Investigating the impact of London's ultra low emission zone on children's health: children's health in London and Luton (CHILL) protocol for a prospective parallel cohort study.

BACKGROUND: Air pollution harms health across the life course. Children are at particular risk of adverse effects during development, which may impact on health in later life. Interventions that improve air quality are urgently needed both to improve public health now, and prevent longer-term increased vulnerability to chronic disease. Low Emission Zones are a public health policy intervention aimed at reducing traffic-derived contributions to urban air pollution, but evidence that they deliver health benefits is lacking. We describe a natural experiment study (CHILL: Children's Health in London and Luton) to evaluate the impacts of the introduction of London's Ultra Low Emission Zone (ULEZ) on children's health. METHODS: CHILL is a prospective two-arm parallel longitudinal cohort study recruiting children at age 6-9 years from primary schools in Central London (the focus of the first phase of the ULEZ) and Luton (a comparator site), with the primary outcome being the impact of changes in annual air pollutant exposures (nitrogen oxides [NOx], nitrogen dioxide [NO2], particulate matter with a diameter of less than 2.5micrograms [PM2.5], and less than 10 micrograms [PM10]) across the two sites on lung function growth, measured as post-bronchodilator forced expiratory volume in one second (FEV1) over five years. Secondary outcomes include physical activity, cognitive development, mental health, quality of life, health inequalities, and a range of respiratory and health economic data. DISCUSSION: CHILL's prospective parallel cohort design will enable robust conclusions to be drawn on the effectiveness of the ULEZ at improving air quality and delivering improvements in children's respiratory health. With increasing proportions of the world's population now living in large urban areas exceeding World Health Organisation air pollution limit guidelines, our study findings will have important implications for the design and implementation of Low Emission and Clean Air Zones in the UK, and worldwide. CLINICALTRIALS: GOV: NCT04695093 (05/01/2021).

STOP- a training intervention to optimise treatment for smoking cessation in community pharmacies: cluster randomised controlled trial.

BACKGROUND: Community pharmacies serve people with high levels of tobacco-related illness, but throughput in NHS Stop Smoking Services in pharmacies remains relatively low. We investigated the effectiveness of a complex intervention to increase service uptake and retention. METHODS: We randomised 60 pharmacies in England and Wales to the STOP intervention or usual practice in a pragmatic, parallel-group, controlled trial over 11 months. Smokers were blind to the allocation. The intervention was theory-based consultation skills training for pharmacy staff with environmental prompts (badges, calendars and behavioural cues). The primary outcome was the number of smokers attending an initial consultation and setting a quit date. RESULTS: The intervention made no significant difference in setting a quit date, retention or quit rate. A total of 631 adult smokers (service users) enrolled and set a quit date in intervention pharmacies compared to 641 in usual practice pharmacies, a rate ratio of 0.75 (95% CI 0.46 to 1.23) adjusted for site and number of prescriptions. A total of 432 (68%) service users were retained at 4 weeks in intervention and 500 (78%) in usual practice pharmacies (odds ratio 0.80, 0.41 to 1.55). A total of 265 (42%) service users quit smoking at 4 weeks in intervention and 276 (43%) in usual practice pharmacies (0.96, 0.65 to 1.43). The pharmacy staff were positive about the intervention with 90% (56/62) stating that it had improved their skills. Sixty-eight per cent would strongly recommend the training to others although there was no difference in self-efficacy for service delivery between arms. Seventy of 131 (53%) service users did not complete the 6-month follow-up assessment. However, 55/61 (90%) service users who completed follow-up were satisfied or very satisfied with the service. All usual practice arm service users (n = 33) and all but one in the intervention arm (n = 27) would recommend the service to smokers. CONCLUSIONS: We found high levels of retention and acceptable quit rates in the NHS pharmacy stop smoking service. Despite pharmacy staff providing positive feedback on the STOP intervention, it made no difference to service throughput. Thus, other factors may currently limit service capacity to help smokers to quit. TRIAL REGISTRATION: ISRCTN, ISRCTN16351033 . Retrospectively registered.

