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The 22q11.2 deletion syndrome (22q11.2DS) is associated with high psychiatric morbidity. However, large phenotypic heterogeneity hampers early detection of 22q11.2DS individuals at highest risk. Here, we investigated whether individuals with 22q11.2DS can be subdivided into clinically relevant subgroups based on their severity of cognitive impairments and whether such subgroups differ in polygenic risk. Using a cross-sectional design, we examined the number of lifetime psychiatric diagnoses and polygenic risk scores for schizophrenia in an unselected nationwide biobank cohort of individuals with 22q11.2DS (n = 183). Approximately 35% of this sample, aged 10-30 years, had a history with one or more psychiatric diagnosis. In a representative nested subgroup of 28 children and youth, we performed additional comprehensive cognitive evaluation and assessed psychiatric symptoms. Unsupervised hierarchical cluster analysis was performed to divide the subgroup of 22q11.2DS individuals, based on their performance on the cognitive testing battery. This produced two groups that did not differ in mean age or gender composition, but were characterized by low cognitive (LF) and high cognitive (HF) functional levels. The LF group, which had significantly lower global cognitive functioning scores, also displayed higher negative symptom scores; whereas, the HF group displayed lower rate of current psychiatric disorders than the LF group and the reminder of the biobank cohort. The polygenic risk score for schizophrenia was insignificantly lower for the low functioning group than for the high functioning group, after adjustment. Cognitive functioning may provide useful information on psychiatric risk.
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Background: Guidelines for sepsis recommend treating those at highest risk within 1 hour. The emergency care system can only achieve this if sepsis is recognised and prioritised. Ambulance services can use prehospital early warning scores alongside paramedic diagnostic impression to prioritise patients for treatment or early assessment in the emergency department. Objectives: To determine the accuracy, impact and cost-effectiveness of using early warning scores alongside paramedic diagnostic impression to identify sepsis requiring urgent treatment. Design: Retrospective diagnostic cohort study and decision-analytic modelling of operational consequences and cost-effectiveness. Setting: Two ambulance services and four acute hospitals in England. Participants: Adults transported to hospital by emergency ambulance, excluding episodes with injury, mental health problems, cardiac arrest, direct transfer to specialist services, or no vital signs recorded. Interventions: Twenty-one early warning scores used alongside paramedic diagnostic impression, categorised as sepsis, infection, non-specific presentation, or other specific presentation. Main outcome measures: Proportion of cases prioritised at the four hospitals; diagnostic accuracy for the sepsis-3 definition of sepsis and receiving urgent treatment (primary reference standard); daily number of cases with and without sepsis prioritised at a large and a small hospital; the minimum treatment effect associated with prioritisation at which each strategy would be cost-effective, compared to no prioritisation, assuming willingness to pay £20,000 per quality-adjusted life-year gained. Results: Data from 95,022 episodes involving 71,204 patients across four hospitals showed that most early warning scores operating at their pre-specified thresholds would prioritise more than 10% of cases when applied to non-specific attendances or all attendances. Data from 12,870 episodes at one hospital identified 348 (2.7%) with the primary reference standard. The National Early Warning Score, version 2 (NEWS2), had the highest area under the receiver operating characteristic curve when applied only to patients with a paramedic diagnostic impression of sepsis or infection (0.756, 95% confidence interval 0.729 to 0.783) or sepsis alone (0.655, 95% confidence interval 0.63 to 0.68). None of the strategies provided high sensitivity (> 0.8) with acceptable positive predictive value (> 0.15). NEWS2 provided combinations of sensitivity and specificity that were similar or superior to all other early warning scores. Applying NEWS2 to paramedic diagnostic impression of sepsis or infection with thresholds of > 4, > 6 and > 8 respectively provided sensitivities and positive predictive values (95% confidence interval) of 0.522 (0.469 to 0.574) and 0.216 (0.189 to 0.245), 0.447 (0.395 to 0.499) and 0.274 (0.239 to 0.313), and 0.314 (0.268 to 0.365) and 0.333 (confidence interval 0.284 to 0.386). The mortality relative risk reduction from prioritisation at which each strategy would be cost-effective exceeded 0.975 for all strategies analysed. Limitations: We estimated accuracy using a sample of older patients at one hospital. Reliable evidence was not available to estimate the effectiveness of prioritisation in the decision-analytic modelling. Conclusions: No strategy is ideal but using NEWS2, in patients with a paramedic diagnostic impression of infection or sepsis could identify one-third to half of sepsis cases without prioritising unmanageable numbers. No other score provided clearly superior accuracy to NEWS2. Research is needed to develop better definition, diagnosis and treatments for sepsis. Study registration: This study is registered as Research Registry (reference: researchregistry5268). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/136/10) and is published in full in Health Technology Assessment; Vol. 28, No. 16. See the NIHR Funding and Awards website for further award information.
Sepsis is a life-threatening condition in which an abnormal response to infection causes heart, lung or kidney failure. People with sepsis need urgent treatment. They need to be prioritised at the emergency department rather than waiting in the queue. Paramedics attempt to identify people with possible sepsis using an early warning score (based on simple measurements, such as blood pressure and heart rate) alongside their impression of the patient's diagnosis. They can then alert the hospital to assess the patient quickly. However, an inaccurate early warning score might miss cases of sepsis or unnecessarily prioritise people without sepsis. We aimed to measure how accurately early warning scores identified people with sepsis when used alongside paramedic diagnostic impression. We collected data from 71,204 people that two ambulance services transported to four different hospitals in 2019. We recorded paramedic diagnostic impressions and calculated early warning scores for each patient. At one hospital, we linked ambulance records to hospital records and identified who had sepsis. We then calculated the accuracy of using the scores alongside diagnostic impression to diagnose sepsis. Finally, we used modelling to predict how many patients (with and without sepsis) paramedics would prioritise using different strategies based on early warning scores and diagnostic impression. We found that none of the currently available early warning scores were ideal. When they were applied to all patients, they prioritised too many people. When they were only applied to patients whom the paramedics thought had infection, they missed many cases of sepsis. The NEWS2, score, which ambulance services already use, was as good as or better than all the other scores we studied. We found that using the NEWS2, score in people with a paramedic impression of infection could achieve a reasonable balance between prioritising too many patients and avoiding missing patients with sepsis.
