Factores psicosociales, estrés psicológico y burnout en enfermería: un modelo de trayectorias / Psychosocial factors, psychological stress, and burnout in nursing: a model of trajectories / Fatores psicossociais, estresse psicológico e burnout em enfermagem: um modelo de trajetórias

Resumen Introducción: El personal de enfermería se enfrenta cotidianamente a diferentes eventos asociados al estrés, factores psicosociales y otros mecanismos que afectan su salud mental. Objetivo: Evaluar la correlación entre la demanda psicológica, el control laboral, el apoyo social, el estrés psicológico, y las dimensiones del Síndrome de Burnout (ilusión por el trabajo, desgaste psíquico, indolencia y culpa), en un modelo de trayectorias en enfermeras mexicanas. Metodología: Estudio transversal, observacional, analítico, conducido en 357 profesionales de enfermería de Morelos, México, seleccionados por conveniencia. Los datos fueron colectados empleando tres cuestionarios, la Escala de Estrés Percibido, el Cuestionario del Contenido del Trabajo y el Cuestionario para la Evaluación del Síndrome de Quemarse por el Trabajo. Los programas SPSS 19 y LISREL 8.3 fueron empleados para el procesamiento y modelaje de los datos. Resultados: En el modelo de trayectorias, se especificó como variable mediadora de los factores psicosociales y de las dimensiones del Síndrome de Quemarse por el Trabajo (SQT), al estrés psicológico. Los índices de ajuste fueron aceptables. Se encontraron altos niveles de apoyo social, control laboral e ilusión por el trabajo; grados moderados de demanda psicológica y estrés psicológico; y bajos niveles de desgaste psíquico, indolencia y culpa. Conclusión: Implicaciones para la disciplina, se propone implementar estrategias de intervención efectivas para mantener en el personal de enfermería bajos niveles de demandas psicológicas, altos niveles de control laboral, altos niveles de apoyo social, y niveles moderados de estrés, para prevenir, el SQT.

Abstract Introduction: Nurses frequently face different events associated with stress, psychosocial factors, and other issues which have impacts on their mental health. Objective: To assess the correlation between psychological demand, work control, social support, psychological stress, and burnout dimensions (illusion for the activity, psychic wear, indolence, guilt), within a model of trajectories among Mexican nurses. Methodology: This is a transversal, observational, and analytical study conducted on a convenience sample of 357 nursing professionals from the state of Morelos, Mexico. Data were gathered using three questionnaires, the Perceived Stress Scale, the Job Content Questionnaire, y el Maslach Burnout Inventory. SPSS 19 and LISREL 8.3 were used to process and model the data. Results: Psychological Stress was specified as the mediating variable of the psychosocial factors and dimensions of burnout within the model of trajectories. Adjustment indexes were acceptable. High levels of social support, work control, and illusion for the activity were found. Moderate degrees of psychological demand and psychological stress were found. Low levels of psychic wear, indolence, and guilt were found. Conclusion: It is recommended to implement effective intervention strategies to maintain nursing personnel within low levels of psychological demand, high levels of work control, high levels of social support, and moderate levels of stress, all these in order to prevent the Syndrome of Burnout.

Resumo Introdução: O pessoal de enfermagem se enfrenta cotidianamente a diferentes eventos associados ao estresse, fatores psicossociais e outros mecanismos que afetam sua saúde mental. Objetivo: Avaliar a correlação entre a demanda psicológica, o controle laboral, o apoio social, o estresse psicológico, e as dimensões e da Síndrome de Burnout (ilusão pelo trabalho, desgaste psíquico, indolência e culpa), em um modelo de trajetórias em enfermeiras mexicanas. Metodologia: Estudo transversal, observacional, analítico, conduzido em 357 profissionais de enfermagem de Morelos, México, selecionados por conveniência. Os dados foram coletados empregando três questionários, a Escala de Estresse Percebido, o Questionário do Conteúdo do Trabalho e o Questionário para a Avaliação da Síndrome de Burnout no Trabalho. Os programas SPSS 19 e LISREL 8.3 foram empregados para o processamento e modelagem dos dados. Resultados: No modelo de trajetórias, especificou-se como variável mediadora dos fatores psicossociais e das dimensões da Síndrome de Burnout no Trabalho (SQT), ao estresse psicológico. Os índices de ajuste foram aceitáveis. Encontraram-se altos níveis de apoio social, controle laboral e ilusão pelo trabalho; graus moderados de demanda psicológica e estresse psicológico; e baixos níveis de desgaste psíquico, indolência e culpa. Conclusão: Implicações para a disciplina, propõe-se implementar estratégias de intervenção efetivas para manter no pessoal de enfermagem baixos níveis de demandas psicológicas, altos níveis de controle laboral, altos níveis de apoio social, e níveis moderados de estresse, para prevenir, o SQT.