Understanding the value of social networks in life satisfaction of elderly people: a comparative study of 16 European countries using SHARE data.

BACKGROUND: Networks of family and friends are a source of support and are generally associated with higher life satisfaction values among older adults. On the other hand, older adults who are satisfied with their life may be more able to develop and maintain a wider social network. For this reason, the causal link between size and composition of the social networks and satisfaction with life is yet to be explored. This paper investigates the effect of the 'size', (number of family and friends, and network) and the 'composition' (the proportion of friends over total number of persons) of the social network on life satisfaction among older adults (50+). Moreover, we also investigate the patterns of this relation between different European countries. METHOD: Data from the 4th wave of Survey of Health, Ageing and Retirement in Europe and an instrumental variable approach are used to estimate the extent of the relation between life satisfaction and size and composition of social networks. RESULTS: Respondents in Western and Northern European (WNE) countries report larger networks than respondents in Eastern and Southern European (ESE) countries. However, the positive relationship between network size and life satisfaction is consistent across countries. On the other hand, the share of friends in the network appears to be generally negatively related to satisfaction with life, though results are not statistically significant for all countries. CONCLUSIONS: Apparently, a larger personal network is important for older adults (50+) to be more satisfied with life. Our results suggest that this relation is particularly positive if the network is comprised of family members.

Informal care and gifts to and from older people in Europe: The interlinks between giving and receiving.

BACKGROUND: Transfers of money and help with daily activities by family and friends are important sources of support for older people and contribute to their well being. On the other hand, older adults are not only recipients of support but also important providers of support and financial transfers as giving and receiving are often reciprocal. For this, it is important to understand the determinants of receiving and giving money and help as well as the relationship between these two. METHODS: The aim of this paper is to explore the relationship between giving and receiving of the same or of different types of transfers as well as to get more insights in the motivation behind giving and receiving of money gifts or informal care. We use data from the Survey of Health Aging and Retirement in Europe and employ a multinomial logit model to analyse 16 different categories resulting from combining information on the incidence of giving and receiving of both informal care and financial gifts. RESULTS: We show that despite the differences that exist in the incidence of giving and receiving of both informal care and financial gifts there are clearly a few patterns that are consistent between the European countries in our analysis. Both 'altruistic-like' and 'exchange-like' motives are more likely to increase by age, gender and physical proximity of network members, while 'reciprocal-like' giving and receiving is more likely among females and those with a network at close distance. CONCLUSIONS: Our results show that the incidence of informal care and gifts to and from older people is related to particular characteristics and transfers patterns. Further research should be dedicated to exploring the situations leading to the 'altruistic-like' and 'exchange-like' combinations of transfers.

Cost-effectiveness of a specialized atrial fibrillation clinic vs. usual care in patients with atrial fibrillation.

AIMS: A recent randomized controlled trial demonstrated significant reductions in cardiovascular hospitalizations and deaths with a nurse-led integrated chronic care approach in patients with atrial fibrillation (AF) compared with usual care. The aim of the present study is to assess cost-effectiveness of this nurse-led care programme vs. usual care. METHODS AND RESULTS: A cost-effectiveness analysis was undertaken alongside the randomized controlled trial in which 712 patients were included at the Maastricht University Medical Centre, The Netherlands, and allocated to nurse-led care or usual care. Nurse-led care implied guideline-adherent management, steered by dedicated software, supervised by cardiologists. Usual care was regular outpatient care performed by cardiologists. A cost per life-year and a cost per quality-adjusted life-year (QALY) analysis was performed, both from a hospital perspective. The nurse-led care programme was associated with slightly more life-years and QALYs at a lower cost. Specifically, the nurse-led programme contributed to 0.009 QALY gains with a reduced cost of €1109 per patient and a gain of 0.02 life-years with a reduced cost of €735 per patient. Therefore, the nurse-led programme would be considered dominant. In fact, for all the possible values of willingness to pay for a QALY the nurse-led programme is considered to be more likely cost-effective than the care as usual. CONCLUSION: The cost-effectiveness analysis in the present study demonstrated that a nurse-led integrated care approach will save costs and improve survival and quality of life, and is therefore a cost-effective management strategy for patients with AF.