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Escore de Alerta Precoce , Serviços Médicos de Emergência , Sepse , Adulto , Humanos , Análise Custo-Benefício , Estudos Retrospectivos , Sepse/diagnósticoRESUMO
Aim: To describe the protocol for a multi-centre randomised controlled trial to determine whether treatment protocols monitoring daily CRP (C-reactive protein) or PCT (procalcitonin) safely allow a reduction in duration of antibiotic therapy in hospitalised adult patients with sepsis. Design: Multicentre three-arm randomised controlled trial. Setting: UK NHS hospitals. Target population: Hospitalised critically ill adults who have been commenced on intravenous antibiotics for sepsis. Health technology: Three protocols for guiding antibiotic discontinuation will be compared: (a) standard care; (b) standard care + daily CRP monitoring; (c) standard care + daily PCT monitoring. Standard care will be based on routine sepsis management and antibiotic stewardship. Measurement of outcomes and costs. Outcomes will be assessed to 28 days. The primary outcomes are total duration of antibiotics and safety outcome of all-cause mortality. Secondary outcomes include: escalation of care/re-admission; infection re-lapse/recurrence; antibiotic dose; length and level of critical care stay and length of hospital stay. Ninety-day all-cause mortality rates will also be collected. An assessment of cost effectiveness will be performed. Conclusion: In the setting of routine NHS care, if this trial finds that a treatment protocol based on monitoring CRP or PCT safely allows a reduction in duration of antibiotic therapy, and is cost effective, then this has the potential to change clinical practice for critically ill patients with sepsis. Moreover, if a biomarker-guided protocol is not found to be effective, then it will be important to avoid its use in sepsis and prevent ineffective technology becoming widely adopted in clinical practice.
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Background: Severe acute respiratory syndrome coronavirus 2 is the virus that causes coronavirus disease 2019. Over six million deaths worldwide have been associated with coronavirus disease 2019. Objective: To assess the cost-effectiveness of treatments used for the treatment of coronavirus disease 2019 in hospital or used in the community in patients with coronavirus disease 2019 at high risk of hospitalisation. Setting: Treatments provided in United Kingdom hospital and community settings. Methods: Clinical effectiveness estimates were taken from the coronavirus disease-network meta-analyses initiative and the metaEvidence initiative. A mathematical model was constructed to explore how the interventions impacted on patient health, measured in quality-adjusted life-years gained. The costs associated with treatment, including those of hospital care, were also estimated and used to form a cost per quality-adjusted life-year gained value which was compared with thresholds published by the National Institute for Health and Care Excellence. Estimates of cost-effectiveness compared against current standard of care were produced in both the hospital and community settings at three different levels of efficacy: mean, low and high. Public list prices were used for interventions with neither confidential patient access schemes nor confidential list prices considered. Results incorporating confidential pricing data were provided to the National Institute for Health and Care Excellence appraisal committee. Results: The treatments were estimated to be clinically effective although not all reached statistical significance. All treatments in the hospital setting, or community, were estimated to plausibly have a cost per quality-adjusted life-year gained value below National Institute for Health and Care Excellence's thresholds when compared with standard of care. However, almost all drugs could plausibly have cost per quality-adjusted life-years above National Institute for Health and Care Excellence's thresholds. However, there is considerable uncertainty in the results as the prevalent severe acute respiratory syndrome coronavirus 2 variant, vaccination status, history of being infected with severe acute respiratory syndrome coronavirus 2 and standard of care have all evolved since the pivotal studies were conducted which could have significant impact on the efficacy of each drug. For drugs used in high-risk patients in the community setting, the proportion of people at high risk who need hospital admission was a large driver of the cost per quality-adjusted life-year. Limitations: No studies were identified that were conducted in current conditions. This may be a large limitation as the severe acute respiratory syndrome coronavirus 2 variant changes. No head-to-head studies of interventions were identified. Conclusions: The results produced could be informative to decision-makers, although conclusions regarding the most clinical - and cost-effectiveness of each intervention should be tentative due to the evolving nature of the decision problem and, in this report, the use of list prices only. Comparisons between interventions should also be treated with caution due to potentially large heterogeneity between studies. Future work: Research assessing the relative clinical effectiveness of interventions within head-to-head studies in current conditions would be beneficial. Contemporary information related to the probability of hospital admission and death for patients at high risk in the community would improve the precision of the estimates generated. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR135564) and will be published in full in Health Technology Assessment; Vol. 27, No. 14. See the NIHR Journals Library website for further project information.
Coronavirus disease 2019 is an infectious disease that can cause death and long-term ill-health. Treatments exist that can be provided in hospital to reduce the number of deaths from coronavirus disease 2019. Treatments also exist which can be provided in the community for people at high risk of needing to be admitted to hospital to reduce the number of admissions and to reduce the number of deaths from coronavirus disease 2019. However, the value for money of these treatments has not been estimated. We took the clinical effectiveness of nine treatments from published literature sources and built a model that estimated the value for money of six treatments compared with care without these treatments. Three treatments were excluded due to confidential prices. The results of the model showed that many treatments in a hospital setting had estimates of cost-effectiveness that would normally be seen to be good value for money using the thresholds published by the National Institute of Health and Care Excellence. The same was true for some treatments in a community setting. However, it is also possible that these treatments are not good value for money. The benefit of the drugs and value for money is highly uncertain as studies trying to estimate the gain have been done with (1) previous variants of the virus causing coronavirus disease 2019 being widespread, (2) where the proportion of people who have had vaccinations or who had previously had coronavirus disease 2019 is low and (3) where standard treatment was that when coronavirus disease 2019 was first identified, and not the drugs used now. Because of these differences, and the unknown price of some interventions, we cannot confidently say which (if any) treatments help patients the most, or which treatment represents the best value for money. Further research, in current conditions, would improve the accuracy of our answers.
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COVID-19 , SARS-CoV-2 , Humanos , Análise Custo-Benefício , Reino Unido , Anos de Vida Ajustados por Qualidade de VidaRESUMO
BACKGROUND: Extrapolation of survival data is a key task in health technology assessments (HTAs), which may be improved by incorporating general population mortality data via relative survival models. Dynamic survival models are a promising method for extrapolation that may be expanded to dynamic relative survival models (DRSMs), a novel development presented here. There are currently neither examples of dynamic models in HTA nor comparisons of DRSMs with other relative survival models when used for survival extrapolation. METHODS: An existing appraisal, for which there had been disagreement over the approach to survival extrapolation, was chosen and the health economic model recreated. The sensitivity of estimates of cost-effectiveness to different model choices (standard survival models, DSMs, and DRSMs) and specifications was examined. The appraisal informed a simulation study to evaluate DRSMs with relative survival models based on both standard and spline-based (flexible) models. RESULTS: Dynamic models provided insight into the behavior of the trend in the hazard function and how it may vary during the extrapolated phase. DRSMs led to extrapolations with improved plausibility for which model choice may be based on clinical input. In the simulation study, the flexible and dynamic relative survival models performed similarly and provided highly variable extrapolations. LIMITATIONS: Further experience with these models is required to identify settings when they are most useful, and they provide sufficiently accurate extrapolations. CONCLUSIONS: Dynamic models provide a flexible and attractive method for extrapolating survival data and facilitate the use of clinical input for model choice. Flexible and dynamic relative survival models make few structural assumptions and can improve extrapolation plausibility, but further research is required into methods for reducing the variability in extrapolations.