Modeling the economic outcomes of immuno-oncology drugs: alternative model frameworks to capture clinical outcomes.

BACKGROUND: Economic models in oncology are commonly based on the three-state partitioned survival model (PSM) distinguishing between progression-free and progressive states. However, the heterogeneity of responses observed in immuno-oncology (I-O) suggests that new approaches may be appropriate to reflect disease dynamics meaningfully. MATERIALS AND METHODS: This study explored the impact of incorporating immune-specific health states into economic models of I-O therapy. Two variants of the PSM and a Markov model were populated with data from one clinical trial in metastatic melanoma patients. Short-term modeled outcomes were benchmarked to the clinical trial data and a lifetime model horizon provided estimates of life years and quality adjusted life years (QALYs). RESULTS: The PSM-based models produced short-term outcomes closely matching the trial outcomes. Adding health states generated increased QALYs while providing a more granular representation of outcomes for decision making. The Markov model gave the greatest level of detail on outcomes but gave short-term results which diverged from those of the trial (overstating year 1 progression-free survival by around 60%). CONCLUSION: Increased sophistication in the representation of disease dynamics in economic models is desirable when attempting to model treatment response in I-O. However, the assumptions underlying different model structures and the availability of data for health state mapping may be important limiting factors.

Apixaban in patients with atrial fibrillation: patient characteristics of the Latin America cohort from a multinational clinical trial

Patients with Atrial fibrillation (AF), have a five-fold increase in the risk of stroke. Treatment for AF include stroke prevention therapy. Vitamin K antagonists (VKAs) have shown to prevent stroke in AF patients. Apixaban, a novel oral direct factor Xa inhibitor was studied in AF patients whom VKA therapy was unsuitable. Apixaban demonstrated clinical benefit in stroke or systemic embolism reduction without impacting the risk of major bleeding or intracranial hemorrhage. Patient characteristics of the Latin America (LA) cohort and overall population are presented.

Antenatal screening for haemoglobinopathies in primary care: a cohort study and cluster randomised trial to inform a simulation model. The Screening for Haemoglobinopathies in First Trimester (SHIFT) trial.