Strong and graded associations between level of asthma severity and all-cause hospital care use and costs in the UK.

BACKGROUND: Hospital admissions account for a large share of the healthcare costs incurred by people with asthma. We assessed the hospital care use and costs associated with asthma severity using the UK Biobank cohort and linked healthcare data. METHODS: Adult participants with asthma at recruitment were classified using their prescription data into mild and moderate-to-severe asthma and matched separately to asthma-free controls by age, sex, ethnicity and location. The associations of asthma, by severity, with the annual number of all-cause hospital admissions, days spent in hospital and hospital costs were estimated over a 10-year follow-up period using three specifications of negative binomial regression models that differed according to the sociodemographic and clinical characteristics adjusted for. RESULTS: Of the 25 031 participants with active asthma, 80% had mild asthma and 20% had moderate-to-severe asthma. Compared with participants with mild asthma, those with moderate-to-severe asthma were on average 2.7 years older, more likely to be current (13.7% vs 10.4%) or previous (40.2% vs 35.2%) smokers, to have a higher body mass index (BMI), and to be suffering from a variety of comorbid diseases. Following adjustments for age, sex, ethnicity and location, people with mild asthma experienced on average 36% more admissions (95% CI 28% to 40%), 43% more days in hospital (95% CI 35% to 51%) and 36% higher hospital costs (95% CI 31% to 41%) annually than asthma-free individuals, while people with moderate-to-severe asthma experienced excesses of 93% (95% CI 81% to 107%), 142% (95% CI 124% to 162%) and 98% (95% CI 88% to 108%), respectively. Further adjustments for socioeconomic deprivation, smoking status, BMI and comorbidities resulted in smaller though still highly significant positive associations, graded by severity, between asthma and hospital use and costs. CONCLUSIONS: Strong graded associations are reported between asthma severity and the extent of hospital use and costs in the UK. These findings could inform future assessments of the value of asthma management interventions.

Device-Measured Change in Physical Activity in Primary School Children During the UK COVID-19 Pandemic Lockdown: A Longitudinal Study.

BACKGROUND: Lockdown measures, including school closures, due to the COVID-19 pandemic have caused widespread disruption to children's lives. The aim of this study was to explore the impact of a national lockdown on children's physical activity using seasonally matched accelerometry data. METHODS: Using a pre/post observational design, 179 children aged 8 to 11 years provided physical activity data measured using hip-worn triaxial accelerometers worn for 5 consecutive days prepandemic and during the January to March 2021 lockdown. Multilevel regression analyses adjusted for covariates were used to assess the impact of lockdown on time spent in sedentary and moderate to vigorous physical activity. RESULTS: A 10.8-minute reduction in daily time spent in moderate to vigorous physical activity (standard error: 2.3 min/d, P < .001) and a 33.2-minute increase in daily sedentary activity (standard error: 5.5 min/d, P < .001) were observed during lockdown. This reflected a reduction in daily moderate to vigorous physical activity for those unable to attend school (-13.1 [2.3] min/d, P < .001) during lockdown, with no significant change for those who continued to attend school (0.4 [4.0] min/d, P < .925). CONCLUSION: These findings suggest that the loss of in-person schooling was the single largest impact on physical activity in this cohort of primary school children in London, Luton, and Dunstable, United Kingdom.

Magnetic resonance enterography compared with ultrasonography in newly diagnosed and relapsing Crohn's disease patients: the METRIC diagnostic accuracy study.