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Modelos Econômicos , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício , Humanos , Análise de SobrevidaRESUMO
AIMS: Accurately estimating mean survival after solid organ transplant (SOT) is crucial for efficient healthcare resource allocation decisions. However, registry-based post-transplant recipient survival estimates vary greatly and are incomplete. Often, the methods used in lifetime survival extrapolation may not fit complex transplant data and therefore alternative methods are required. We aimed to explore the flexible cubic spline methodology as a meaningful alternative for estimating lifetime survival following SOT. METHODS: Survival analyses were conducted in kidney, liver, heart, and lung transplant recipients. Mean survival was estimated using flexible cubic splines on the hazard scale fitted with three knots, based on where hazards changed direction, clinical advice, and best-fit curve using Akaike and Bayesian information criterion. The tail was extrapolated when data were no longer available. Extrapolation tails were compared with general population mortality, using age-matched life table hazards, and the highest hazards were taken at all times. RESULTS: We found that mean survival post-transplant was longest for kidney transplants (US: 22.79 years; UK: 26.58 years), followed by liver (US: 20.90 years; UK: 20.38 years), heart (US: 14.82 years; UK: 15.85 years), and lung (US: 9.28 years; UK: 9.21 years). A sensitivity analysis using two knots found differences in survival ranging from -1.30 to +4.83 years across SOTs examined. LIMITATIONS: This study does not represent individual patient survival, survival by age groups, multiple-organ transplants, or assess factors that may impact overall or organ survival. CONCLUSIONS: Our study estimates reflect real-world survival following SOTs and demonstrate the importance of including long-term hazards in survival estimations. These lifetime survival estimates can be used by decision-makers in situations where means are preferred over medians (e.g. population projections, budgetary estimates, and cost-effectiveness models) and can thus offer a meaningful alternative to the estimates used and accepted in current practice.
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Transplante de Rim , Transplante de Órgãos , Teorema de Bayes , Humanos , Análise de Sobrevida , Reino Unido/epidemiologiaRESUMO
AIM: To determine how varenicline, bupropion, nicotine replacement therapy (NRT) and electronic cigarettes compare with respect to their clinical effectiveness and safety. METHOD: Systematic reviews and Bayesian network meta-analyses of randomized controlled trials, in any setting, of varenicline, bupropion, NRT and e-cigarettes (in high, standard and low doses, alone or in combination) in adult smokers and smokeless tobacco users with follow-up duration of 24 weeks or greater (effectiveness) or any duration (safety). Nine databases were searched until 19 February 2019. Primary outcomes were sustained tobacco abstinence and serious adverse events (SAEs). We estimated odds ratios (ORs) and treatment rankings and conducted meta-regression to explore covariates. RESULTS: We identified 363 trials for effectiveness and 355 for safety. Most monotherapies and combination therapies were more effective than placebo at helping participants to achieve sustained abstinence; the most effective of these, estimated with some imprecision, were varenicline standard [OR = 2.83, 95% credible interval (CrI) = 2.34-3.39] and varenicline standard + NRT standard (OR = 5.75, 95% CrI = 2.27-14.88). Estimates were higher in smokers receiving counselling than in those without and in studies with higher baseline nicotine dependence scores than in those with lower scores. Varenicline standard + NRT standard showed a high probability of being ranked best or second-best. For safety, only bupropion at standard dose increased the odds of experiencing SAEs compared with placebo (OR = 1.27, 95% CrI = 1.04-1.58), and we found no evidence of effect modification. CONCLUSIONS: Most tobacco cessation monotherapies and combination therapies are more effective than placebo at helping participants to achieve sustained abstinence, with varenicline appearing to be most effective based on current evidence. There does not appear to be strong evidence of associations between most tobacco cessation pharmacotherapies and adverse events; however, the data are limited and there is a need for improved reporting of safety data.
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Sistemas Eletrônicos de Liberação de Nicotina , Abandono do Hábito de Fumar , Abandono do Uso de Tabaco , Adulto , Teorema de Bayes , Bupropiona/efeitos adversos , Humanos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Abandono do Hábito de Fumar/métodos , Dispositivos para o Abandono do Uso de Tabaco , Resultado do Tratamento , Vareniclina/uso terapêuticoRESUMO
BACKGROUND: Estimates of future survival can be a key evidence source when deciding if a medical treatment should be funded. Current practice is to use standard parametric models for generating extrapolations. Several emerging, more flexible, survival models are available which can provide improved within-sample fit. This study aimed to assess if these emerging practice models also provided improved extrapolations. METHODS: Both a simulation study and a case-study were used to assess the goodness of fit of five classes of survival model. These were: current practice models, Royston Parmar models (RPMs), Fractional polynomials (FPs), Generalised additive models (GAMs), and Dynamic survival models (DSMs). The simulation study used a mixture-Weibull model as the data-generating mechanism with varying lengths of follow-up and sample sizes. The case-study was long-term follow-up of a prostate cancer trial. For both studies, models were fit to an early data-cut of the data, and extrapolations compared to the known long-term follow-up. RESULTS: The emerging practice models provided better within-sample fit than current practice models. For data-rich simulation scenarios (large sample sizes or long follow-up), the GAMs and DSMs provided improved extrapolations compared with current practice. Extrapolations from FPs were always very poor whilst those from RPMs were similar to current practice. With short follow-up all the models struggled to provide useful extrapolations. In the case-study all the models provided very similar estimates, but extrapolations were all poor as no model was able to capture a turning-point during the extrapolated period. CONCLUSIONS: Good within-sample fit does not guarantee good extrapolation performance. Both GAMs and DSMs may be considered as candidate extrapolation models in addition to current practice. Further research into when these flexible models are most useful, and the role of external evidence to improve extrapolations is required.
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Análise de Sobrevida , Simulação por Computador , Humanos , Tamanho da AmostraRESUMO
OBJECTIVES: Curative treatments can result in complex hazard functions. The use of standard survival models may result in poor extrapolations. Several models for data which may have a cure fraction are available, but comparisons of their extrapolation performance are lacking. A simulation study was performed to assess the performance of models with and without a cure fraction when fit to data with a cure fraction. METHODS: Data were simulated from a Weibull cure model, with 9 scenarios corresponding to different lengths of follow-up and sample sizes. Cure and noncure versions of standard parametric, Royston-Parmar, and dynamic survival models were considered along with noncure fractional polynomial and generalized additive models. The mean-squared error and bias in estimates of the hazard function were estimated. RESULTS: With the shortest follow-up, none of the cure models provided good extrapolations. Performance improved with increasing follow-up, except for the misspecified standard parametric cure model (lognormal). The performance of the flexible cure models was similar to that of the correctly specified cure model. Accurate estimates of the cured fraction were not necessary for accurate hazard estimates. Models without a cure fraction provided markedly worse extrapolations. CONCLUSIONS: For curative treatments, failure to model the cured fraction can lead to very poor extrapolations. Cure models provide improved extrapolations, but with immature data there may be insufficient evidence to choose between cure and noncure models, emphasizing the importance of clinical knowledge for model choice. Dynamic cure fraction models were robust to model misspecification, but standard parametric cure models were not.