OBJECTIVES: To assess the effectiveness, cost-effectiveness, acceptability and feasibility of offering universal antenatal sickle cell and thalassaemia (SCT) screening in primary care when pregnancy is first confirmed and to model the cost-effectiveness of early screening in primary care versus standard care. DESIGN: A population-based cohort study, cluster randomised trial and refinement of a published decision model. SETTING: Twenty-five general practices from two UK primary care trusts (PCTs) in two inner city boroughs with a high proportion of residents from minority ethnic groups. PARTICIPANTS: Practices were considered eligible if they agreed to be randomised and they were able to provide anonymous data on all eligible pregnant women. Participants were at least 18 years old and consented to take part in the evaluation. INTERVENTIONS: Practices were allocated to intervention, using minimisation and stratifying for PCT and number of partners at the practice, as follows: screening in primary care with parallel father testing (test offered to mother and father simultaneously; n = 8 clusters, 1010 participants); screening in primary care with sequential father testing (test offered to father only if mother identified as carrier; n = 9 clusters, 792 participants); and screening in secondary care with sequential father testing (standard care; n = 8 clusters, 619 participants). MAIN OUTCOME MEASURES: Data on gestational age at pregnancy confirmation and screening date were collected from trial practices for 6 months before randomisation in the cohort phase. The primary outcome measure was timing of SCT screening, measured as the proportion of women screened before 70 days' (10 weeks') gestation. Other outcomes included: offer of screening, rates of informed choice and proportion of women who knew the carrier status of their baby's father by 77 days (11 weeks). RESULTS: For 1441 eligible women in the cohort phase, the median [interquartile range (IQR)] gestational age at pregnancy confirmation was 7.6 weeks (6.0 to 10.7 weeks) and 74% presented in primary care before 10 weeks. The median gestational age at screening was 15.3 weeks (IQR 12.6 to 18.0 weeks). Only 4.4% were screened before 10 weeks. The median delay between pregnancy confirmation and screening was 6.9 weeks (4.7 to 9.3 weeks). In the intervention phase, 1708 pregnancies from 25 practices were assessed for the primary outcome measure. Completed questionnaires were obtained from 464 women who met eligibility criteria for the main analysis. The proportion of women screened by 10 weeks (70 days) was 9/441 (2%) in standard care, compared with 161/677 (24%) in primary care with parallel testing, and 167/590 (28%) in primary care with sequential testing. The proportion of women offered screening by 10 weeks (70 days) was 3/90 (3%) in standard care (note offer of test ascertained for questionnaire respondents only), compared with 321/677 (47%) in primary care with parallel testing, and 281/590 (48%) in primary care with sequential testing. The proportion of women screened by 26 weeks (182 days) was similar across the three groups: 324/441 (73%) in standard care, 571/677 (84%, 0.09) in primary care with parallel testing, and 481/590 (82%, 0.148) in primary care with sequential testing. The screening uptake of fathers was 51/677 (8%) in primary care with parallel testing, and 16/590 (3%) in primary care with sequential testing, and 13/441 (3%) in standard care. The predicted average total cost per pregnancy of offering antenatal SCT screening was estimated to be 13 pounds in standard care, 18.50 pounds in primary care with parallel testing, and 16.40 pounds in primary care with sequential testing. The incremental cost-effectiveness ratio (ICER) was 23 pounds in primary care with parallel testing and 12 pounds in primary care with sequential testing when compared with standard care. Women offered testing in primary care were as likely to make an informed choice as those offered screening by midwives later in pregnancy, but less than one-third of women overall made an informed choice about screening. CONCLUSIONS: Offering antenatal SCT screening as part of pregnancy-confirmation consultations significantly increased the proportion of women screened before 10 weeks (70 days), from 2% in standard care to between 16% and 27% in primary care, but additional resources may be required to implement this. There was no evidence to support offering fathers screening at the same time as women. TRIAL REGISTRATION: Current Controlled Trials ISRCTN00677850.

Infliximab for the treatment of ulcerative colitis.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of infliximab for moderately to severely active ulcerative colitis (UC) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellent (NICE) as part of the single technology appraisal (STA) process. The submission indicated that the efficacy of infliximab (5 mg/kg) had been demonstrated in terms of higher response rates and a sustained response in health-related quality of life. For the cost-effectiveness analysis, the manufacturer built a Markov model to compare infliximab with standard care. It estimated the incremental cost per quality-adjusted life-year (QALY) gained was between 25,044 pounds and 33,866 pounds depending on the strategy used. The ERG report generally agreed with the evidence on effectiveness of infliximab for subacute exacerbations of UC. However, there were several areas of uncertainty, of which the interpretation of the importance of the quality of life changes in the subacute situation and the assessment of the adequacy of the evidence of effectiveness of infliximab in the acute hospital-based situation were considered pre-eminent by the ERG. This challenged the estimates of cost-effectiveness offered and suggested that there should be a separate assessment of infliximab for acute exacerbations of moderately to severely active UC. The summary of the NICE guidance issued in April 2008 as a result of the STA states that: infliximab is not recommended for the treatment of subacute manifestations of moderately to severely active UC.

Cost-effectiveness of a disease management programme for secondary prevention of coronary heart disease and heart failure in primary care.

