers (DPIS) were used to deliver the drugs]. When a formoterol fumarate (FF)/salmeterol (SAL) combination inhaler and a budesonide (BUD)/FF combination inhaler were each compared with their constituent drugs delivered in separate inhalers, there were very few statistically significant differences between the treatments across the various efficacy outcomes and the rate of adverse events. Combination inhalers were more often cheaper than doubling the dose of ICS alone. However, the costs were highly variable and dependent on both the dose required and the preparation used in the trials. The estimated mean annual cost of FP/SAL combination varied from being 94 pounds cheaper to 109 pounds more expensive than the alternative of BUD at a higher dose. The BUD/FF combination varied from being 163 pounds cheaper to 66 pounds more expensive than the higher dose of either BUD or FP. When the combination inhalers were compared to each other, the results were mixed, with the FP/SAL combination significantly superior on some outcomes and the BUD/FF combination superior on others; however, meta-analysis showed that there were no significant differences between the two treatments in the rate of adverse events. Taking an ICS with a LABA as either of the two currently available combination products, FP/SAL and BUD/FF, is usually cheaper than taking the relevant constituent drugs in separate inhalers. At very high doses of BUD (1600 microg/day), however, the BUD/FF combination inhaler can be up to 156 pounds more expensive than having the same drugs in separate inhalers. In terms of the relative costs associated with taking one of the combination inhalers, at low dose (400 microg BUD or 200 microg FP/day) the cheapest combination inhaler is FP/SAL as a pressurised metered dose inhaler (pMDI) (Seretide Evohaler). However, this is only slightly cheaper than using BUD/FF as a DPI (Symbicort Turbohaler). At higher dose levels (800 microg BUD or 500 microg FP/day) FP/SAL as either pMDI aerosol (Seretide Evohaler) or a DPI (Seretide Accuhaler) is the cheapest combination product available, but again only slightly cheaper than the DPI BUD/FF combination (Symbicort Turbohaler). It should be highlighted, however, that the three head-to-head trials that compared the effects of FP/SAL with BUD/FF used the FP/SAL DPI combination inhaler, Seretide Accuhaler. CONCLUSIONS: The evidence indicates that there are few consistent significant differences in effects between the five ICS licensed for use in adults and adolescents over the age of 12 years, at either low or high dose. On average, BDP products currently tend to be the cheapest ICS available and tend to remain so as the daily ICS dose required increases. There is evidence that the addition of a LABA to an ICS is potentially more clinically effective than doubling the dose of ICS alone, although consistent significant differences between the two treatment strategies are not observed for all outcome measures. The cost differences between combination therapy compared with ICS monotherapy are highly variable and dependent on the dose required and the particular preparations used. For the combination therapies of ICS/LABA there are potential cost savings with the use of combination inhalers compared with separate inhalers, with few differences between the two treatment strategies in terms of effects. The only exception to this cost saving is with BUD/FF at doses higher than 1200 microg/day, where separate inhaler devices can become equivalent to or cheaper than combination inhalers. Neither of the two combination inhalers (FP/SAL or BUD/FF) is consistently superior in terms of treatment effect. A comparison of the costs associated with each combination therapy indicates that at low dose FP/SAL delivered via a pMDI is currently the cheapest combination inhaler but only marginally cheaper than BUD/FF delivered as a DPI. At higher doses, both the FP/SAL combination inhalers (PMDI and DPI) are marginally cheaper than BUD/FF (DPI). Future trials of treatment for chronic asthma should standardise the way in which outcome measures are defined and measured, with a greater focus on patient-centred outcomes. For informing future cost-utility and cost-effectiveness analyses from a UK NHS perspective, there is a need for longitudinal studies that comprehensively track the care pathways followed when people experience asthma exacerbations of different severity. Further research synthesis, quantifying the adverse effects of the different ICS, is required for treatment choices by patients and clinicians to be fully informed.

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.