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Intervalo Livre de Doença , Modelos Teóricos , Análise de Sobrevida , Humanos , Tamanho da AmostraRESUMO
BACKGROUND: Cigarette smoking is one of the leading causes of early death. Varenicline [Champix (UK), Pfizer Europe MA EEIG, Brussels, Belgium; or Chantix (USA), Pfizer Inc., Mission, KS, USA], bupropion (Zyban; GlaxoSmithKline, Brentford, UK) and nicotine replacement therapy are licensed aids for quitting smoking in the UK. Although not licensed, e-cigarettes may also be used in English smoking cessation services. Concerns have been raised about the safety of these medicines and e-cigarettes. OBJECTIVES: To determine the clinical effectiveness, safety and cost-effectiveness of smoking cessation medicines and e-cigarettes. DESIGN: Systematic reviews, network meta-analyses and cost-effectiveness analysis informed by the network meta-analysis results. SETTING: Primary care practices, hospitals, clinics, universities, workplaces, nursing or residential homes. PARTICIPANTS: Smokers aged ≥ 18 years of all ethnicities using UK-licensed smoking cessation therapies and/or e-cigarettes. INTERVENTIONS: Varenicline, bupropion and nicotine replacement therapy as monotherapies and in combination treatments at standard, low or high dose, combination nicotine replacement therapy and e-cigarette monotherapies. MAIN OUTCOME MEASURES: Effectiveness - continuous or sustained abstinence. Safety - serious adverse events, major adverse cardiovascular events and major adverse neuropsychiatric events. DATA SOURCES: Ten databases, reference lists of relevant research articles and previous reviews. Searches were performed from inception until 16 March 2017 and updated on 19 February 2019. REVIEW METHODS: Three reviewers screened the search results. Data were extracted and risk of bias was assessed by one reviewer and checked by the other reviewers. Network meta-analyses were conducted for effectiveness and safety outcomes. Cost-effectiveness was evaluated using an amended version of the Benefits of Smoking Cessation on Outcomes model. RESULTS: Most monotherapies and combination treatments were more effective than placebo at achieving sustained abstinence. Varenicline standard plus nicotine replacement therapy standard (odds ratio 5.75, 95% credible interval 2.27 to 14.90) was ranked first for sustained abstinence, followed by e-cigarette low (odds ratio 3.22, 95% credible interval 0.97 to 12.60), although these estimates have high uncertainty. We found effect modification for counselling and dependence, with a higher proportion of smokers who received counselling achieving sustained abstinence than those who did not receive counselling, and higher odds of sustained abstinence among participants with higher average dependence scores. We found that bupropion standard increased odds of serious adverse events compared with placebo (odds ratio 1.27, 95% credible interval 1.04 to 1.58). There were no differences between interventions in terms of major adverse cardiovascular events. There was evidence of increased odds of major adverse neuropsychiatric events for smokers randomised to varenicline standard compared with those randomised to bupropion standard (odds ratio 1.43, 95% credible interval 1.02 to 2.09). There was a high level of uncertainty about the most cost-effective intervention, although all were cost-effective compared with nicotine replacement therapy low at the £20,000 per quality-adjusted life-year threshold. E-cigarette low appeared to be most cost-effective in the base case, followed by varenicline standard plus nicotine replacement therapy standard. When the impact of major adverse neuropsychiatric events was excluded, varenicline standard plus nicotine replacement therapy standard was most cost-effective, followed by varenicline low plus nicotine replacement therapy standard. When limited to licensed interventions in the UK, nicotine replacement therapy standard was most cost-effective, followed by varenicline standard. LIMITATIONS: Comparisons between active interventions were informed almost exclusively by indirect evidence. Findings were imprecise because of the small numbers of adverse events identified. CONCLUSIONS: Combined therapies of medicines are among the most clinically effective, safe and cost-effective treatment options for smokers. Although the combined therapy of nicotine replacement therapy and varenicline at standard doses was the most effective treatment, this is currently unlicensed for use in the UK. FUTURE WORK: Researchers should examine the use of these treatments alongside counselling and continue investigating the long-term effectiveness and safety of e-cigarettes for smoking cessation compared with active interventions such as nicotine replacement therapy. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016041302. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 59. See the NIHR Journals Library website for further project information.
Cigarette smoking is one of the main causes of early death both in the UK and worldwide. Three medicines, varenicline, bupropion and nicotine replacement therapy, are licensed in the UK to help people stop smoking. E-cigarettes can also be used as a stop smoking aid. We combined information from previous studies, including clinical trials, to determine which product was the safest, most effective and best value for money for the NHS. We compared treatments that were given alone as well as treatments that were combined with others, such as combination nicotine replacement therapy, varenicline combined with nicotine replacement therapy, varenicline combined with bupropion and bupropion combined with nicotine replacement therapy. The last three combined treatments are not currently licensed in the UK for smoking cessation. We also compared different treatment doses (low, high and standard doses). We found that most treatments were more effective than placebo in helping people to quit smoking. One of the combination treatments (varenicline at standard dose combined with nicotine replacement therapy at standard dose) was the most effective at getting people to quit smoking, followed by e-cigarette at low dose, varenicline at standard dose combined with bupropion at standard dose, and e-cigarette at high dose. We also found that smokers with higher tobacco dependence and smokers treated with counselling alongside medicines achieved a higher proportion of continuous quitting. We also found evidence that the standard dose of bupropion was associated with an increased risk of serious side effects compared with placebo. There was inconclusive evidence that any of the treatments increased the risk of major cardiovascular side effects. There was some evidence that smokers who received a standard dose of varenicline had an increased risk of major neurological and psychiatric side effects compared with those receiving a standard dose of bupropion. E-cigarette at low dose, varenicline standard plus nicotine replacement therapy standard and varenicline standard plus bupropion standard were the best value for money interventions, but further clinical trials comparing treatments against each other are needed to increase confidence in these findings.
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Sistemas Eletrônicos de Liberação de Nicotina , Abandono do Hábito de Fumar , Análise Custo-Benefício , Humanos , Metanálise em Rede , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina/efeitos adversosRESUMO
OBJECTIVES: Smoking is a leading cause of death worldwide. Cessation aids include varenicline, bupropion, nicotine replacement therapy (NRT), and e-cigarettes at various doses (low, standard and high) and used alone or in combination with each other. Previous cost-effectiveness analyses have not fully accounted for adverse effects nor compared all cessation aids. The objective was to determine the relative cost-effectiveness of cessation aids in the United Kingdom. METHODS: An established Markov cohort model was adapted to incorporate health outcomes and costs due to depression and self-harm associated with cessation aids, alongside other health events. Relative efficacy in terms of abstinence and major adverse neuropsychiatric events was informed by a systematic review and network meta-analysis. Base case results are reported for UK-licensed interventions only. Two sensitivity analyses are reported, one including unlicensed interventions and another comparing all cessation aids but removing the impact of depression and self-harm. The sensitivity of conclusions to model inputs was assessed by calculating the expected value of partial perfect information. RESULTS: When limited to UK-licensed interventions, varenicline standard-dose and NRT standard-dose were most cost-effective. Including unlicensed interventions, e-cigarette low-dose appeared most cost-effective followed by varenicline standard-dose + bupropion standard-dose combined. When the impact of depression and self-harm was excluded, varenicline standard-dose + NRT standard-dose was most cost-effective, followed by varenicline low-dose + NRT standard-dose. CONCLUSION: Although found to be most cost-effective, combined therapy is currently unlicensed in the United Kingdom and the safety of e-cigarettes remains uncertain. The value-of-information analysis suggested researchers should continue to investigate the long-term effectiveness and safety outcomes of e-cigarettes in studies with active comparators.