OBJECTIVE: To determine if a disease management programme for patients with coronary heart disease and heart failure represents an efficient use of health services resources. METHODS: We carried out an economic evaluation alongside a cluster randomised control trial of 1163 patients with coronary heart disease and chronic heart failure in 20 primary care practices in the United Kingdom. Practices were randomised to either a control group, where patients received standard general practice care, or an intervention group where patients had access to a specialist nurse-led disease management programme. We estimated costs in both groups for coronary heart disease-related resource use. The main outcome measure used in the economic evaluation was quality adjusted life years (QALY) measured using the EuroQol. RESULTS: The disease management programme was associated with an increase in the QALY measured of 0.03 per year and an increase in the total NHS costs of 425 pounds (540 euros), of this only 83 pounds was directly associated with the provision of the nurse clinics. The clinics generated additional QALY at an incremental cost of 13 pounds 158 per QALY compared to the control group. CONCLUSIONS: The use of a nurse-led disease management programme is associated with increased costs in other coronary heart disease-related services as well as for the costs of the clinics. They are also associated with improvements in health. Even in the short term these disease management programmes may represent a cost-effective service, as additional QALY are generated at an acceptable extra cost.

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

OBJECTIVES: To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia. DATA SOURCES: Major electronic databases were searched to January 2005 at least. REVIEW METHODS: Systematic reviews were carried out for test accuracy and effectiveness. Quality assessment was carried out using standard tools. For test accuracy, meta-analyses used a bivariate approach. Effectiveness reviews were conducted under the auspices of the Cochrane Pregnancy and Childbirth Group and used standard Cochrane review methods. The economic evaluation was from an NHS perspective and used a decision tree model. RESULTS: For the 27 tests reviewed, the quality of included studies was generally poor. Some tests appeared to have high specificity, but at the expense of compromised sensitivity. Tests that reached specificities above 90% were body mass index greater than 34, alpha-foetoprotein and uterine artery Doppler (bilateral notching). The only Doppler test with a sensitivity of over 60% was resistance index and combinations of indices. A few tests not commonly found in routine practice, such as kallikreinuria and SDS-PAGE proteinuria, seemed to offer the promise of high sensitivity, without compromising specificity, but these would require further investigation. For the 16 effectiveness reviews, the quality of included studies was variable. The largest review was of antiplatelet agents, primarily low-dose aspirin, and included 51 trials (36,500 women). This was the only review where the intervention was shown to prevent both pre-eclampsia and its consequences for the baby. Calcium supplementation also reduced the risk of pre-eclampsia, but with some uncertainty about the impact on outcomes for the baby. The only other intervention associated with a reduction in RR of pre-eclampsia was rest at home, with or without a nutritional supplement, for women with normal blood pressure. However, this review included just two small trials and its results should be interpreted with caution. The cost of most of the tests was modest, ranging from 5 pounds for blood tests such as serum uric acid to approximately 20 pounds for Doppler tests. Similarly, the cost of most interventions was also modest. In contrast, the best estimate of additional average cost associated with an average case of pre-eclampsia was high at approximately 9000 pounds. The results of the modelling revealed that prior testing with the test accuracy sensitivities and specificities identified appeared to offer little as a way of improving cost-effectiveness. Based on the evidence reviewed, none of the tests appeared sufficiently accurate to be clinically useful and the results of the model favoured no-test/treat-all strategies. Rest at home without any initial testing appeared to be the most cost-effective 'test-treatment' combination. Calcium supplementation to all women, without any initial testing, appeared to be the second most cost-effective. The economic model provided little support that any form of Doppler test has sufficiently high sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia. It also suggested that the pattern of cost-effectiveness was no different in high-risk mothers than the low-risk mothers considered in the base case. CONCLUSIONS: The tests evaluated are not sufficiently accurate, in our opinion, to suggest their routine use in clinical practice. Calcium and antiplatelet agents, primarily low-dose aspirin, were the interventions shown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is likely to be the provision of an effective, affordable and safe intervention applied to all mothers without prior testing to assess levels of risk. It is probably premature to suggest the implementation of a treat-all intervention strategy at present, however the feasibility and acceptability of this to women could be explored. Rigorous evaluation is needed of tests with modest cost whose initial assessments suggest that they may have high levels of both sensitivity and specificity. Similarly, there is a need for high-quality, adequately powered randomised controlled trials to investigate whether interventions such as advice to rest are indeed effective in reducing pre-eclampsia. In future, an economic model should be developed that considers not just pre-eclampsia, but other related outcomes, particularly those relevant to the infant such as perinatal death, preterm birth and small for gestational age. Such a modelling project should make provision for primary data collection on the safety of interventions and their associated costs.