OBJECTIVES: To assess the clinical and cost-effectiveness of inhaled corticosteroids (ICS) alone and ICS used in combination with a long-acting beta2 agonist (LABA) in the treatment of chronic asthma in children aged under 12 years. DATA SOURCES: Major electronic bibliographic databases, e.g. MEDLINE and EMBASE, were searched up to February/March 2006 (and updated again in October 2006). REVIEW METHODS: A systematic review of clinical and cost-effectiveness studies and economic analyses were carried out. A flexible framework was used to allow different types of economic analyses as appropriate, with either a cost comparison or cost-consequence comparison conducted. RESULTS: Of 5175 records identified through systematic literature searching, 34 records describing 25 studies were included (16 were fully published randomised controlled trials, six were systematic reviews, and three were post-2004 conference abstracts). The most frequently reported relevant outcomes in the 16 RCTs were peak expiratory flow rate (13 trials), FEV1 (13 trials), symptoms (13 trials), adverse events or exacerbations (13 trials), use of rescue medication (12 trials), markers of adrenal function (e.g. blood or urine cortisol concentrations) (13 trials), height and/or growth rate (seven trials) and markers of bone metabolism (two trials). In the trials that compared low-dose ICS versus ICS and high-dose ICS versus ICS, no consistent significant differences or patterns in differential treatment effect among the outcomes were evident. Where differences were statistically significant at high doses, such as for lung function and growth, they favoured formoterol fumarate (FF), but this was generally in studies that did not compare the ICS at the accepted clinically equivalent doses. Differences between the drugs in impact on adrenal suppression were only significant in two studies. At doses of 200, 400 and 800 microg/day, beclometasone dipropionate (BDP) appears to be the current cheapest ICS product both with the inclusion and exclusion of chlorofluorocarbon (CFC)-propelled products. In the trials comparing ICS at a higher dose with ICS and LABA in combination, most outcomes favoured the combined inhaler. Only the combination inhaler, Seretide Evohaler, is slightly cheaper than the weighted mean cost of all types of ICS at increased dose except BDP 400 microg/day (including CFC-propelled products). Both the combination inhalers, Seretide Accuhaler and Symbicort Turbohaler, are more expensive than the weighted mean cost for all types of ICS at a two-fold increased dose. Compared with the lowest cost preparation for each ICS drug, all the combination inhalers are always more expensive than the ICS products at increased dose. CONCLUSIONS: The limited evidence available indicates that there are no consistent significant differences in effectiveness between the three ICS licensed for use in children at either low or high dose. BDP CFC-propelled products are often the cheapest ICS currently available at both low and high dose, and may remain so even when CFC-propelled products are excluded. Exclusion of CFC-propelled products increases the mean annual cost of all budesonide (BUD) and BDP, while the overall cost differences between the comparators diminish. There is very limited evidence available for the efficacy and safety of ICS and LABAs in children. From this limited evidence, there appear to be no significant clinical differences in effects between the use of a combination inhaler versus the same drugs in separate inhalers. There is a lack of evidence comparing ICS at a higher dose with ICS and LABA in combination and comparing the combination products with each other. In the absence of any evidence concerning the effectiveness of ICS at higher dose with ICS and LABA, a cost-consequence analysis gives mixed results. There are potential cost savings with the use of combination inhalers compared to separate inhalers. At present prices, the BUD/FF combination is more expensive than those containing FP/SAL, but it is not known whether there are clinically significant differences between them. A scoping review is required to assess the requirements for additional primary research on the clinical effectiveness of treatment for asthma in children under 5 years old. Such a review could also usefully include all treatment options, pharmacological and non-pharmacological, for asthma. A direct head-to-head trial that compares the two combination therapies of FP/SAL and BUD/FF is warranted, and it is important to assess whether the addition of a LABA to a lower dose of ICS could potentially be as effective as an increased dose of ICS alone, but also be steroid sparing. There is also a need for the long-term adverse events associated with ICS use to be assessed systematically. Future trials of treatment for chronic asthma in children should aim to standardise further the way in which outcome measures are defined. There should be a greater focus on patient-centred outcomes to provide a more meaningful estimation of the impact of treatment on asthma control. Methods of reporting also require standardisation.