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Depressão/epidemiologia , Custos de Medicamentos , Sistemas Eletrônicos de Liberação de Nicotina/economia , Comportamento Autodestrutivo/epidemiologia , Agentes de Cessação do Hábito de Fumar/efeitos adversos , Agentes de Cessação do Hábito de Fumar/economia , Abandono do Hábito de Fumar/economia , Fumar/efeitos adversos , Dispositivos para o Abandono do Uso de Tabaco/efeitos adversos , Dispositivos para o Abandono do Uso de Tabaco/economia , Bupropiona/efeitos adversos , Bupropiona/economia , Análise Custo-Benefício , Depressão/economia , Depressão/psicologia , Humanos , Cadeias de Markov , Modelos Econômicos , Método de Monte Carlo , Metanálise em Rede , Agonistas Nicotínicos/efeitos adversos , Agonistas Nicotínicos/economia , Anos de Vida Ajustados por Qualidade de Vida , Recidiva , Medição de Risco , Fatores de Risco , Comportamento Autodestrutivo/economia , Comportamento Autodestrutivo/psicologia , Fumar/economia , Fumar/mortalidade , Fatores de Tempo , Resultado do Tratamento , Reino Unido/epidemiologia , Vareniclina/efeitos adversos , Vareniclina/economiaRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), which at the time of writing (January 2021) was responsible for more than 2.25 million deaths worldwide and over 100,000 deaths in the UK. SARS-CoV-2 appears to be highly transmissible and could rapidly spread in residential care homes. OBJECTIVE: The work undertaken aimed to estimate the clinical effectiveness and cost-effectiveness of viral detection point-of-care tests for detecting SARS-CoV-2 compared with laboratory-based tests in the setting of a hypothetical care home facility for elderly residents. PERSPECTIVE/SETTING: The perspective was that of the NHS in 2020. The setting was a hypothetical care home facility for elderly residents. Care homes with en suite rooms and with shared facilities were modelled separately. METHODS: A discrete event simulation model was constructed to model individual residents and simulate the spread of SARS-CoV-2 once it had entered the residential care facility. The numbers of COVID-19-related deaths and critical cases were recorded in addition to the number of days spent in isolation. Thirteen strategies involving different hypothetical SARS-CoV-2 tests were modelled. Recently published desirable and acceptable target product profiles for SARS-CoV-2 point-of-care tests and for hospital-based SARS-CoV-2 tests were modelled. Scenario analyses modelled early release from isolation based on receipt of a negative SARS-CoV-2 test result and the impact of vaccination. Incremental analyses were undertaken using both incremental cost-effectiveness ratios and net monetary benefits. RESULTS: Cost-effectiveness results depended on the proportion of residential care facilities penetrated by SARS-CoV-2. SARS-CoV-2 point-of-care tests with desirable target product profiles appear to have high net monetary benefit values. In contrast, SARS-CoV-2 point-of-care tests with acceptable target product profiles had low net monetary benefit values because of unnecessary isolations. The benefit of allowing early release from isolation depended on whether or not the facility had en suite rooms. The greater the assumed efficacy of vaccination, the lower the net monetary benefit values associated with SARS-CoV-2 point-of-care tests, when assuming that a vaccine lowers the risk of contracting SARS-CoV-2. LIMITATIONS: There is considerable uncertainty in the values for key parameters within the model, although calibration was undertaken in an attempt to mitigate this. Some degree of Monte Carlo sampling error persists because of the timelines of the project. The example care home simulated will also not match those of decision-makers deciding on the clinical effectiveness and cost-effectiveness of introducing SARS-CoV-2 point-of-care tests. Given these limitations, the results should be taken as indicative rather than definitive, particularly the cost-effectiveness results when the relative cost per SARS-CoV-2 point-of-care test is uncertain. CONCLUSIONS: SARS-CoV-2 point-of-care tests have considerable potential for benefit for use in residential care facilities, but whether or not this materialises depends on the diagnostic accuracy and costs of forthcoming SARS-CoV-2 point-of-care tests. FUTURE WORK: More accurate results would be obtained when there is more certainty on the diagnostic accuracy of and the reduction in time to test result associated with SARS-CoV-2 point-of-care tests when used in the context of residential care facilities, the proportion of care home penetrated by SARS-CoV-2 and the levels of immunity once vaccination is administered. These parameters are currently uncertain. FUNDING: This report was commissioned by the National Institute for Health Research (NIHR) Evidence Synthesis programme as project number 132154. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 39. See the NIHR Journals Library website for further project information.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 is highly infectious, and this can cause problems in care homes, where the virus can spread quickly. Laboratory-based tests can determine whether or not someone has SARS-CoV-2, but these tests are not perfect and can take a long time to provide a result. Point-of-care tests that can be performed quickly in the care home to detect SARS-CoV-2 are being developed and they may have much shorter times to get a result than laboratory-based tests, although with worse accuracy. The benefit of quicker tests is that decisions to put residents into or release them from isolation can be made sooner, reducing the risk of spreading SARS-CoV-2 and reducing time in isolation. The disadvantage of reduced accuracy is that wrong decisions could be made, resulting in either unnecessary isolation or increased spread of SARS-CoV-2. A computer model was built to explore the impact of using SARS-CoV-2 point-of-care tests for residents of care homes. The model estimated the number of SARS-CoV-2 infections, deaths due to COVID-19 and days in isolation. Strategies were run using different values, including the time to get a test result back, the accuracy of tests, the proportion of care homes where there is a case of SARS-CoV-2, whether residents were isolated individually or in groups and how well vaccines work. The results of the model indicated that point-of-care tests could be good if there was a large decrease in the time to get a test result back, if accuracy was high and if vaccination protection was moderate. However, the accuracy and speed of future point-of-care tests is uncertain. When newer SARS-CoV-2 tests are available, the model will allow an estimate of the clinical effectiveness and cost-effectiveness of the tests to be made.