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

OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of naltrexone for relapse prevention in detoxified formerly opioid-dependent individuals compared with any strategy that does not use naltrexone, including treatment with placebo, other pharmacological treatments, psychosocial interventions or no treatment. DATA SOURCES: Major electronic databases were searched from inception to September 2005. REVIEW METHODS: Selected studies were screened and quality assessed. Meta-analyses were carried out as appropriate. A decision-analytic model using Monte Carlo simulation was developed that compared naltrexone as an adjunctive therapy to no naltrexone. It assumed compliance rates that were not enhanced by contingent management rewards (because this is current UK practice). Utility values could not be identified from the literature and so were obtained by research specially commissioned from the Value of Health Panel. RESULTS: The methodological quality of the 26 randomised controlled trials (RCTs) that met the inclusion criteria was poor to moderate. The results suggest that naltrexone as maintenance therapy may be better than placebo in terms of retention in treatment, but this was not statistically significant. A meta-analysis of seven included RCTs gave the relative risk (RR) of loss of retention in treatment in the naltrexone arm as 0.94. The pooled hazard ratio (HR) reported in five of the RCTs for retention in treatment data followed up to 35 weeks was calculated as 0.90 in favour of naltrexone and also did not reach statistical significance. The risk of drug abuse in naltrexone versus placebo, with or without psychological support given in both arms, gave a pooled RR of 0.72, which was a statistically significant difference in favour of naltrexone. The pooled HR from three RCTs for opioid relapse-free rates was significantly different from placebo in favour of naltrexone 0.53; however, this fell off over time and may be of limited clinical significance. The RR of reimprisonment while on naltrexone therapy showed results in favour of naltrexone in the combined two studies of parolees or people on probation, but the number of participants was small. One study of 52 participants found that the difference in improvement score for risky sexual behaviour in the naltrexone group compared with the placebo group was not statistically significant. The adverse events data reported showed no significant difference between the naltrexone and placebo arms. The quality of the nine RCTs of interventions designed to increase retention with naltrexone was poor to moderate; however, all three different modalities of enhanced care showed some evidence of effectiveness. All of the contingency management programmes used incentive vouchers; the mean duration of treatment retention was 7.4 weeks for the contingency management intervention compared with 2.3-5.6 weeks for the naltrexone treatment alone. The mean length of time for which patients stayed on naltrexone was 84-103 days with additional psychosocial therapy compared with 43-64 days for the control group. In trials with added pharmacological agents the RRs of stopping treatment were 1.63 at 6 months and 1.31 at 12 months (in favour of naltrexone plus fluoxetine). It became statistically significant at 6 months, but not at 12 months. A meta-analysis of the RR of stopping treatment at week 12 (the minimum follow-up period) was carried out using six of the nine studies. The pooled RR of stopping treatment was 0.81. The results indicated that overall the intervention groups had 19% fewer patients who stopped treatment compared with the control group, but there was only a small number of studies and their quality was relatively poor. No existing economic evaluations were identified. The point estimate for the cost-effectiveness of naltrexone was pound42,500 per quality-adjusted life-year (QALY). Sensitivity analysis was carried out and the incremental cost-effectiveness ratio varied between pound34,600 and pound42,500 per QALY gained. CONCLUSIONS: Following successful withdrawal from opioids, naltrexone may be administered on a chronic basis to block any future effects of opioids. Naltrexone appears to have some limited benefit in helping formerly opioid-dependent individuals to remain abstinent, although the quality of the evidence is relatively poor and heterogeneous. The limited quality and extent of the studies precluded an analysis of subgroups likely to benefit from naltrexone prescribing. Oral naltrexone is used infrequently in current UK practice, and this review suggests that this is appropriate as there is little evidence to support its wider implementation. There is an important deficit in information about the quality of life of people who use illicit opioids and this would perhaps be a worthwhile area of research in informing policy questions about the cost-effectiveness of different programmes and interventions.