BACKGROUND: Magnetic resonance enterography and enteric ultrasonography are used to image Crohn's disease patients. Their diagnostic accuracy for presence, extent and activity of enteric Crohn's disease was compared. OBJECTIVE: To compare diagnostic accuracy, observer variability, acceptability, diagnostic impact and cost-effectiveness of magnetic resonance enterography and ultrasonography in newly diagnosed or relapsing Crohn's disease. DESIGN: Prospective multicentre cohort study. SETTING: Eight NHS hospitals. PARTICIPANTS: Consecutive participants aged ≥ 16 years, newly diagnosed with Crohn's disease or with established Crohn's disease and suspected relapse. INTERVENTIONS: Magnetic resonance enterography and ultrasonography. MAIN OUTCOME MEASURES: The primary outcome was per-participant sensitivity difference between magnetic resonance enterography and ultrasonography for small bowel Crohn's disease extent. Secondary outcomes included sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease extent, and sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease presence; identification of active disease; interobserver variation; participant acceptability; diagnostic impact; and cost-effectiveness. RESULTS: Out of the 518 participants assessed, 335 entered the trial, with 51 excluded, giving a final cohort of 284 (133 and 151 in new diagnosis and suspected relapse cohorts, respectively). Across the whole cohort, for small bowel Crohn's disease extent, magnetic resonance enterography sensitivity [80%, 95% confidence interval (CI) 72% to 86%] was significantly greater than ultrasonography sensitivity (70%, 95% CI 62% to 78%), with a 10% difference (95% CI 1% to 18%; p = 0.027). For small bowel Crohn's disease extent, magnetic resonance enterography specificity (95%, 95% CI 85% to 98%) was significantly greater than ultrasonography specificity (81%, 95% CI 64% to 91%), with a 14% difference (95% CI 1% to 27%). For small bowel Crohn's disease presence, magnetic resonance enterography sensitivity (97%, 95% CI 91% to 99%) was significantly greater than ultrasonography sensitivity (92%, 95% CI 84% to 96%), with a 5% difference (95% CI 1% to 9%). For small bowel Crohn's disease presence, magnetic resonance enterography specificity was 96% (95% CI 86% to 99%) and ultrasonography specificity was 84% (95% CI 65% to 94%), with a 12% difference (95% CI 0% to 25%). Test sensitivities for small bowel Crohn's disease presence and extent were similar in the two cohorts. For colonic Crohn's disease presence in newly diagnosed participants, ultrasonography sensitivity (67%, 95% CI 49% to 81%) was significantly greater than magnetic resonance enterography sensitivity (47%, 95% CI 31% to 64%), with a 20% difference (95% CI 1% to 39%). For active small bowel Crohn's disease, magnetic resonance enterography sensitivity (96%, 95% CI 92% to 99%) was significantly greater than ultrasonography sensitivity (90%, 95% CI 82% to 95%), with a 6% difference (95% CI 2% to 11%). There was some disagreement between readers for both tests. A total of 88% of participants rated magnetic resonance enterography as very or fairly acceptable, which is significantly lower than the percentage (99%) of participants who did so for ultrasonography. Therapeutic decisions based on magnetic resonance enterography alone and ultrasonography alone agreed with the final decision in 122 out of 158 (77%) cases and 124 out of 158 (78%) cases, respectively. There were no differences in costs or quality-adjusted life-years between tests. LIMITATIONS: Magnetic resonance enterography and ultrasonography scans were interpreted by practitioners blinded to clinical data (but not participant cohort), which does not reflect use in clinical practice. CONCLUSIONS: Magnetic resonance enterography has higher accuracy for detecting the presence, extent and activity of small bowel Crohn's disease than ultrasonography does. Both tests have variable interobserver agreement and are broadly acceptable to participants, although ultrasonography produces less participant burden. Diagnostic impact and cost-effectiveness are similar. Recommendations for future work include investigation of the comparative utility of magnetic resonance enterography and ultrasonography for treatment response assessment and investigation of non-specific abdominal symptoms to confirm or refute Crohn's disease. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03982913. 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. 23, No. 42. See the NIHR Journals Library website for further project information.