Assuntos
Teste para COVID-19 , Análise Custo-Benefício , Modelos Teóricos , Testes Imediatos , Instituições Residenciais , Idoso , COVID-19 , Teste para COVID-19/normas , Humanos , Avaliação da Tecnologia BiomédicaRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019. At the time of writing (October 2020), the number of cases of COVID-19 had been approaching 38 million and more than 1 million deaths were attributable to it. SARS-CoV-2 appears to be highly transmissible and could rapidly spread in hospital wards. OBJECTIVE: The work undertaken aimed to estimate the clinical effectiveness and cost-effectiveness of viral detection point-of-care tests for detecting SARS-CoV-2 compared with laboratory-based tests. A further objective was to assess occupancy levels in hospital areas, such as waiting bays, before allocation to an appropriate bay. PERSPECTIVE/SETTING: The perspective was that of the UK NHS in 2020. The setting was a hypothetical hospital with an accident and emergency department. METHODS: An individual patient model was constructed that simulated the spread of disease and mortality within the hospital and recorded occupancy levels. Thirty-two strategies involving different hypothetical SARS-CoV-2 tests were modelled. Recently published desirable and acceptable target product profiles for SARS-CoV-2 point-of-care tests were modelled. Incremental analyses were undertaken using both incremental cost-effectiveness ratios and net monetary benefits, and key patient outcomes, such as death and intensive care unit care, caused directly by COVID-19 were recorded. RESULTS: A SARS-CoV-2 point-of-care test with a desirable target product profile appears to have a relatively small number of infections, a low occupancy level within the waiting bays, and a high net monetary benefit. However, if hospital laboratory testing can produce results in 6 hours, then the benefits of point-of-care tests may be reduced. The acceptable target product profiles performed less well and had lower net monetary benefits than both a laboratory-based test with a 24-hour turnaround time and strategies using data from currently available SARS-CoV-2 point-of-care tests. The desirable and acceptable point-of-care test target product profiles had lower requirement for patients to be in waiting bays before being allocated to an appropriate bay than laboratory-based tests, which may be of high importance in some hospitals. Tests that appeared more cost-effective also had better patient outcomes. LIMITATIONS: There is considerable uncertainty in the values for key parameters within the model, although calibration was undertaken in an attempt to mitigate this. The example hospital simulated will also not match those of decision-makers deciding on the clinical effectiveness and cost-effectiveness of introducing SARS-CoV-2 point-of-care tests. Given these limitations, the results should be taken as indicative rather than definitive, particularly cost-effectiveness results when the relative cost per SARS-CoV-2 point-of-care test is uncertain. CONCLUSIONS: Should a SARS-CoV-2 point-of-care test with a desirable target product profile become available, this appears promising, particularly when the reduction on the requirements for waiting bays before allocation to a SARS-CoV-2-infected bay, or a non-SARS-CoV-2-infected bay, is considered. The results produced should be informative to decision-makers who can identify the results most pertinent to their specific circumstances. FUTURE WORK: More accurate results could be obtained when there is more certainty on the diagnostic accuracy of, and the reduction in time to test result associated with, SARS-CoV-2 point-of-care tests, and on the impact of these tests on occupancy of waiting bays and isolation bays. These parameters are currently uncertain. FUNDING: This report was commissioned by the National Institute for Health Research (NIHR) Evidence Synthesis programme as project number 132154. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 21. See the NIHR Journals Library website for further project information.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 is highly infectious, and this can cause problems in hospitals, where the virus can spread quickly. Laboratory-based tests can determine whether or not a patient has SARS-CoV-2, but these tests are not perfect and can require a considerable time to provide a result. Point-of-care tests to detect SARS-CoV-2 are being developed that may have much shorter times to a test result, although these are likely to be less accurate than laboratory-based tests. The benefit of quicker tests is that a decision to put a patient in a SARS-CoV-2-infected bay or in a non-SARS-CoV-2-infected bay can be made sooner, limiting contact between patients with SARS-CoV-2 and patients without SARS-CoV-2 and reducing the risk of infection transmission. The disadvantage of reduced accuracy is that some patients may be allocated to the wrong bay, increasing the risk of SARS-CoV-2 infection. A computer model was built to explore the impact of using SARS-CoV-2 point-of-care tests for people admitted to hospital. This model estimated the number of infections and deaths due to COVID-19, the costs of testing, and the number of people waiting to be put in an appropriate bay. Strategies were run using different values, including the time to get a test result, the accuracy of tests and whether or not staff who do not have symptoms should be tested. The results of the model indicated that point-of-care tests could be good if there was a large reduction in the time to get a test result and if accuracy was high. However, it is not certain whether or not such tests will become available. When newer SARS-CoV-2 tests are available, the model will allow an estimate of the clinical effectiveness and cost-effectiveness of the test to be made.
Assuntos
COVID-19/diagnóstico , Serviço Hospitalar de Emergência/organização & administração , Admissão do Paciente , Testes Imediatos/economia , Testes Imediatos/normas , COVID-19/epidemiologia , Análise Custo-Benefício , Serviço Hospitalar de Emergência/economia , Serviço Hospitalar de Emergência/normas , Reações Falso-Negativas , Reações Falso-Positivas , Humanos , SARS-CoV-2 , Medicina Estatal , Reino UnidoRESUMO
AIMS: Hemophilia B (HB) is a rare congenital disorder characterized by bleeding-related complications which are managed by prophylactic or post-bleeding event ("on-demand") replacement of clotting factor IX (FIX). The standard of care for severe HB is life-long prophylaxis with standard half-life (SHL) or extended half-life (EHL) products given every 2-3 or 7-14 days, respectively. FIX treatment costs in the US have been investigated, but the lifetime costs of HB treatment have not been well characterized, particularly related to the impact of joint health deterioration and associated health resource utilization. We developed a decision-analytic model to explore outcomes, costs and underlying cost drivers associated with FIX treatment options over the lifetime of an adult with severe or moderately severe HB. MATERIALS AND METHODS: With participation from clinicians, health technology assessment specialists and patient advocates, a Markov model was constructed to estimate bleeding events and costs associated with health states including "bleed into joint", "bleed not into joint", "no bleed" and "death". Sub-models of joint health were based on 0, 1, or ≥2 areas of chronic joint damage. US third-party payer and societal perspectives were considered with a lifetime horizon; sensitivity analyses tested the robustness of primary findings. RESULTS: Total adult lifetime costs per patient with severe and moderately severe HB were $21,086,607 for SHL FIX prophylaxis, $22,987,483 for EHL FIX prophylaxis, and $20,971,826 for on-demand FIX treatment. For FIX prophylaxis, the cost of FIX treatment accounts for >90% of the total HB treatment costs. CONCLUSIONS: This decision analytic model demonstrated significant economic burden associated with the current HB treatment paradigm.
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Hemofilia A , Hemofilia B , Adulto , Fator IX/uso terapêutico , Meia-Vida , Custos de Cuidados de Saúde , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , HumanosRESUMO
BACKGROUND: The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. METHODS: Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. RESULTS: We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. CONCLUSIONS: Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. FURTHER RESEARCH: Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.