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

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals. DATA SOURCES: Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed. REVIEW METHODS: The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective. RESULTS: Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses. CONCLUSIONS: Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.

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

OBJECTIVES: The aim of this review is to determine the clinical effectiveness and cost-effectiveness of enzyme replacement therapy (ERT) in the treatment of symptomatic Gaucher's disease. DATA SOURCES: Major electronic databases were searched from their inception to August 2003; and updated from January 2003 to July/August 2004. REVIEW METHODS: Databases were searched for studies that met the criteria and selected data were extracted and evaluated. Studies were assessed for their relevance to the UK context and the review objective. The bibliographic databases were also searched to identify existing cost studies, economic evaluations and models. A Markov decision model was constructed based on patients moving between states defined by the modified Severity Score Index (SSI). Most of the parameters were derived from the published literature. ERT was assumed to restore patients to full health in the base case. RESULTS: Sixty-three studies were included, all suggestive of benefit with ERT. However, the way in which the effects translate into patient well-being and survival or the need for services and resources has not been reliably estimated. Quality of life improvements with ERT have been reported. Nonetheless, studies based on the Short Form 36 (SF-36) indicate that patients treated with ERT continue to have reduced health-related quality of life (HRQoL) compared with the general population. No study attached utility values to quality of life measures for ERT-treated patients. Thirty-one studies relevant to the natural history of the disease were found. Sixteen looked at multiple clinical characteristics of a cohort of patients with type I Gaucher's disease. There was considerable within-study and between-study heterogeneity, but all showed that Gaucher's disease was a progressive condition. Some suggested that the disease may become more indolent in adulthood; however, studies were discrepant on this point. Most disease is diagnosed in adulthood, although about one-quarter presented in childhood, these patients having the most severe symptoms and greatest rate of progression. Modelling of natural history was undertaken using the five papers that reported the SSI for each patient, along with patient-level data on age, age at diagnosis, splenectomy status and genotype, to address the question of whether disease stabilises in adulthood and the degree of correlation between phenotype and genotype. Analysis of the available data suggested that disease progression is likely to slow markedly in adulthood and that genotype is a useful predictor of clinical expression of the disease. Five studies looked at quality of life. Data on this topic were also obtained from the registries. The evidence suggests that the vast majority of the clinical characteristics of type I Gaucher's disease have little impact on subjective HRQoL and that therefore for the majority of people with type I Gaucher's disease this may not be a severe condition. Bone and skeletal symptoms contribute most to the morbidity of the disease and can lead to severe pain and immobility. The mean cost per patient treated was approximately pounds sterling 86,000 per annum in England and Wales. The cost per patient varied considerably by dose. Four existing economic evaluations were found, all of which calculated a very high cost per quality-adjusted life-year (QALY). Using the Markov decision model, ERT was assumed to restore patients to full health in the base case. The estimated incremental cost per QALY [incremental cost-effectiveness ratio (ICER)] in the base case ranged from pounds sterling 380,000 to pounds sterling 476,000 per QALY, depending on genotype. Univariate sensitivity analyses examined ERT not restoring full health, more severe disease progression in the untreated cohort, and only treating the most severely affected patients. These produced ICERs of approximately pounds sterling 1.4 million, pounds sterling 296,000 and pounds sterling 275,000 per QALY, respectively. The base-case unit cost of the drug is pounds sterling 2.975. The unit cost would have had to be reduced ten-fold, to pounds sterling 0.30, to obtain an ICER of pounds sterling 30,000 per QALY. At a unit cost of pounds sterling 1 the ICER would be pounds sterling 120,000 per QALY. CONCLUSIONS: Although ERT for treating the 'average' Gaucher's disease patient exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over ten-fold, some argue that since orphan drug legislation encouraged the manufacture of Cerezyme, and Gaucher's disease can be defined as an orphan disease, the NHS has little option but to provide it, despite its great expense. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, these were very thin indeed. Nonetheless, even large errors in estimates of the distribution of genotype, genotype--phenotype associations, effectiveness and numbers of patients will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. Further research could help to clarify the many uncertainties that exist. However, although doing so will be of clinical interest, it is questionable whether, within the current pricing environment, such research would have any substantive impact on policy decisions. It is highly improbable that, whatever the findings of such research, the ICER could be brought down by the orders of magnitude required to make ERT an efficient use of health service resources. (The possible exception to this would be investigating the most efficient alternative treatment strategies for using ERT in a paediatric population only.) Moreover, if under equity considerations for orphan diseases the NHS feels it is important to provide this drug, regardless of its cost-effectiveness, then refining the precision of the ICER estimate also becomes superfluous.