Crohn's disease is a waxing and waning lifelong inflammatory condition that affects the colon (large bowel) and small bowel. Treatment relies on accurately determining disease extent and underlying inflammation. Colonoscopy is very good for examining the colon, but it is invasive and, at best, can only visualise a few centimetres of the small bowel, so radiological imaging is very important. Magnetic resonance enterography (a type of magnetic resonance imaging scan) and ultrasonography are both radiological tests commonly performed in the NHS, and it is unclear which method is better. We performed a study to compare the accuracy of magnetic resonance enterography and ultrasonography for determining the extent of Crohn's disease in the bowel of participants newly diagnosed and in those participants with established Crohn's disease but with suspected deterioration. We also investigated how often radiologists agree with each other during test interpretation, the participant experience of undergoing the tests and their cost-effectiveness. We compared the tests in 284 participants (133 newly diagnosed and 151 with suspected deterioration). We found that both tests were accurate for detecting the presence (97% for magnetic resonance enterography and 92% for ultrasonography) and location (80% for magnetic resonance enterography and 70% for ultrasonography) of disease in the small bowel, but magnetic resonance enterography was better than ultrasonography for both (correctly classifying disease extent in 107 more participants for every 1000 participants with Crohn's disease). Magnetic resonance enterography was similarly better than ultrasonography at determining if the bowel was inflamed. The results were similar in newly diagnosed participants and those participants with suspected deterioration. Agreement between radiologists interpreting the same images was, at best, moderate for both tests. A total of 88% of participants tolerated magnetic resonance enterography well or fairly well, which was less than the percentage (99%) of participants who tolerated ultrasonography well or fairly well. Both tests had a similar effect on the treatment decisions made by doctors. Both tests were also similar in their value for money for the NHS.

Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Janssen, the company manufacturing abiraterone acetate (AA; tradename Zytiga®), to submit evidence for the clinical and cost effectiveness of AA in combination with prednisone/prednisolone (AAP) compared with watchful waiting (i.e. best supportive care [BSC]) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG report, subsequent addenda, and the development of the NICE guidance for the use of this drug in England and Wales by the Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of AAP based on the CS. An important question in this appraisal was, according to the ERG, whether AAP followed by docetaxel is more effective than BSC followed by docetaxel. In the COU-AA-302 trial, 239 of 546 (43.8 %) AAP patients and 304 of 542 (56.1 %) BSC patients received docetaxel as subsequent therapy, following AA or placebo. The results for this specific group of patients were not presented in the CS; therefore, the ERG asked the company to provide these data in the clarification letter; however, these data were presented as commercial-in-confidence and cannot therefore be reported here. The ERG's critical assessment of the company's economic evaluation highlighted a number of concerns, including (a) not using the intention-to-treat (ITT) population; (b) inconsistencies in estimating prediction equations; (c) not fully incorporating the impact of adverse events; (d) incorrectly incorporating the new patient access scheme (PAS); and (e) the assumption that AA non-compliance leads to recoverable drug costs. Although some of these issues were adjusted in the ERG base case, the ERG could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. With the exception of the ERG's preference for using the ITT population, the AC agreed with the approach taken in the ERG base case. The original company and ERG base-case incremental cost-effectiveness ratios (ICERs) were £46,722 and £57,688 per QALY gained, respectively; these changed to £28,563 and £38,061 per QALY gained, respectively, in the revised base cases applying a new PAS. Regarding the end-of-life criteria, after 24 months approximately 63 % of patients in the control group of the COU-AA-302 trial were still alive, and the median survival was 30.1 months (95 % CI 27.3-34.1). Therefore, it is unlikely that life expectancy would be less than 24 months. The AC stated that the most plausible ICER is likely between £28,600 and £32,800 per QALY gained, and concluded that AAP at this stage in the treatment pathway did not meet the end-of-life criterion for short life expectancy. Moreover, in March 2016, the AC produced the final guidance, stating that AAP is recommended, within its marketing authorisation, as an option for treating mCRPC.

Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost-effectiveness analysis.

BACKGROUND: Determination of the presence or absence of bacterial infection is important to guide appropriate therapy and reduce antibiotic exposure. Procalcitonin (PCT) is an inflammatory marker that has been suggested as a marker for bacterial infection. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of adding PCT testing to the information used to guide antibiotic therapy in adults and children (1) with confirmed or highly suspected sepsis in intensive care and (2) presenting to the emergency department (ED) with suspected bacterial infection. METHODS: Twelve databases were searched to June 2014. Randomised controlled trials were assessed for quality using the Cochrane Risk of Bias tool. Summary relative risks (RRs) and weighted mean differences (WMDs) were estimated using random-effects models. Heterogeneity was assessed visually using forest plots and statistically using the I (2) and Q statistics and investigated through subgroup analysis. The cost-effectiveness of PCT testing in addition to current clinical practice was compared with current clinical practice using a decision tree with a 6 months' time horizon. RESULTS: Eighteen studies (36 reports) were included in the systematic review. PCT algorithms were associated with reduced antibiotic duration [WMD -3.19 days, 95% confidence interval (CI) -5.44 to -0.95 days, I (2) = 95.2%; four studies], hospital stay (WMD -3.85 days, 95% CI -6.78 to -0.92 days, I (2) = 75.2%; four studies) and a trend towards reduced intensive care unit (ICU) stay (WMD -2.03 days, 95% CI -4.19 to 0.13 days, I (2) = 81.0%; four studies). There were no differences for adverse clinical outcomes. PCT algorithms were associated with a reduction in the proportion of adults (RR 0.77, 95% CI 0.68 to 0.87; seven studies) and children (RR 0.86, 95% CI 0.80 to 0.93) receiving antibiotics, reduced antibiotic duration (two studies). There were no differences for adverse clinical outcomes. All but one of the studies in the ED were conducted in people presenting with respiratory symptoms. Cost-effectiveness: the base-case analyses indicated that PCT testing was cost-saving for (1) adults with confirmed or highly suspected sepsis in an ICU setting; (2) adults with suspected bacterial infection presenting to the ED; and (3) children with suspected bacterial infection presenting to the ED. Cost-savings ranged from £368 to £3268. Moreover, PCT-guided treatment resulted in a small quality-adjusted life-year (QALY) gain (ranging between < 0.001 and 0.005). Cost-effectiveness acceptability curves showed that PCT-guided treatment has a probability of ≥ 84% of being cost-effective for all settings and populations considered (at willingness-to-pay thresholds of £20,000 and £30,000 per QALY). CONCLUSIONS: The limited available data suggest that PCT testing may be effective and cost-effective when used to guide discontinuation of antibiotics in adults being treated for suspected or confirmed sepsis in ICU settings and initiation of antibiotics in adults presenting to the ED with respiratory symptoms and suspected bacterial infection. However, it is not clear that observed costs and effects are directly attributable to PCT testing, are generalisable outside people presenting with respiratory symptoms (for the ED setting) and would be reproducible in the UK NHS. Further studies are needed to assess the effectiveness of adding PCT algorithms to the information used to guide antibiotic treatment in children with suspected or confirmed sepsis in ICU settings. Additional research is needed to examine whether the outcomes presented in this report are fully generalisable to the UK. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014010822. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Catastrophic and impoverishing effects of out-of-pocket payments for health care in Albania: evidence from Albania Living Standards Measurement Surveys 2002, 2005 and 2008.