In May 2017, the US Food and Drug Administration granted the first approval for a cancer treatment based on a common biomarker rather than the location in the body at which the tumour originated (the tumour site); that is, a site-agnostic or 'histology-independent' indication was granted. Research from the National Institute for Health and Care Excellence suggests that there are approximately 20 technologies currently in development for histology-independent indications. The first marketing authorisation was granted in Europe in 2019. Histology-independent treatments have the potential to have important effects in patient populations for whom there are currently limited or no available treatment options. However, it is also important to ensure that the use of these treatments in the NHS is supported by systematic and robust assessments of clinical evidence (i.e. how well the medicine or treatment works) and economic evidence (i.e. the medicine's value for money). These assessments are undertaken by the National Institute for Health and Care Excellence, usually for treatments targeting specific tumours sites. However, a histology-independent marketing authorisation would probably include many tumour sites and it is not possible for the National Institute for Health and Care Excellence to conduct a separate assessment for each tumour site for which the treatment could be beneficial. As a result, the National Institute for Health and Care Excellence needs to consider how these products can be appropriately assessed without creating unnecessary delays in patient access. This research explores the extent to which the National Institute for Health and Care Excellence's existing approaches for assessing clinical and economic value can be applied to histology-independent indications, and any changes that might be required. We explore the nature and amount of evidence that is typically available at the point of initial marketing authorisation and develop recommendations to establish the evidence and analyses required to help inform the National Institute for Health and Care Excellence's decisions. We use case studies to highlight possible challenges and to explore ways that these challenges might be addressed. This research will help to inform future National Institute for Health and Care Excellence policy on how to appraise cancer drugs with histology-independent indications. It will also inform the development of guidance for those developing these treatments to help their understanding of the clinical effectiveness and cost-effectiveness assessments that will be required to inform the National Institute for Health and Care Excellence's appraisals.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Teorema de Bayes , Análise Custo-Benefício , Humanos , Neoplasias/tratamento farmacológico , Qualidade de Vida , Avaliação da Tecnologia BiomédicaRESUMO
BACKGROUND: Existing research indicates that spending time in nature is associated with diverse aspects of children's health and wellbeing. Although fundamental to later life chances and health, no systematic reviews, to our knowledge, have focused specifically on the effects of interaction with nature on socioemotional functioning in childhood. OBJECTIVES: Amongst children, what is the consistency of associations between the availability of or spending time in nature on socioemotional function and development? Furthermore, which child behaviours and states independently associate with socioemotional function and availability of or spending time in nature, and what is the consistency of associations between these behaviours and states and contact with nature? DATA SOURCES: Embase, Environment Complete, MEDLINE, and APA PsycINFO. Eligible studies were backward and forward snowball-searched. STUDY ELIGIBILITY CRITERIA: Studies investigating effects of, or associations between, availability of or interaction with nature on socioemotional or proximal outcomes in children under the age of 12 years were included in this review. STUDY APPRAISAL AND SYNTHESIS METHODS: The internal validity of studies investigating socioemotional outcomes were based on assessments of elements of study design, conduct, and reporting to identify potential issues related to confounding or other biases. The number of analyses indicating positive, negative, and non-significant associations between availability or interaction with green space and the outcomes were summed. RESULTS: A total of 223 eligible full-texts, of which 43 pertained to socioemotional outcomes and 180 to proximal outcomes, met eligibility criteria. Positive associations between availability of and spending time in green space were found with children's intra- and interpersonal socioemotional function and development. Proportions of positive findings ranged from 13.9% to 55% across experimental and observational research, exposures, populations, and contexts. Modifying and mediating factors were identified. We found consistent evidence for improved aspects of cognition and, for children over six years, reduced risk of obesity and overweight in association with green space; consistent links between movement behaviours in the experimental, but not observational research; tentative trends suggesting associations with play, motor skills, language, screen time, and communication skills; little evidence for positive associations between green space and mood, physical wellbeing, and stress; some evidence for associations with healthy birth outcomes, and little evidence for direct associations between availability of green space and asthma and allergy prevalence, however, mediation via, for example, air pollution was likely. LIMITATIONS: We identified few studies without either probable or severe risk of bias in at least one item. Improved study quality may therefore result in different results. Restricting analyses to include only studies considered at low risk of bias indicated similar or slightly lower proportions of positive findings. Risk of bias in proximal outcomes was not assessed. CONCLUSIONS: The empirical evidence for benefits of availability of and interaction green space for child socioemotional function and development must currently be considered limited. A number of proximal indicators were identified. Systematic review registration number. PROSPERO ID: CRD42019135016.
Assuntos
Poluição do Ar , Criança , Nível de Saúde , HumanosRESUMO
BACKGROUND: Patients with infantile-onset spinal muscular atrophy (SMA), a rare, genetic neuromuscular disease, do not achieve key motor function milestones (e.g., sitting) and have short life expectancy in the absence of treatment. Nusinersen is a disease-modifying therapy for patients with SMA. OBJECTIVE: The aim of this study was to estimate the cost-effectiveness of nusinersen compared to best supportive care (BSC) in patients diagnosed with infantile-onset SMA in the US. METHODS: A de novo economic model was developed with the following health states: "permanent ventilation", "not sitting", "sitting", "walking", and "death". Short-term data were sourced from the pivotal clinical trials and studies of nusinersen (ENDEAR and SHINE). Motor function milestones achieved at the end of follow-up in the clinical trials were assumed to be sustained until death. Mortality risks were based on survival modelling of relevant published Kaplan-Meier data. Costs, life years (LYs), and quality-adjusted life years (QALYs) were discounted at 3% per annum, and the analyses were performed from a US health care sector perspective. Scenario analyses and sensitivity analyses were conducted to assess the robustness of the results to key parameters. RESULTS: In our base-case analysis, nusinersen treatment achieves greater QALYs and more LYs (3.24 and 7.64, respectively) compared with BSC (0.46 QALYs and 2.40 LYs, respectively), resulting in an incremental cost per QALY gained of approximately $1,112,000 and an incremental cost per LY gained of $590,000 for nusinersen compared to BSC. The incremental cost effectiveness ratios did not fall below $990,000 per QALY gained in scenario and sensitivity analyses. Results were most sensitive to the length of survival, background health care costs, and utility in the "not sitting" and "sitting" health states. CONCLUSIONS: The estimated incremental cost-effectiveness of nusinersen from a US health care sector perspective exceeded traditional cost-effectiveness thresholds. Cost-effectiveness was dependent on assumptions made regarding survival, costs, utilities, and whether the motor function milestones were sustained over lifetime. Given the relatively short-term effectiveness data available for the treatment, a registry to collect long-term data of infantile-onset SMA patients is recommended.