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

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of pegylated interferon alpha (PEG) and non-pegylated interferon alpha (IFN) and ribavirin (RBV) for the treatment of adults with histologically mild chronic hepatitis C (HCV) infection. DATA SOURCES: Electronic bibliographic databases were searched up to July 2005. REVIEW METHODS: A systematic review and an economic evaluation were carried out. A Markov state transition model was developed to estimate the cost-effectiveness of treatment strategies for adults with mild chronic HCV. RESULTS: Among the included studies, eight randomised controlled trials (RCTs) of antiviral treatment in mild HCV were identified and included. In general these RCTs were of good quality. The results suggested that effectiveness, particularly with respect to sustained virological response was similar in patients with mild disease to the results obtained in patients with moderate/severe disease. This finding was supported by RCTs reporting the results for mild HCV sub-groups. The authors' cost-effectiveness analysis showed that early treatment compared with watchful waiting is associated with quality-adjusted life-year (QALY) gains but with increased treatment costs. The base-case incremental costs per QALY for 48 weeks of treatment are: watchful waiting with IFN + RBV versus best supportive care = pound 3097-6585; early treatment with IFN + RBV versus watchful waiting with IFN + RBV = pound 5043-8092; watchful waiting with PEG 2a + RBV versus best supportive care = pound 3052; early treatment with PEG 2a + RBV versus watchful waiting with PEG 2a + RBV = pound 5900; watchful waiting with PEG 2b + RBV versus best supportive care = pound 2534; and early treatment with PEG 2b + RBV versus watchful waiting with PEG 2b + RBV = pound 5774. These results were consistent with previous assessments of cost-effectiveness. CONCLUSION: This systematic review and economic evaluation show that patients with histologically mild HCV can be successfully treated with both pegylated and non-pegylated interferon alpha. Early treatment and watchful waiting strategies are associated with acceptable cost-per-QALY estimates. Research needs to be directed towards newer, potentially more effective interventions, particularly those that improve treatment response in patients with genotype 1, with minimal adverse effects. Further research is required into the natural history of HCV to estimate better the rate of liver disease progression, and also into the effectiveness of non-invasive biochemical markers of liver disease, as an alternative to liver biopsy.

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

OBJECTIVES: To review the clinical evidence comparing immediate angioplasty with thrombolysis, and to consider whether it would be cost-effective. DATA SOURCES: Electronic databases. Experts in the field. REVIEW METHODS: For clinical effectiveness, a comprehensive review of randomised control trials (RCTs) was used for efficacy, and a selection of observational studies such as case series or audit data used for effectiveness in routine practice. RCTs of thrombolysis were used to assess the relative value of prehospital and hospital thrombolysis. Observational studies were used to assess the representativeness of patients in the RCTs, and to determine whether different groups have different capacity to benefit. Clinical effectiveness was synthesised through a narrative review with full tabulation of results of all included studies and a meta-analysis to provide a precise estimate of absolute clinical benefit. Consideration was given to the effect of the growing use of stents. The economic modelling adopted an NHS perspective to develop a decision-analytical model of cost-effectiveness focusing on opportunity costs over the short term (6 months). RESULTS: The results were consistent in showing an advantage of immediate angioplasty over hospital thrombolysis. The updated meta-analysis showed that mortality is reduced by about one-third, from 7.6% to 4.9% in the first 6 months, and by about the same in studies of up to 24 months. Reinfarction is reduced by over half, from 7.6% to 3.1%. Stroke is reduced by about two-thirds, from 2.3% with thrombolysis to 0.7% with percutaneous coronary intervention (PCI), with the difference being due to haemorrhagic stroke. The need for coronary artery bypass graft is reduced by about one-third, from 13.2% to 8.4%. Caution is needed in interpreting some of the older trials, as changes such as an increase in stenting and the use of the glycoprotein IIb/IIa inhibitors may improve the results of PCI. There is little evidence comparing prehospital thrombolysis with immediate PCI. Research on thrombolysis followed by PCI, known as 'facilitated PCI', is underway, but results are not yet available. Trials may be done in select centres and results may not be as good in lower volume centres, or out of normal working hours. In addition, much of the marginal mortality benefit of PCI over hospital thrombolysis may be lost if door-to-balloon time were more than an hour longer than door-to-needle time. Conversely, within the initial 6 hours, the later patients present, the greater the relative advantage of PCI. Results suggest that PCI is more cost-effective than thrombolysis, providing additional benefits in health status at some extra cost. In the longer term, the cost difference is expected to be reduced because of higher recurrence and reintervention rates among those who had thrombolysis. CONCLUSIONS: If both interventions were routinely available, the economic analysis favours PCI, given the assumptions of the model. However, very few units in England could offer a routine immediate PCI service at present, and there would be considerable resource implications of setting up such services. Without a detailed survey of existing provision, it is not possible to quantify the implications, but they include both capital and revenue: an increase in catheter laboratory provision and running costs. The greatest problem would be staffing, and that would take some years to resolve. A gradual incrementalist approach based on clinical networks, with transfer to centres able to offer PCI, may be used. In rural areas, one option may be to promote an increase in prehospital thrombolysis, with PCI for thrombolysis failures. There is a need for data on the long-term consequences of treatment, the quality of life of patients after treatment, and the effects of PCI following thrombolysis failure.