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

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of the administration of intravenous enzyme replacement therapy (ERT) to symptomatic patients for the prevention of long-term damage and symptoms in Fabry's disease and in mucopolysaccharidosis type 1 (MPS1). DATA SOURCES: Electronic databases from inception up to mid-2004. Contact with clinical experts. REVIEW METHODS: Relevant studies were identified and assessed using recommended quality criteria. RESULTS: The results suggested beneficial effects of ERT for Fabry's disease on measures of pain, cardiovascular function and some end-points reflecting neurosensory function. Renal function appeared to be stabilised by ERT. At present there are no utility-related health-related quality of life data on which to assess the relative health gain of ERT in MPS1. In order to be able to demonstrate the full extent of health gain from treatment, it was necessary to review the natural history of untreated patients in each disease in order to try to estimate the health loss prevented. The published information for Fabry's disease tallied with descriptions of a multi-system, life-threatening disorder particularly involving kidney, heart and brain with individual patients exhibiting many manifestations. The fragmentary information reviewed in 16 studies relevant to the natural history of MPS1 did not generate a coherent picture of disease progression and could provide little added value to published narrative reviews. For Fabry's disease, the mean cost per patient (50 kg) treated is around pounds sterling 85,000 per annum in England and Wales. The cost per patient varies considerably by dose. No published evidence reporting an economic evaluation of ERT for Fabry's disease was identified by this review. A dynamic decision model was constructed based on a birth cohort of male patients who are followed up until death. Owing to lack of information reported in the literature, many assumptions had to be applied. The key assumptions were that ERT returns patients to full health and a normal life expectancy. As far as possible, all assumptions favoured rather than detracted from the value of ERT. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost-effectiveness ratio (ICER) in the base case was pounds sterling 252,000 per QALY (agalsidase beta). Univariate sensitivity analysis around the key assumptions produced ICERs ranging from pounds sterling 602,000 to pounds sterling 241,000. The base case unit cost of ERT was taken as pounds sterling 65.1/mg based on the cost of agalsidase beta. The unit cost would have had to be reduced to pounds sterling 9 to obtain an ICER of pounds sterling 30,000 per QALY. For MPS1, the mean cost per child patient (20 kg) treated is approximately pounds sterling 95,000 and an adult (70 kg) around pounds sterling 335,000 per annum in England and Wales. The cost per patient varies considerably by dose. There is no published evidence reporting an economic evaluation of ERT for MPS1 and no study was identified that reported the quality of life of MPS1 patients within a utility format. Furthermore, no or minimal information of the severity and rate of change of clinical manifestations of disease or the impact of ERT on these factors was identified. Information on the effect of ERT on mortality is also lacking owing to the relatively short time that the treatment has been available. Given this lack of data, it was not possible to develop a cost-effectiveness model of ERT treatment for MPS1 as the model would consist almost completely of assumptions based on no published evidence, leading to an incremental cost per QALY result that would be meaningless. CONCLUSIONS: Although ERT for treating the 'average' patient with Fabry's disease exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue that, as the disease is classified as an orphan disease under European Union legislation, it has special status, and the NHS has no option but to provide ERT. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, this was very thin indeed. Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. In order to overcome limited evidence on the natural history of the disease and the clinical effectiveness of the intervention, the establishment of disease-specific data registries is suggested to facilitate the process of technology assessment and improving patient care. These registries should attempt to include all affected patients in the UK, and collect longitudinal patient level data on clinically relevant problems, interventions received and quality of life in a utility format.