RESUMO
BACKGROUND: Creutzfeldt-Jakob disease is a fatal neurological disease caused by abnormal infectious proteins called prions. Prions that are present on surgical instruments cannot be completely deactivated; therefore, patients who are subsequently operated on using these instruments may become infected. This can result in surgically transmitted Creutzfeldt-Jakob disease. OBJECTIVE: To update literature reviews, consultation with experts and economic modelling published in 2006, and to provide the cost-effectiveness of strategies to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease. METHODS: Eight systematic reviews were undertaken for clinical parameters. One review of cost-effectiveness was undertaken. Electronic databases including MEDLINE and EMBASE were searched from 2005 to 2017. Expert elicitation sessions were undertaken. An advisory committee, convened by the National Institute for Health and Care Excellence to produce guidance, provided an additional source of information. A mathematical model was updated focusing on brain and posterior eye surgery and neuroendoscopy. The model simulated both patients and instrument sets. Assuming that there were potentially 15 cases of surgically transmitted Creutzfeldt-Jakob disease between 2005 and 2018, approximate Bayesian computation was used to obtain samples from the posterior distribution of the model parameters to generate results. Heuristics were used to improve computational efficiency. The modelling conformed to the National Institute for Health and Care Excellence reference case. The strategies evaluated included neither keeping instruments moist nor prohibiting set migration; ensuring that instruments were kept moist; prohibiting instrument migration between sets; and employing single-use instruments. Threshold analyses were undertaken to establish prices at which single-use sets or completely effective decontamination solutions would be cost-effective. RESULTS: A total of 169 papers were identified for the clinical review. The evidence from published literature was not deemed sufficiently strong to take precedence over the distributions obtained from expert elicitation. Forty-eight papers were identified in the review of cost-effectiveness. The previous modelling structure was revised to add the possibility of misclassifying surgically transmitted Creutzfeldt-Jakob disease as another neurodegenerative disease, and assuming that all patients were susceptible to infection. Keeping instruments moist was estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Based on probabilistic sensitivity analyses, keeping instruments moist was estimated to on average result in 2.36 (range 0-47) surgically transmitted Creutzfeldt-Jakob disease cases (across England) caused by infection occurring between 2019 and 2023. Prohibiting set migration or employing single-use instruments reduced the estimated risk of surgically transmitted Creutzfeldt-Jakob disease cases further, but at considerable cost. The estimated costs per quality-adjusted life-year gained of these strategies in addition to keeping instruments moist were in excess of £1M. It was estimated that single-use instrument sets (currently £350-500) or completely effective cleaning solutions would need to cost approximately £12 per patient to be cost-effective using a £30,000 per quality-adjusted life-year gained value. LIMITATIONS: As no direct published evidence to implicate surgery as a cause of Creutzfeldt-Jakob disease has been found since 2005, the estimations of potential cases from elicitation are still speculative. A particular source of uncertainty was in the number of potential surgically transmitted Creutzfeldt-Jakob disease cases that may have occurred between 2005 and 2018. CONCLUSIONS: Keeping instruments moist is estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Further surgical management strategies can reduce the risks of surgically transmitted Creutzfeldt-Jakob disease but have considerable associated costs. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017071807. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 11. See the NIHR Journals Library website for further project information.
The aims of this report were to summarise evidence relating to surgically transmitted CreutzfeldtJakob disease and to explore the value for money of strategies to reduce the chance of any future surgically transmitted CreutzfeldtJakob disease cases. Current recommendations include keeping sets of surgical instruments together for high-risk operations and using separate instruments for people born after 1996. The project involved reviewing published papers, speaking with experts and building a computer model. The literature reviews found that CreutzfeldtJakob disease occurs in around 12 per million people and that no definite cases of surgically transmitted CreutzfeldtJakob disease have been observed since the 1970s. The reviews also looked for information on the possibility of patients being infected with CreutzfeldtJakob disease after having surgery on high-risk tissues, such as the brain and the back of the eye. They found that there was a great deal of uncertainty regarding who might have CreutzfeldtJakob disease, but not yet have symptoms, as well as the risk of transmission and the ability of strategies to reduce this risk. The computer model aimed to estimate value for money of different strategies to reduce the risks of surgically transmitted CreutzfeldtJakob disease. However, the reviews found that some of the numbers needed for the model were not known, so experts were asked to estimate this information instead along with the range of possible values. This information included the effectiveness of different cleaning practices and the chances of infected tissue being transmitted between patients undergoing high-risk surgery. The model found that keeping surgical instruments moist prior to cleaning was likely to save money and reduce the chance of future surgically transmitted CreutzfeldtJakob disease cases. However, additional measures, such as using only sets of single-use instruments, ensuring that instruments were kept together in their sets or using separate instruments for those born after 1996, appeared to be poor value for money.
Assuntos
Análise Custo-Benefício , Síndrome de Creutzfeldt-Jakob , Modelos Econômicos , Síndrome de Creutzfeldt-Jakob/prevenção & controle , Síndrome de Creutzfeldt-Jakob/transmissão , Inglaterra , Humanos , Príons/efeitos adversos , Anos de Vida Ajustados por Qualidade de Vida , Avaliação da Tecnologia BiomédicaRESUMO
Creutzfeldt-Jakob disease (CJD) is a fatal disease presenting with rapidly progressive dementia, and most patients die within a year of clinical onset. CJD poses a potential risk of iatrogenic transmission, as it can incubate asymptomatically in humans for decades before becoming clinically apparent. In this Review, we sought evidence to understand the current iatrogenic risk of CJD to public health by examining global evidence on all forms of CJD, including clinical incidence and prevalence of subclinical disease. We found that although CJD, particularly iatrogenic CJD, is rare, the incidence of sporadic CJD is increasing. Incubation periods as long as 40 years have been observed, and all genotypes have now been shown to be susceptible to CJD. Clinicians and surveillance programmes should maintain awareness of CJD to mitigate future incidences of its transmission. Awareness is particularly relevant for sporadic CJD, which occurs in older people in whom clinical presentation could resemble rapidly developing dementia.
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Síndrome de Creutzfeldt-Jakob/epidemiologia , Síndrome de Creutzfeldt-Jakob/patologia , Doença Iatrogênica/epidemiologia , Período de Incubação de Doenças Infecciosas , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome de Creutzfeldt-Jakob/transmissão , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Adulto JovemRESUMO
DISCLOSURES: Funding for this summary was contributed by the Laura and John Arnold Foundation and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Cambia Health Solutions and MedSavvy, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Sanofi, Alnylam, Novartis, HealthPartners, Blue Cross Blue Shield of Massachusetts, Health Care Services Corporation, Mallinkrodt Pharmaceuticals, Prime Therapeutics, Regeneron, National Institute for Health Care Management, Commonwealth Fund, Partners Healthcare, New England States Consortium Systems, Allergan, Biogen, Editas, LEO Pharma, and HealthFirst. ICER has also received grants from Kaiser Foundation Health Plan, California Health Care Foundation, and the Laura and John Arnold Foundation. Pearson and Rind are employees of ICER. Thokala and Stevenson have no potential conflicts of interest to disclose.