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

OBJECTIVES: To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis in a UK context. DATA SOURCES: Electronic databases. Data from the commercial use of the drug up to April 2002. Data from the manufacturer submission to the National Institute for Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. Data were synthesised through a narrative review with full tabulation of results from included studies. RESULTS: The evidence on the effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis came primarily from one large pivotal randomised controlled trial, the PROWESS study. This study demonstrated a statistically significant absolute reduction in 28-day mortality of 6.5%. Longer term survival benefit was maintained to 90 days. By 9 months, the trend towards increased median survival was non-significant, although the survival curves did not cross. Results presented by the number of organ dysfunctions were not statistically significant, but when mortality rates for those with two or more organ failures were combined, the relative risk of death was significantly lower in those treated with drotrecogin alfa (activated) compared with placebo. However, this report highlights a number of considerations relevant to the subgroup analyses reported for the PROWESS study. Published cost-effectiveness studies of treatment with drotrecogin alfa (activated) have applied a range of methods to the estimation of benefits, estimating an incremental gain per treated patient of between 0.38 and 0.68 life-years (for patients with severe sepsis). For patients with severe sepsis and multiple organ dysfunction, the manufacturer (Eli Lilly) estimated an incremental gain of 1.115 life-years per treated patient, compared to 1.351 life-years per treated patient estimated by the Southampton Health Technology Assessments Centre (SHTAC). These latter UK analyses are based on a patient group that is more severely affected by disease, where effectiveness is greater and the baseline risk of all-cause mortality is much higher (SHTAC analysis), these factors are associated with the noted difference in effect. The three published cost-effectiveness studies report cost for US and Canadian patient groups; for those patients with severe sepsis they report the additional cost per patient treated in a range around 10,000-16,000 dollars. The manufacturer's submission reports analysis for the UK, based on 28-day survival data in patients with severe sepsis and multiple organ dysfunction (the European licence indication), with the additional mean cost per treated patient estimated to be 5106 pounds. The analysis undertaken by SHTAC, for a UK group of patients with severe sepsis and multiple organ dysfunction, estimates an additional mean cost per patient treated of 6661 pounds. The manufacturer's submission to NICE presents cost-effectiveness estimates for drotrecogin alfa (activated) in the UK, in patients with severe sepsis and multiple organ dysfunction, at 6637 pounds per quality-adjusted life-year (QALY) based on 28-day effectiveness data, and 10,937 pounds per QALY based on longer term follow-up data. SHTAC developed an independent cost-effectiveness model and estimated a base-case cost per QALY of 8228 pounds in patients with severe sepsis and multiple organ failure (based on 28-day survival data). Simulation results indicate that where the NHS is willing to pay 20,000 pounds per QALY, drotrecogin alfa (activated) is a cost-effective use of resources in 98.7% of cases. Published economic evaluations report various sensitivity analyses, with results sensitive to changes in the measure of treatment effect, but otherwise studies reported that results were robust to variations in most assumptions used in the cost-effectiveness analysis. CONCLUSIONS: Drotrecogin alfa (activated) plus best supportive care appears clinically and cost-effective compared with best supportive care alone, in a UK cohort of severe sepsis patients, and in the subgroup of more severely affected patients with severe sepsis and multiple organ failure. The introduction of drotrecogin alfa (activated) will involve a substantial additional cost to the NHS. The treatment-eligible population in England and Wales may comprise up to 16,570 patients, with an estimated annual drug acquisition cost of over 80 million pounds, excluding VAT. Further research is required on the longer term impact of drotrecogin alfa (activated) on both mortality and morbidity in UK patients with severe sepsis, on the clinical and cost-effectiveness of drotrecogin alfa (activated) in children (under 18 years) with severe sepsis, and on the effect of the timing of dosage and duration of treatment on outcomes in severe sepsis.