The absence of or poorly functioning risk pooling mechanisms and high amounts of out-of-pocket payments for health care expose households to financial risks associated with major illnesses or accidents. The aim of this article is to analyse the extent to which out-of-pocket health spending impoverishes households in Albania. The study augments existing evidence by analysing the dynamics of such payments over different years and the weight that informal payments have in the total out-of-pocket health spending. The data used in the study come from the Albania Living Standards Measurement Survey (ALSMS) for 2002, 2005 and 2008. We measure headcount catastrophic payments using different thresholds and the decomposition of indicators by expenditure quintiles to better understand their effects. We find that out-of-pocket and informal payments have increased in real value throughout the years. Even though their catastrophic effect has gone down (due also to declining trends in absolute poverty), the effect for the poorest expenditure quintiles remains high. Out-of-pocket payments deepen the poverty headcount and also enlarge the poverty gap and again the effect is larger for the poorest quintiles. Future policy interventions should provide better protection mechanisms for the poor by providing exemption criteria or subsidized transport. They should also seek to address the widespread informal payments in the country.

Golimumab for the treatment of ankylosing spondylitis: a NICE single technology appraisal.

As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the Evidence Review Group (ERG) produced a report to comment on the clinical and cost effectiveness of golimumab (Simponi(®), Merck Sharp & Dohme) for the treatment of ankylosing spondylitis (AS) relative to other comparators as presented in the manufacturer's submission (MS) to NICE. The population was those with active disease who had not responded to conventional therapy. The specified comparators were conventional care and two other tumour necrosis factor alpha (TNF-α) inhibitors (adalimumab and etanercept). Outcomes to be considered were disease activity, functional capacity, disease progression, adverse effects of treatment and health-related quality of life (HR-QOL). There were no head-to-head trials comparing TNF-α inhibitors. The submission included one trial of golimumab versus placebo (the GO-RAISE trial) and additionally seven placebo-controlled randomized controlled trials (RCTs) of other TNF-α inhibitor agents (five with etanercept, and two with adalimumab). The results of these trials were generally a statistically significant improvement from each of the TNF-α inhibitors. A Bayesian mixed treatment comparison (MTC) showed there was generally overlap in the 95 % credible intervals (CrIs) between the TNF-α inhibitors. Exceptions included a greater risk of discontinuation of treatment for golimumab than for etanercept (relative risk [RR] 4.30; 95 % CrI 1.01-18.50). The cost-effectiveness analysis (CEA) compared all of these TNF-α inhibitors. Relative effectiveness was informed only by RR of response (proportion achieving at least a 50 % improvement in Bath AS Disease Activity Index [BASDAI] score; BASDAI50) from the MTC. In the base-case analysis, the incremental cost-effectiveness ratio (ICER) of golimumab versus conventional care was £26,597 and adalimumab and etanercept were extendedly dominated by golimumab. The manufacturer concluded that golimumab is a cost-effective treatment option. Generally, the ERG agreed with the MTC analyses. The main problem was that the MS used data from one trial, which included a period of cross-over. The ERG found some problems with the CEA model, mainly that it did not allow for comparison of TNF-α inhibitor sequences and did not use MTC estimates for treatment discontinuation or adverse events (AEs). The ERG could not correct the sequencing problem, but re-ran the CEA with discontinuations and AEs estimated from the MTC and using the correct trial data. The results of the ERG analysis were that golimumab was extendedly dominated by etanercept, and the preferred treatment was either conventional treatment or etanercept, depending on the ICER threshold. Uncertainty was also substantial. NICE issued guidance (technology appraisal [TA] 233), which recommended golimumab according to the indications described in TA143 for etanercept and adalimumab, i.e. as first-line therapy among the TNF-α inhibitors unless patients are intolerant to one or both alternatives. Given the factors cited by NICE for their decision, the ERG recommends that there should be greater clarity in the NICE methods guidance on handling uncertainty in CEAs as well as the incorporation of benefit from process of care.