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

OBJECTIVES: To assess the clinical and cost-effectiveness of continuous subcutaneous insulin infusion (CSII) compared with multiple daily injections (MDI) in the delivery of intensive insulin therapy for the treatment of diabetes mellitus. DATA SOURCES: Electronic databases, references of retrieved articles and manufacturer submissions. Experts in the field were consulted. REVIEW METHODS: For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria by two reviewers. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Data on clinical effectiveness were synthesised through a narrative review with full tabulation of all eligible studies, with meta-analysis performed where appropriate. RESULTS: Twenty studies comparing CSII with MDI were identified. Quality was generally poor. In adults with Type 1 diabetes, glycated haemoglobin improved by 0.61% (95% CI -1.29 to 0.07) in longer term studies, although this improvement was smaller when a study using bovine ultralente was excluded. A reduction in insulin dose with CSII of about 12 units per day (-11.90, 95% CI -18.16 to 5.63) was found in short-term studies, with smaller differences in longer term studies. Body weight and cholesterol levels were similar between treatments. Hypoglycaemic events did not differ significantly between CSII and MDI in most trials, but some found fewer events with CSII and one found more hypoglycaemia and hypoglycaemic coma with CSII. There was no consistency between the studies in patient preference, but progress has been made both with insulin pumps and injector pens since the publication of many of the older studies. No difference in glycated haemoglobin between CSII and MDI was found in pregnancy; one study found less insulin was required by patients with CSII, but two other studies found no significant difference. One study of adolescents found lower glycated haemoglobin and insulin dose with CSII whereas a second study found no significant difference. In CSII analogue insulin was associated with lower glycated haemoglobin levels than soluble insulin. No economic evaluations comparing CSII with MDI were identified. The estimated additional cost of CSII compared to MDI varies from GBP1091 per annum to GBP1680 per annum, according to the make of the insulin pump and the estimated life of the device. These estimates include the costs for the insulin pump, the consumables associated with delivery of CSII, and an allowance for the initial education required when patients switch from MDI to CSII. The largest component of the annual cost for CSII is the cost of consumable items (e.g. infusion sets). CONCLUSIONS: When compared with optimised MDI, CSII results in a modest but worthwhile improvement in glycated haemoglobin in adults with Type 1 diabetes. It has not been possible to establish the longer term benefits of such a difference in glycated haemoglobin, although there is an expectation that it would be reflected in a reduction in long-term complications. More immediate primary benefits from CSII may be associated with an impact on the incidence of hypoglycaemic events and the dawn phenomenon, and greater flexibility of lifestyle. However, there is limited evidence on this, and information presented to offer context on quality-of-life is based on testimonies from those patients who have had a positive experience of CSII. The estimated cost to the NHS per year for CSII would be around GBP3.5 million in England and Wales if 1% of people with Type 1 diabetes used CSII, GBP10.5 million for 3%, and GBP17.5 million for 5%. Further research should focus on wider benefits of CSII, such as flexibility of lifestyle and quality of life, and on the psychological impact of wearing a device for 24 hours every day. Research into the use of CSII in children of different ages is also needed.